Drug Therapy

Insulin therapy is one of the most effective tools clinicians can use to help patients reach their individualized hemoglobin A_1c target. However, decisions about when and how to start insulin therapy have to be individualized to the needs and goals of each patient. Many insulin options are available, one of the most common being the addition of basal insulin to oral antidiabetic drugs. Although patients are often reluctant to start insulin, this reluctance can be overcome through patient education and hands-on training.

Here, we review hemoglobin A_1c targets, factors that determine when to start insulin therapy, and the different regimens that can be used.

MOST PATIENTS EVENTUALLY NEED INSULIN

Type 2 diabetes mellitus is a chronic progressive disease associated with insulin resistance, beta-cell dysfunction, and decreased insulin secretion. Consequently, most patients eventually require insulin therapy to reduce the risk of long-term complications.

The efficacy of therapy can be assessed by measuring hemoglobin A_1c, an important marker of the chronic hyperglycemic state. The hemoglobin A_1c value can be reported as a ratio (%) standardized against the results of the Diabetes Control and Complications Trial,¹ or as International Federation of Clinical Chemistry units (mmol/mol).² Table 1 shows the relationship between hemoglobin A_1c and average glucose values.³

WHAT IS AN APPROPRIATE HEMOGLOBIN A_1c TARGET?

The short answer is, “It depends.”

Currently, the American Association of Clinical Endocrinologists (AACE) supports a hemoglobin A_1c goal of less than 6.5% for otherwise healthy patients but states that the goal should be individualized for patients with concurrent illnesses or at risk of hypoglycemia.⁴

On the other hand, the American Diabetes Association (ADA) recommends a higher hemoglobin A_1c target of less than 7% for most adults with type 2 diabetes mellitus.⁵ This value was shown to be associated with a reduction in the microvascular and macrovascular complications of diabetes.

Yet when three large trials^6–8 recently compared intensive and standard glucose control regimens, tighter glucose control failed to improve cardiovascular outcomes. Moreover, in one of the trials,⁷ patients receiving intensive treatment had a higher rate of all-cause mortality. Details:

• Action in Diabetes and Vascular Disease (ADVANCE): 11,140 patients; average hemoglobin A_1c levels 6.5% vs 7.3%⁶
• Action to Control Cardiovascular Risk in Diabetes (ACCORD): 10,251 patients; average hemoglobin A_1c levels 6.4% vs 7.5%⁷
• Veterans Affairs Diabetes Trial (VADT): 1,791 patients; average hemoglobin A_1c levels 6.9% vs 8.4%.⁸

Similarly, a 2013 Cochrane review⁹ that included 28 randomized controlled trials concluded that intensive control (in 18,717 patients) did not decrease all-cause and cardiovascular mortality rates compared with traditional glucose control (in 16,195 patients), and it increased the risk of hypoglycemia and serious adverse events.

The AACE and ADA are moving away from one-size-fits-all and toward individualized recommendations

As a result, the ADA⁵ states that a hemoglobin A_1c target less than 6.5% is optional for patients with a long life expectancy, short duration of diabetes, low risk of hypoglycemia, and no significant cardiovascular disease. The ADA further defines a hemoglobin A_1c goal of less than 8% for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and long-standing diabetes.

Therefore, the AACE and ADA are moving away from “one-size-fits-all” goals and toward individualizing their recommendations.

WHEN SHOULD INSULIN BE STARTED?

Physicians should consider the needs and preferences of each patient and individualize the treatment. The most recent recommendations from the ADA⁵ stress the importance of a patient-centered approach, with multiple factors taken into account. These include the patient’s attitude, expected compliance with treatment, risk of hypoglycemia, disease duration, life expectancy, and comorbidities, and the side effects of oral medications and insulin.

Compared with previous guidelines, there are fewer rules on how and when to start insulin therapy. But absolute and relative indications for insulin therapy should be considered in patients with the following:

Absolute indications for insulin

• Ketoacidosis or catabolic symptoms, including ketonuria
• Newly diagnosed type 2 diabetes with pronounced hyperglycemia (glucose ≥ 300 mg/dL or hemoglobin A_1c ≥ 10.0%) with or without severe symptoms, including weight loss, polyuria, or polydipsia¹⁰
• Uncontrolled type 2 diabetes mellitus despite using one, two, or more oral antidiabetic drugs or glucagon-like peptide 1 (GLP-1) receptor agonists
• Gestational diabetes
• Preference for insulin.

Relative indications for insulin

• Hospitalized for surgery or acute illnesses
• Advanced renal or hepatic disease
• Inability to afford the cost or tolerate the side effects of oral antidiabetic drugs and GLP-1 receptor agonists.

Depending on the situation, blood glucose is measured fasting, before meals, or after meals after initiating or adjusting insulin regimens (Table 2).

WHAT ARE THE INSULIN REGIMENS?

Basal insulin

In the early stages of type 2 diabetes, metformin alone or in combination with another oral antidiabetic drug or with a GLP-1 receptor agonist is often used along with healthy eating, weight control, and increased physical activity.

When the target hemoglobin A_1c cannot be achieved with one or two noninsulin drugs, the ADA suggests basal insulin be added to metformin or a two-medication regimen that includes metformin (Table 3). However, recent evidence suggests that combining a GLP-1 receptor agonist with basal insulin, in a regimen without metformin, is safe and improves glycemic control without hypoglycemia or weight gain.¹¹

While a total daily dose of insulin of 0.1 to 0.2 units/kg could be initially used in patients with a hemoglobin A_1c level less than 8%, a higher dose of 0.2 to 0.3 units/kg is required if the hemoglobin A_1c level is between 8% and 10%. The dose can be titrated once or twice weekly if the fasting glucose is above the target level (usually < 130 mg/dL). If hypoglycemia develops (glucose < 70 mg/dL), the insulin dose should be reduced by 10% to 20%.¹⁰

Available basal insulins include glargine, detemir, and neutral protamine Hagedorn (NPH) (Table 4).^12–14 Because glargine and detemir offer better pharmacokinetic properties, less variability in response, and less risk of hypoglycemia, they are preferred over NPH. Glargine has a relatively constant plasma concentration over 24 hours, allowing once-daily dosing at any time during the day (Figure 1).¹⁵ The dose should be taken at the same time every day. Detemir and NPH are usually taken once or twice daily.

Adapted from Hirsch IB. Insulin analogues. N Engl J Med 2005; 352:174-183. Copyright 2005, Massachusetts Medical Society.

Patients treated once daily should take the dose with the evening meal or at bedtime. Patients who require a twice-daily regimen can take the first dose with breakfast and the second one with the evening meal, at bedtime, or 12 hours after the morning dose.

The randomized Treat-to-Target trial,¹⁶ in 756 patients, showed that both glargine and NPH, when added to oral therapy in patients with type 2 diabetes, achieve the target hemoglobin A_1c, but NPH is associated with more episodes of nocturnal hypoglycemia. Similar results were found when NPH was compared with detemir insulin.¹⁷

A Cochrane review¹⁸ suggested that glargine and detemir are similar in efficacy and safety. However, detemir often needs to be injected twice daily, in a higher dose, and is associated with less weight gain. Furthermore, a meta-analysis of 46 randomized clinical trials¹⁹ showed that the weight increase at 1 year is less in patients treated with basal than with twice-daily or prandial regimens.

The ADA suggests basal insulin be added to metformin alone or a regimen that includes metformin

A noninterventional longitudinal study²⁰ in 2,179 patients newly started on insulin showed that the mean weight increase at 1 year was 1.78 kg, and 24% of patients gained more than 5 kg. However, the factors independently associated with the weight gain were a higher hemoglobin A_1c at baseline, a higher insulin dose at baseline and at 1 year, and a lower baseline body mass index, but not the type of insulin regimen.

Currently, a new class of ultralong-acting basal insulins is being studied. Insulins in this class are approved in other countries, but the US Food and Drug Administration requires additional data for approval. Ultralong-acting insulins are expected to reduce the risk of hypoglycemia, specifically the risk of nocturnal episodes. Also, given their longer duration of action and stable steady-state pharmacokinetics, they will offer flexibility in the dose timing.²¹

Basal-bolus regimens

Basal insulin often does not control postprandial hyperglycemia. The need for multiple doses of insulin (including one or more preprandial doses) is suggested by postprandial glucose values above target (usually > 180 mg/dL) or by a hemoglobin A_1c above goal despite well-controlled fasting glucose levels. This usually becomes evident when the total daily dose of basal insulin exceeds 0.5 units/kg. Patients newly diagnosed with diabetes who have a hemoglobin A_1c higher than 10% may also respond better to an initial basal-bolus regimen.

Available bolus insulins include lispro, aspart, glulisine, regular insulin, and the newly approved Technosphere inhaled regular insulin (Table 4).^12–14 They can be taken before each meal, and the total bolus dose usually represents 50% of the total daily dose.²² Rapid-acting insulins have faster onset, shorter duration of action, and more predictable pharmacokinetics, which makes them preferable to regular insulin (Figure 1).¹⁵ Inhaled insulin is another option, but it is contraindicated in patients with chronic obstructive pulmonary disease or asthma because of the increased risk of acute bronchospasm.¹²

Alternatively, the transition to a basal-bolus regimen can be accomplished with a single dose of bolus insulin before the main meal, using a dose that represents approximately 10% of the total daily dose. Additional bolus doses can be added later based on the glycemic control. The adjustment of the preprandial insulin dose is done once or twice weekly, based on the postprandial glucose levels.¹⁰

Premixed combinations of long- and short-acting insulins in ratios of 50% to 50%, 70% to 30%, or 75% to 25% can be considered in patients who cannot adhere to a complex insulin regimen. A propensity-matched comparison of different insulin regimens (basal, premixed, mealtime plus basal, and mealtime) in patients with type 2 diabetes revealed that the hemoglobin A_1c reduction was similar between the different groups.²³ However, the number of hypoglycemic episodes was higher in the premixed insulin group, and the weight gain was less in the basal insulin group.

While premixed insulins require fewer injections, they do not provide dosing flexibility. In other words, dose adjustments for premixed insulins lead to increases in both basal and bolus amounts even though a dose adjustment is needed for only one insulin type. Thus, this is a common reason for increased hypoglycemic episodes.

Continuous subcutaneous insulin infusion

Patients who are engaged in their care are more likely to succeed in their treatment

A meta-analysis showed that continuous subcutaneous insulin infusion (ie, use of an insulin pump) was similar to intensive therapy with multiple daily insulin injections in terms of glycemic control and hypoglycemia.²⁴ Since both options can lead to similar glucose control, additional factors to consider when initiating insulin infusion include lifestyle and technical expertise. Some patients may or may not prefer having a pump attached for nearly all daily activities. Additionally, this type of therapy is complex and requires significant training to ensure efficacy and safety.²⁵

WHAT IS THE COST OF INSULIN THERAPY?

A final factor to keep in mind when initiating insulin is cost (Table 4).^12–14 Asking patients to check their prescription insurance formulary is important to ensure that an affordable option is selected. If patients do not have prescription insurance, medication assistance programs could be an option. However, if a patient is considering an insulin pump, insurance coverage is essential. Depending on the manufacturer, insulin pumps cost about $6,000 to $7,000, and the additional monthly supplies for the pump are also expensive.

If patients are engaged when considering and selecting insulin therapy, the likelihood of treatment success is greater.^26–28

Insulin therapy is one of the most effective tools clinicians can use to help patients reach their individualized hemoglobin A_1c target. However, decisions about when and how to start insulin therapy have to be individualized to the needs and goals of each patient. Many insulin options are available, one of the most common being the addition of basal insulin to oral antidiabetic drugs. Although patients are often reluctant to start insulin, this reluctance can be overcome through patient education and hands-on training.

Here, we review hemoglobin A_1c targets, factors that determine when to start insulin therapy, and the different regimens that can be used.

MOST PATIENTS EVENTUALLY NEED INSULIN

Type 2 diabetes mellitus is a chronic progressive disease associated with insulin resistance, beta-cell dysfunction, and decreased insulin secretion. Consequently, most patients eventually require insulin therapy to reduce the risk of long-term complications.

The efficacy of therapy can be assessed by measuring hemoglobin A_1c, an important marker of the chronic hyperglycemic state. The hemoglobin A_1c value can be reported as a ratio (%) standardized against the results of the Diabetes Control and Complications Trial,¹ or as International Federation of Clinical Chemistry units (mmol/mol).² Table 1 shows the relationship between hemoglobin A_1c and average glucose values.³

WHAT IS AN APPROPRIATE HEMOGLOBIN A_1c TARGET?

The short answer is, “It depends.”

Currently, the American Association of Clinical Endocrinologists (AACE) supports a hemoglobin A_1c goal of less than 6.5% for otherwise healthy patients but states that the goal should be individualized for patients with concurrent illnesses or at risk of hypoglycemia.⁴

On the other hand, the American Diabetes Association (ADA) recommends a higher hemoglobin A_1c target of less than 7% for most adults with type 2 diabetes mellitus.⁵ This value was shown to be associated with a reduction in the microvascular and macrovascular complications of diabetes.

Yet when three large trials^6–8 recently compared intensive and standard glucose control regimens, tighter glucose control failed to improve cardiovascular outcomes. Moreover, in one of the trials,⁷ patients receiving intensive treatment had a higher rate of all-cause mortality. Details:

• Action in Diabetes and Vascular Disease (ADVANCE): 11,140 patients; average hemoglobin A_1c levels 6.5% vs 7.3%⁶
• Action to Control Cardiovascular Risk in Diabetes (ACCORD): 10,251 patients; average hemoglobin A_1c levels 6.4% vs 7.5%⁷
• Veterans Affairs Diabetes Trial (VADT): 1,791 patients; average hemoglobin A_1c levels 6.9% vs 8.4%.⁸

Similarly, a 2013 Cochrane review⁹ that included 28 randomized controlled trials concluded that intensive control (in 18,717 patients) did not decrease all-cause and cardiovascular mortality rates compared with traditional glucose control (in 16,195 patients), and it increased the risk of hypoglycemia and serious adverse events.

The AACE and ADA are moving away from one-size-fits-all and toward individualized recommendations

As a result, the ADA⁵ states that a hemoglobin A_1c target less than 6.5% is optional for patients with a long life expectancy, short duration of diabetes, low risk of hypoglycemia, and no significant cardiovascular disease. The ADA further defines a hemoglobin A_1c goal of less than 8% for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and long-standing diabetes.

Therefore, the AACE and ADA are moving away from “one-size-fits-all” goals and toward individualizing their recommendations.

WHEN SHOULD INSULIN BE STARTED?

Physicians should consider the needs and preferences of each patient and individualize the treatment. The most recent recommendations from the ADA⁵ stress the importance of a patient-centered approach, with multiple factors taken into account. These include the patient’s attitude, expected compliance with treatment, risk of hypoglycemia, disease duration, life expectancy, and comorbidities, and the side effects of oral medications and insulin.

Compared with previous guidelines, there are fewer rules on how and when to start insulin therapy. But absolute and relative indications for insulin therapy should be considered in patients with the following:

Absolute indications for insulin

• Ketoacidosis or catabolic symptoms, including ketonuria
• Newly diagnosed type 2 diabetes with pronounced hyperglycemia (glucose ≥ 300 mg/dL or hemoglobin A_1c ≥ 10.0%) with or without severe symptoms, including weight loss, polyuria, or polydipsia¹⁰
• Uncontrolled type 2 diabetes mellitus despite using one, two, or more oral antidiabetic drugs or glucagon-like peptide 1 (GLP-1) receptor agonists
• Gestational diabetes
• Preference for insulin.

Relative indications for insulin

• Hospitalized for surgery or acute illnesses
• Advanced renal or hepatic disease
• Inability to afford the cost or tolerate the side effects of oral antidiabetic drugs and GLP-1 receptor agonists.

Depending on the situation, blood glucose is measured fasting, before meals, or after meals after initiating or adjusting insulin regimens (Table 2).

WHAT ARE THE INSULIN REGIMENS?

Basal insulin

In the early stages of type 2 diabetes, metformin alone or in combination with another oral antidiabetic drug or with a GLP-1 receptor agonist is often used along with healthy eating, weight control, and increased physical activity.

When the target hemoglobin A_1c cannot be achieved with one or two noninsulin drugs, the ADA suggests basal insulin be added to metformin or a two-medication regimen that includes metformin (Table 3). However, recent evidence suggests that combining a GLP-1 receptor agonist with basal insulin, in a regimen without metformin, is safe and improves glycemic control without hypoglycemia or weight gain.¹¹

While a total daily dose of insulin of 0.1 to 0.2 units/kg could be initially used in patients with a hemoglobin A_1c level less than 8%, a higher dose of 0.2 to 0.3 units/kg is required if the hemoglobin A_1c level is between 8% and 10%. The dose can be titrated once or twice weekly if the fasting glucose is above the target level (usually < 130 mg/dL). If hypoglycemia develops (glucose < 70 mg/dL), the insulin dose should be reduced by 10% to 20%.¹⁰

Available basal insulins include glargine, detemir, and neutral protamine Hagedorn (NPH) (Table 4).^12–14 Because glargine and detemir offer better pharmacokinetic properties, less variability in response, and less risk of hypoglycemia, they are preferred over NPH. Glargine has a relatively constant plasma concentration over 24 hours, allowing once-daily dosing at any time during the day (Figure 1).¹⁵ The dose should be taken at the same time every day. Detemir and NPH are usually taken once or twice daily.

Adapted from Hirsch IB. Insulin analogues. N Engl J Med 2005; 352:174-183. Copyright 2005, Massachusetts Medical Society.

Patients treated once daily should take the dose with the evening meal or at bedtime. Patients who require a twice-daily regimen can take the first dose with breakfast and the second one with the evening meal, at bedtime, or 12 hours after the morning dose.

The randomized Treat-to-Target trial,¹⁶ in 756 patients, showed that both glargine and NPH, when added to oral therapy in patients with type 2 diabetes, achieve the target hemoglobin A_1c, but NPH is associated with more episodes of nocturnal hypoglycemia. Similar results were found when NPH was compared with detemir insulin.¹⁷

A Cochrane review¹⁸ suggested that glargine and detemir are similar in efficacy and safety. However, detemir often needs to be injected twice daily, in a higher dose, and is associated with less weight gain. Furthermore, a meta-analysis of 46 randomized clinical trials¹⁹ showed that the weight increase at 1 year is less in patients treated with basal than with twice-daily or prandial regimens.

The ADA suggests basal insulin be added to metformin alone or a regimen that includes metformin

A noninterventional longitudinal study²⁰ in 2,179 patients newly started on insulin showed that the mean weight increase at 1 year was 1.78 kg, and 24% of patients gained more than 5 kg. However, the factors independently associated with the weight gain were a higher hemoglobin A_1c at baseline, a higher insulin dose at baseline and at 1 year, and a lower baseline body mass index, but not the type of insulin regimen.

Currently, a new class of ultralong-acting basal insulins is being studied. Insulins in this class are approved in other countries, but the US Food and Drug Administration requires additional data for approval. Ultralong-acting insulins are expected to reduce the risk of hypoglycemia, specifically the risk of nocturnal episodes. Also, given their longer duration of action and stable steady-state pharmacokinetics, they will offer flexibility in the dose timing.²¹

Basal-bolus regimens

Basal insulin often does not control postprandial hyperglycemia. The need for multiple doses of insulin (including one or more preprandial doses) is suggested by postprandial glucose values above target (usually > 180 mg/dL) or by a hemoglobin A_1c above goal despite well-controlled fasting glucose levels. This usually becomes evident when the total daily dose of basal insulin exceeds 0.5 units/kg. Patients newly diagnosed with diabetes who have a hemoglobin A_1c higher than 10% may also respond better to an initial basal-bolus regimen.

Available bolus insulins include lispro, aspart, glulisine, regular insulin, and the newly approved Technosphere inhaled regular insulin (Table 4).^12–14 They can be taken before each meal, and the total bolus dose usually represents 50% of the total daily dose.²² Rapid-acting insulins have faster onset, shorter duration of action, and more predictable pharmacokinetics, which makes them preferable to regular insulin (Figure 1).¹⁵ Inhaled insulin is another option, but it is contraindicated in patients with chronic obstructive pulmonary disease or asthma because of the increased risk of acute bronchospasm.¹²

Alternatively, the transition to a basal-bolus regimen can be accomplished with a single dose of bolus insulin before the main meal, using a dose that represents approximately 10% of the total daily dose. Additional bolus doses can be added later based on the glycemic control. The adjustment of the preprandial insulin dose is done once or twice weekly, based on the postprandial glucose levels.¹⁰

Premixed combinations of long- and short-acting insulins in ratios of 50% to 50%, 70% to 30%, or 75% to 25% can be considered in patients who cannot adhere to a complex insulin regimen. A propensity-matched comparison of different insulin regimens (basal, premixed, mealtime plus basal, and mealtime) in patients with type 2 diabetes revealed that the hemoglobin A_1c reduction was similar between the different groups.²³ However, the number of hypoglycemic episodes was higher in the premixed insulin group, and the weight gain was less in the basal insulin group.

While premixed insulins require fewer injections, they do not provide dosing flexibility. In other words, dose adjustments for premixed insulins lead to increases in both basal and bolus amounts even though a dose adjustment is needed for only one insulin type. Thus, this is a common reason for increased hypoglycemic episodes.

Continuous subcutaneous insulin infusion

Patients who are engaged in their care are more likely to succeed in their treatment

A meta-analysis showed that continuous subcutaneous insulin infusion (ie, use of an insulin pump) was similar to intensive therapy with multiple daily insulin injections in terms of glycemic control and hypoglycemia.²⁴ Since both options can lead to similar glucose control, additional factors to consider when initiating insulin infusion include lifestyle and technical expertise. Some patients may or may not prefer having a pump attached for nearly all daily activities. Additionally, this type of therapy is complex and requires significant training to ensure efficacy and safety.²⁵

WHAT IS THE COST OF INSULIN THERAPY?

A final factor to keep in mind when initiating insulin is cost (Table 4).^12–14 Asking patients to check their prescription insurance formulary is important to ensure that an affordable option is selected. If patients do not have prescription insurance, medication assistance programs could be an option. However, if a patient is considering an insulin pump, insurance coverage is essential. Depending on the manufacturer, insulin pumps cost about $6,000 to $7,000, and the additional monthly supplies for the pump are also expensive.

If patients are engaged when considering and selecting insulin therapy, the likelihood of treatment success is greater.^26–28

Insulin therapy is one of the most effective tools clinicians can use to help patients reach their individualized hemoglobin A_1c target. However, decisions about when and how to start insulin therapy have to be individualized to the needs and goals of each patient. Many insulin options are available, one of the most common being the addition of basal insulin to oral antidiabetic drugs. Although patients are often reluctant to start insulin, this reluctance can be overcome through patient education and hands-on training.

Here, we review hemoglobin A_1c targets, factors that determine when to start insulin therapy, and the different regimens that can be used.

MOST PATIENTS EVENTUALLY NEED INSULIN

Type 2 diabetes mellitus is a chronic progressive disease associated with insulin resistance, beta-cell dysfunction, and decreased insulin secretion. Consequently, most patients eventually require insulin therapy to reduce the risk of long-term complications.

The efficacy of therapy can be assessed by measuring hemoglobin A_1c, an important marker of the chronic hyperglycemic state. The hemoglobin A_1c value can be reported as a ratio (%) standardized against the results of the Diabetes Control and Complications Trial,¹ or as International Federation of Clinical Chemistry units (mmol/mol).² Table 1 shows the relationship between hemoglobin A_1c and average glucose values.³

WHAT IS AN APPROPRIATE HEMOGLOBIN A_1c TARGET?

The short answer is, “It depends.”

Currently, the American Association of Clinical Endocrinologists (AACE) supports a hemoglobin A_1c goal of less than 6.5% for otherwise healthy patients but states that the goal should be individualized for patients with concurrent illnesses or at risk of hypoglycemia.⁴

On the other hand, the American Diabetes Association (ADA) recommends a higher hemoglobin A_1c target of less than 7% for most adults with type 2 diabetes mellitus.⁵ This value was shown to be associated with a reduction in the microvascular and macrovascular complications of diabetes.

Yet when three large trials^6–8 recently compared intensive and standard glucose control regimens, tighter glucose control failed to improve cardiovascular outcomes. Moreover, in one of the trials,⁷ patients receiving intensive treatment had a higher rate of all-cause mortality. Details:

• Action in Diabetes and Vascular Disease (ADVANCE): 11,140 patients; average hemoglobin A_1c levels 6.5% vs 7.3%⁶
• Action to Control Cardiovascular Risk in Diabetes (ACCORD): 10,251 patients; average hemoglobin A_1c levels 6.4% vs 7.5%⁷
• Veterans Affairs Diabetes Trial (VADT): 1,791 patients; average hemoglobin A_1c levels 6.9% vs 8.4%.⁸

Similarly, a 2013 Cochrane review⁹ that included 28 randomized controlled trials concluded that intensive control (in 18,717 patients) did not decrease all-cause and cardiovascular mortality rates compared with traditional glucose control (in 16,195 patients), and it increased the risk of hypoglycemia and serious adverse events.

The AACE and ADA are moving away from one-size-fits-all and toward individualized recommendations

As a result, the ADA⁵ states that a hemoglobin A_1c target less than 6.5% is optional for patients with a long life expectancy, short duration of diabetes, low risk of hypoglycemia, and no significant cardiovascular disease. The ADA further defines a hemoglobin A_1c goal of less than 8% for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and long-standing diabetes.

Therefore, the AACE and ADA are moving away from “one-size-fits-all” goals and toward individualizing their recommendations.

WHEN SHOULD INSULIN BE STARTED?

Physicians should consider the needs and preferences of each patient and individualize the treatment. The most recent recommendations from the ADA⁵ stress the importance of a patient-centered approach, with multiple factors taken into account. These include the patient’s attitude, expected compliance with treatment, risk of hypoglycemia, disease duration, life expectancy, and comorbidities, and the side effects of oral medications and insulin.

Compared with previous guidelines, there are fewer rules on how and when to start insulin therapy. But absolute and relative indications for insulin therapy should be considered in patients with the following:

Absolute indications for insulin

• Ketoacidosis or catabolic symptoms, including ketonuria
• Newly diagnosed type 2 diabetes with pronounced hyperglycemia (glucose ≥ 300 mg/dL or hemoglobin A_1c ≥ 10.0%) with or without severe symptoms, including weight loss, polyuria, or polydipsia¹⁰
• Uncontrolled type 2 diabetes mellitus despite using one, two, or more oral antidiabetic drugs or glucagon-like peptide 1 (GLP-1) receptor agonists
• Gestational diabetes
• Preference for insulin.

Relative indications for insulin

• Hospitalized for surgery or acute illnesses
• Advanced renal or hepatic disease
• Inability to afford the cost or tolerate the side effects of oral antidiabetic drugs and GLP-1 receptor agonists.

Depending on the situation, blood glucose is measured fasting, before meals, or after meals after initiating or adjusting insulin regimens (Table 2).

WHAT ARE THE INSULIN REGIMENS?

Basal insulin

In the early stages of type 2 diabetes, metformin alone or in combination with another oral antidiabetic drug or with a GLP-1 receptor agonist is often used along with healthy eating, weight control, and increased physical activity.

When the target hemoglobin A_1c cannot be achieved with one or two noninsulin drugs, the ADA suggests basal insulin be added to metformin or a two-medication regimen that includes metformin (Table 3). However, recent evidence suggests that combining a GLP-1 receptor agonist with basal insulin, in a regimen without metformin, is safe and improves glycemic control without hypoglycemia or weight gain.¹¹

While a total daily dose of insulin of 0.1 to 0.2 units/kg could be initially used in patients with a hemoglobin A_1c level less than 8%, a higher dose of 0.2 to 0.3 units/kg is required if the hemoglobin A_1c level is between 8% and 10%. The dose can be titrated once or twice weekly if the fasting glucose is above the target level (usually < 130 mg/dL). If hypoglycemia develops (glucose < 70 mg/dL), the insulin dose should be reduced by 10% to 20%.¹⁰

Available basal insulins include glargine, detemir, and neutral protamine Hagedorn (NPH) (Table 4).^12–14 Because glargine and detemir offer better pharmacokinetic properties, less variability in response, and less risk of hypoglycemia, they are preferred over NPH. Glargine has a relatively constant plasma concentration over 24 hours, allowing once-daily dosing at any time during the day (Figure 1).¹⁵ The dose should be taken at the same time every day. Detemir and NPH are usually taken once or twice daily.

Adapted from Hirsch IB. Insulin analogues. N Engl J Med 2005; 352:174-183. Copyright 2005, Massachusetts Medical Society.

Patients treated once daily should take the dose with the evening meal or at bedtime. Patients who require a twice-daily regimen can take the first dose with breakfast and the second one with the evening meal, at bedtime, or 12 hours after the morning dose.

The randomized Treat-to-Target trial,¹⁶ in 756 patients, showed that both glargine and NPH, when added to oral therapy in patients with type 2 diabetes, achieve the target hemoglobin A_1c, but NPH is associated with more episodes of nocturnal hypoglycemia. Similar results were found when NPH was compared with detemir insulin.¹⁷

A Cochrane review¹⁸ suggested that glargine and detemir are similar in efficacy and safety. However, detemir often needs to be injected twice daily, in a higher dose, and is associated with less weight gain. Furthermore, a meta-analysis of 46 randomized clinical trials¹⁹ showed that the weight increase at 1 year is less in patients treated with basal than with twice-daily or prandial regimens.

The ADA suggests basal insulin be added to metformin alone or a regimen that includes metformin

A noninterventional longitudinal study²⁰ in 2,179 patients newly started on insulin showed that the mean weight increase at 1 year was 1.78 kg, and 24% of patients gained more than 5 kg. However, the factors independently associated with the weight gain were a higher hemoglobin A_1c at baseline, a higher insulin dose at baseline and at 1 year, and a lower baseline body mass index, but not the type of insulin regimen.

Currently, a new class of ultralong-acting basal insulins is being studied. Insulins in this class are approved in other countries, but the US Food and Drug Administration requires additional data for approval. Ultralong-acting insulins are expected to reduce the risk of hypoglycemia, specifically the risk of nocturnal episodes. Also, given their longer duration of action and stable steady-state pharmacokinetics, they will offer flexibility in the dose timing.²¹

Basal-bolus regimens

Basal insulin often does not control postprandial hyperglycemia. The need for multiple doses of insulin (including one or more preprandial doses) is suggested by postprandial glucose values above target (usually > 180 mg/dL) or by a hemoglobin A_1c above goal despite well-controlled fasting glucose levels. This usually becomes evident when the total daily dose of basal insulin exceeds 0.5 units/kg. Patients newly diagnosed with diabetes who have a hemoglobin A_1c higher than 10% may also respond better to an initial basal-bolus regimen.

Available bolus insulins include lispro, aspart, glulisine, regular insulin, and the newly approved Technosphere inhaled regular insulin (Table 4).^12–14 They can be taken before each meal, and the total bolus dose usually represents 50% of the total daily dose.²² Rapid-acting insulins have faster onset, shorter duration of action, and more predictable pharmacokinetics, which makes them preferable to regular insulin (Figure 1).¹⁵ Inhaled insulin is another option, but it is contraindicated in patients with chronic obstructive pulmonary disease or asthma because of the increased risk of acute bronchospasm.¹²

Alternatively, the transition to a basal-bolus regimen can be accomplished with a single dose of bolus insulin before the main meal, using a dose that represents approximately 10% of the total daily dose. Additional bolus doses can be added later based on the glycemic control. The adjustment of the preprandial insulin dose is done once or twice weekly, based on the postprandial glucose levels.¹⁰

Premixed combinations of long- and short-acting insulins in ratios of 50% to 50%, 70% to 30%, or 75% to 25% can be considered in patients who cannot adhere to a complex insulin regimen. A propensity-matched comparison of different insulin regimens (basal, premixed, mealtime plus basal, and mealtime) in patients with type 2 diabetes revealed that the hemoglobin A_1c reduction was similar between the different groups.²³ However, the number of hypoglycemic episodes was higher in the premixed insulin group, and the weight gain was less in the basal insulin group.

While premixed insulins require fewer injections, they do not provide dosing flexibility. In other words, dose adjustments for premixed insulins lead to increases in both basal and bolus amounts even though a dose adjustment is needed for only one insulin type. Thus, this is a common reason for increased hypoglycemic episodes.

Continuous subcutaneous insulin infusion

Patients who are engaged in their care are more likely to succeed in their treatment

A meta-analysis showed that continuous subcutaneous insulin infusion (ie, use of an insulin pump) was similar to intensive therapy with multiple daily insulin injections in terms of glycemic control and hypoglycemia.²⁴ Since both options can lead to similar glucose control, additional factors to consider when initiating insulin infusion include lifestyle and technical expertise. Some patients may or may not prefer having a pump attached for nearly all daily activities. Additionally, this type of therapy is complex and requires significant training to ensure efficacy and safety.²⁵

WHAT IS THE COST OF INSULIN THERAPY?

A final factor to keep in mind when initiating insulin is cost (Table 4).^12–14 Asking patients to check their prescription insurance formulary is important to ensure that an affordable option is selected. If patients do not have prescription insurance, medication assistance programs could be an option. However, if a patient is considering an insulin pump, insurance coverage is essential. Depending on the manufacturer, insulin pumps cost about $6,000 to $7,000, and the additional monthly supplies for the pump are also expensive.

If patients are engaged when considering and selecting insulin therapy, the likelihood of treatment success is greater.^26–28

More and more we are realizing that we need trials that use hard clinical end points to inform our clinical practice. Several things we used to do based on observational studies have fallen from grace after being evaluated in interventional trials. And faced with the US Food and Drug Administration’s mandate to demonstrate clinical impact, pharmaceutical companies can rarely count on using even well-accepted biomarkers instead of clinical outcomes when trying to bring new drugs to market.

This atmosphere often makes us a bit uncomfortable when prescribing older drugs that have passed the test of time and collective anecdotal experience but not rigorous clinical testing. In some cases this is good, and robust evaluation provides greater confidence in our choice of therapy: witness the demise of digoxin for heart failure.

Many older drugs have never been compared with newer drugs in well-designed trials using hard clinical outcomes and likely never will, owing to cost, marketing, and logistic reasons. But sometimes these trials are done, and the results are surprising. For instance, methotrexate in appropriate doses may actually be comparable to newer and far more expensive tumor necrosis factor inhibitors when used to treat rheumatoid arthritis.

Should we be willing to sometimes accept data on surrogate markers (eg, low-density lipoprotein cholesterol levels, blood pressure, hemoglobin A_1c ) or even extensive clinical experience in the absence of hard outcome data when using older, tried-and-true drugs? Markers can mislead: consider the higher number of deaths recorded in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in the group receiving more aggressive control of their glucose levels.

So we should not be totally sanguine when using older drugs instead of newer ones. But some drugs may have slipped out of our mental formularies yet still have real value in niche or even common settings. Methyldopa remains an effective antihypertensive drug and may be especially useful in peripartum patients. Yet relatively few young physicians know the drug.

And so it may be with chlorthalidone. In this issue of the Journal, Cooney et al remind us not only that this drug is still around, but that it has proven efficacy and, compared with its more popular cousin hydrochlorothiazide, favorable pharmacokinetic properties such as longer action. Not to mention that it was a comparator drug in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial.

In our current cost-saving environment, we should remember that some old dogs can still do good tricks.

More and more we are realizing that we need trials that use hard clinical end points to inform our clinical practice. Several things we used to do based on observational studies have fallen from grace after being evaluated in interventional trials. And faced with the US Food and Drug Administration’s mandate to demonstrate clinical impact, pharmaceutical companies can rarely count on using even well-accepted biomarkers instead of clinical outcomes when trying to bring new drugs to market.

This atmosphere often makes us a bit uncomfortable when prescribing older drugs that have passed the test of time and collective anecdotal experience but not rigorous clinical testing. In some cases this is good, and robust evaluation provides greater confidence in our choice of therapy: witness the demise of digoxin for heart failure.

Many older drugs have never been compared with newer drugs in well-designed trials using hard clinical outcomes and likely never will, owing to cost, marketing, and logistic reasons. But sometimes these trials are done, and the results are surprising. For instance, methotrexate in appropriate doses may actually be comparable to newer and far more expensive tumor necrosis factor inhibitors when used to treat rheumatoid arthritis.

Should we be willing to sometimes accept data on surrogate markers (eg, low-density lipoprotein cholesterol levels, blood pressure, hemoglobin A_1c ) or even extensive clinical experience in the absence of hard outcome data when using older, tried-and-true drugs? Markers can mislead: consider the higher number of deaths recorded in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in the group receiving more aggressive control of their glucose levels.

So we should not be totally sanguine when using older drugs instead of newer ones. But some drugs may have slipped out of our mental formularies yet still have real value in niche or even common settings. Methyldopa remains an effective antihypertensive drug and may be especially useful in peripartum patients. Yet relatively few young physicians know the drug.

And so it may be with chlorthalidone. In this issue of the Journal, Cooney et al remind us not only that this drug is still around, but that it has proven efficacy and, compared with its more popular cousin hydrochlorothiazide, favorable pharmacokinetic properties such as longer action. Not to mention that it was a comparator drug in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial.

In our current cost-saving environment, we should remember that some old dogs can still do good tricks.

More and more we are realizing that we need trials that use hard clinical end points to inform our clinical practice. Several things we used to do based on observational studies have fallen from grace after being evaluated in interventional trials. And faced with the US Food and Drug Administration’s mandate to demonstrate clinical impact, pharmaceutical companies can rarely count on using even well-accepted biomarkers instead of clinical outcomes when trying to bring new drugs to market.

This atmosphere often makes us a bit uncomfortable when prescribing older drugs that have passed the test of time and collective anecdotal experience but not rigorous clinical testing. In some cases this is good, and robust evaluation provides greater confidence in our choice of therapy: witness the demise of digoxin for heart failure.

Many older drugs have never been compared with newer drugs in well-designed trials using hard clinical outcomes and likely never will, owing to cost, marketing, and logistic reasons. But sometimes these trials are done, and the results are surprising. For instance, methotrexate in appropriate doses may actually be comparable to newer and far more expensive tumor necrosis factor inhibitors when used to treat rheumatoid arthritis.

Should we be willing to sometimes accept data on surrogate markers (eg, low-density lipoprotein cholesterol levels, blood pressure, hemoglobin A_1c ) or even extensive clinical experience in the absence of hard outcome data when using older, tried-and-true drugs? Markers can mislead: consider the higher number of deaths recorded in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in the group receiving more aggressive control of their glucose levels.

So we should not be totally sanguine when using older drugs instead of newer ones. But some drugs may have slipped out of our mental formularies yet still have real value in niche or even common settings. Methyldopa remains an effective antihypertensive drug and may be especially useful in peripartum patients. Yet relatively few young physicians know the drug.

And so it may be with chlorthalidone. In this issue of the Journal, Cooney et al remind us not only that this drug is still around, but that it has proven efficacy and, compared with its more popular cousin hydrochlorothiazide, favorable pharmacokinetic properties such as longer action. Not to mention that it was a comparator drug in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial.

In our current cost-saving environment, we should remember that some old dogs can still do good tricks.

The thiazide diuretic hydrochlorothiazide and the thiazidelike diuretic chlorthalidone are two old drugs that are still useful. Although similar, they differ in important ways still not fully appreciated more than a half century after they were introduced.

Most hypertension guidelines recommend thiazide diuretics as one of the classes of agents that can be used either as initial antihypertensive drug therapy or as part of combination therapy.^1–3

In the United States, hydrochlorothiazide is used more often than chlorthalidone, but many clinical trials of antihypertensive therapy have used chlorthalidone.^4,5 In recent years, particularly after the publication of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), interest in chlorthalidone has been increasing, and new data are now available comparing these two diuretics.⁶ While current US guidelines do not recommend one over the other, British guidelines prefer chlorthalidone.⁷

This review summarizes the data comparing the two drugs’ pharmacology, antihypertensive effect, and impact on clinical outcomes to help guide clinicians in choosing antihypertensive drug therapy.

PHARMACOLOGY AND MECHANISM OF ACTION

Many of the differences in effectiveness and adverse effects of hydrochlorothiazide and chlorthalidone are thought to be due to their different pharmacodynamic and pharmacokinetic effects.

Pharmacodynamic effects

Hydrochlorothiazide and chlorthalidone differ significantly in chemical structure (Figure 1), but both contain a sulfonamide group that inhibits carbonic anhydrase activity, which may be associated with lower vascular contractility. Both drugs are concentrated in the kidney and secreted into the tubular lumen⁸; therefore, their therapeutic diuretic effects are often achieved with relatively low plasma concentrations.

Both drugs inhibit the sodium-chloride cotransporter in the luminal membrane of the distal convoluted tubule of the ascending loop of Henle, leading to a modest natriuresis and diuresis. The exact mechanism by which they lower blood pressure is not known: while the initial response is from diuresis and volume changes, long-term reduction in blood pressure is through uncertain mechanisms. In addition, chlorthalidone may have beneficial effects on endothelial function and oxidative stress.^9,10

Both drugs also increase secretion of potassium and hydrogen ions and promote increased reabsorption of calcium through increased expression of a sodium-calcium exchange channel.⁸ Chlorthalidone may cause more inhibition of carbonic anhydrase than hydrochlorothiazide, which can lead to lower intracellular pH and cell volume. This effect may in part explain a pleiotropic effect of chlorthalidone, ie, inhibition of platelet function, which in turn may contribute to this drug’s beneficial effect on cardiovascular outcomes.⁹

Pharmacokinetic differences

Hydrochlorothiazide and chlorthalidone have important differences in their pharmacokinetic properties (Table 1).¹¹

Hydrochlorothiazide has its onset of action in about 2 hours, and it reaches its peak in 4 to 6 hours. Though its duration of action is short—up to 12 hours—its pharmacodynamic response can be much longer than predicted by its kinetics, allowing once-daily dosing.⁸

Chlorthalidone has a longer duration of action than hydrochlorothiazide. This may be because it has a very high volume of distribution, since it is taken up into red blood cells and is bound to carbonic anhydrase.¹² This may result in a “drug reservoir” that keeps drug levels higher for a longer time.¹³ Its long duration of action makes it a favorable choice for patients who have difficulty adhering to medication instructions. In addition, a missed dose is unlikely to have a “rebound” effect like that seen with some other antihypertensive agents. However, both chlorthalidone and hydrochlorothiazide are effective if taken once daily.

BLOOD PRESSURE-LOWERING

Both hydrochlorothiazide and chlorthalidone are effective antihypertensive agents. Table 2 summarizes findings from studies that evaluated their blood pressure-lowering effect at various doses.^14–33 However, relatively few studies have directly compared these two agents’ effects on blood pressure.

Ernst et al,³⁴ in a small study (but probably the best one to address this issue), compared chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and hydrochlorothiazide 25 mg/day (force-titrated to 50 mg/day) in untreated hypertensive patients. After 8 weeks, ambulatory blood pressure monitoring indicated a greater reduction from baseline in systolic blood pressure with chlorthalidone 25 mg/day than with hydrochlorothiazide 50 mg/day (24-hour mean –12.4 vs –7.4 mm Hg, P = .05). Interestingly, the change in nighttime blood pressure was greater in the chlorthalidone group (–13.5 mm Hg) than in the hydrochlorothiazide group (–6.4 mm Hg; P = .009). These data suggest that at the doses studied, chlorthalidone is more effective than hydrochlorothiazide in lowering systolic blood pressure.

Bakris et al,³⁵ using a different study design, compared the single-pill combination of azilsartan medoxomil and chlorthalidone vs coadministration of azilsartan medoxomil and hydrochlorothiazide in participants with stage 2 primary hypertension (≥ 160/100 mm Hg). Systolic blood pressure, as measured in the clinic, declined more with the chlorthalidone combination (–35.1 mm Hg) than with the hydrochlorothiazide combination (–29.5 mm Hg, mean difference –5.6 mm Hg, P < .001).

Meta-analyses also support the conclusion that chlorthalidone is more potent than hydrochlorothiazide in lowering blood pressure.^35,36 Several studies have shown that chlorthalidone at the same dose is 1.5 to 2 times as potent as hydrochlorothiazide.^33,36,37 Therefore, for clinical purposes, it is reasonable to consider chlorthalidone 12.5 mg daily as similar to 25 mg of hydrochlorothiazide daily.

ADVERSE EFFECTS

Electrolyte disturbances are a common adverse effect of thiazide diuretics.

Hypokalemia. All thiazide diuretics cause potassium wasting. The frequency of hypokalemia depends on the dose, frequency of administration, diet, and other pharmacologic agents used.

Two large clinical trials, the Systolic Hypertension in the Elderly Program and ALLHAT, found that chlorthalidone caused hypokalemia requiring therapy in about 6% to 8% of patients.^38,39 Chlorthalidone therapy was associated with a lowering of serum potassium levels of 0.2 to 0.5 mmol/L.³⁶ In ALLHAT, chlorthalidone was associated with a reduction in potassium levels of approximately 0.2 mmol/L after 4 years.³⁸

All diuretics require monitoring of electrolytes, especially during the first 2 weeks of therapy. Once a steady state is reached, patients are not usually at risk of hypokalemia  unless the dose is increased, extrarenal losses of potassium increase, or dietary potassium is reduced.

Other electrolyte changes. Thiazide and thiazide-like diuretics can cause other metabolic and endocrine abnormalities such as hypochloremic alkalosis, hyponatremia, and hypercalcemia.^40,41 They can also cause photosensitivity and can precipitate gout.⁴²

Observational studies have suggested that metabolic adverse effects such as hypokalemia and hyperuricemia are more common with chlorthalidone than with hydrochlorothiazide.⁴³ It is prudent to monitor laboratory values periodically in patients on diuretic therapy.

DRUG INTERACTIONS

The drug interaction profiles of hydrochlorothiazide and chlorthalidone are also similar. The most common interactions are pharmacodynamic interactions resulting from potassium depletion caused by the diuretics.

Antiarrythymic drugs. Hypokalemia is a risk factor for arrhythmias such as torsades de pointes, and the risk is magnified with concomitant therapy with antiarrhythmic agents that prolong the QT interval independently of serum potassium concentration (eg, sotalol, dronedarone, ibutilide, propafenone). Therefore, combinations of drugs that can cause hypokalemia (eg, diuretics) and antiarrhythmic agents require vigilant monitoring of potassium and appropriate replenishment.⁴⁴

Dofetilide is a class III antiarrhythmic agent and, like other antiarrhythmic drugs, carries a risk of QT prolongation and torsades de pointes, which is magnified by hypokalemia.⁴⁵ In addition, dofetilide undergoes active tubular secretion in the kidney via the cation transport system, which is inhibited by hydrochlorothiazide.⁴⁵ The resulting increase in plasma concentrations of dofetilide may magnify the risk of arrhythmias. Chlorthalidone has not been specifically studied in combination with dofetilide, but thiazide diuretics in general are thought to have a similar effect on tubular secretion and, therefore, should be considered similar to hydrochlorothiazide in this regard.

Digoxin. Similarly, digoxin toxicity may be enhanced in hypokalemia. As with antiarrhythmic agents, serum potassium should be carefully monitored and replenished appropriately when diuretics are used in combination with digoxin.

Lithium is reabsorbed in the proximal tubule along with sodium. Diuretics including hydrochlorothiazide and chlorthalidone that alter sodium reabsorption can also alter lithium absorption.⁴⁶ When sodium reabsorption is decreased, lithium ion reabsorption is increased and may result in lithium toxicity. Although this combination is not contraindicated, monitoring of serum lithium concentrations and clinical signs and symptoms of lithium toxicity is recommended during initiation and dose adjustments of thiazide diuretics.

Nonsteroidal anti-inflammatory drugs can decrease the natriuretic, diuretic, and antihypertensive effects of both hydrochlorothiazide and chlorthalidone.⁴⁷

Renin-angiotensin-aldosterone system antagonists, ie, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and the renin inhibitor aliskiren, have potentially beneficial interactions with hydrochlorothiazide and chlorthalidone, producing additive decreases in blood pressure when coadministered with these diuretics. These effects may be particularly potent early in concomitant therapy and allow use of lower doses of diuretics, typically 12.5 mg of hydrochlorothiazide in combination therapy.

LONG-TERM EFFECTS ON CARDIOVASCULAR EVENTS

The long-term goal in treating hypertension is to lower the risk of cardiovascular disease. Therefore, the clinician needs to consider the effect of antihypertensive drug therapy on long-term clinical outcomes.

Antihypertensive drug therapy based on thiazide diuretics has been shown to lower cardiovascular risk when compared with placebo.⁴⁸ In addition, the effect of chlorthalidone-based antihypertensive therapy was similar to that of other antihypertensive drug classes in preventing most cardiovascular outcomes in ALLHAT.⁴

However, no study has directly compared hydrochlorothiazide and chlorthalidone with the primary outcome of reduction in long-term cardiovascular events. The data to date come from observational studies and meta-analyses. For example, in a retrospective analysis of the Multiple Risk Factor Intervention Trial, cardiovascular events were significantly fewer in those receiving chlorthalidone vs hydrochlorothiazide (P = .0016).⁴³

In a systematic review and meta-analysis, chlorthalidone was associated with a 23% lower risk of heart failure and a 21% lower risk of all cardiovascular events.⁴⁹

However, a Canadian observational study of 29,873 patients found no difference in the composite outcome of death or hospitalization for heart failure, stroke, or myocardial infarction between chlorthalidone recipients (3.2 events per 100 person-years) and hydrochlorothiazide recipients (3.4 events per 100 person-years; adjusted hazard ratio 0.93, 95% confidence interval 0.81–1.06).⁵⁰

In summary, it is unclear whether chlorthalidone or hydrochlorothiazide is superior in preventing cardiovascular events.

SUMMARY

Thiazide and thiazidelike diuretics play an important role in managing hypertension in most patients. The eighth Joint National Committee guidelines do not recommend either hydrochlorothiazide or chlorthalidone over the other. The target dose recommendations are hydrochlorothiazide 25 to 50 mg or chlorthalidone 12.5 to 25 mg daily, with lower doses considered for the elderly.

There are important differences between hydrochlorothiazide and chlorthalidone in pharmacology, potency, and frequency of metabolic side effects. Clinicians should consider these factors to tailor the choice of thiazide diuretic therapy in hypertensive patients.

The thiazide diuretic hydrochlorothiazide and the thiazidelike diuretic chlorthalidone are two old drugs that are still useful. Although similar, they differ in important ways still not fully appreciated more than a half century after they were introduced.

Most hypertension guidelines recommend thiazide diuretics as one of the classes of agents that can be used either as initial antihypertensive drug therapy or as part of combination therapy.^1–3

In the United States, hydrochlorothiazide is used more often than chlorthalidone, but many clinical trials of antihypertensive therapy have used chlorthalidone.^4,5 In recent years, particularly after the publication of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), interest in chlorthalidone has been increasing, and new data are now available comparing these two diuretics.⁶ While current US guidelines do not recommend one over the other, British guidelines prefer chlorthalidone.⁷

This review summarizes the data comparing the two drugs’ pharmacology, antihypertensive effect, and impact on clinical outcomes to help guide clinicians in choosing antihypertensive drug therapy.

PHARMACOLOGY AND MECHANISM OF ACTION

Many of the differences in effectiveness and adverse effects of hydrochlorothiazide and chlorthalidone are thought to be due to their different pharmacodynamic and pharmacokinetic effects.

Pharmacodynamic effects

Hydrochlorothiazide and chlorthalidone differ significantly in chemical structure (Figure 1), but both contain a sulfonamide group that inhibits carbonic anhydrase activity, which may be associated with lower vascular contractility. Both drugs are concentrated in the kidney and secreted into the tubular lumen⁸; therefore, their therapeutic diuretic effects are often achieved with relatively low plasma concentrations.

Both drugs inhibit the sodium-chloride cotransporter in the luminal membrane of the distal convoluted tubule of the ascending loop of Henle, leading to a modest natriuresis and diuresis. The exact mechanism by which they lower blood pressure is not known: while the initial response is from diuresis and volume changes, long-term reduction in blood pressure is through uncertain mechanisms. In addition, chlorthalidone may have beneficial effects on endothelial function and oxidative stress.^9,10

Both drugs also increase secretion of potassium and hydrogen ions and promote increased reabsorption of calcium through increased expression of a sodium-calcium exchange channel.⁸ Chlorthalidone may cause more inhibition of carbonic anhydrase than hydrochlorothiazide, which can lead to lower intracellular pH and cell volume. This effect may in part explain a pleiotropic effect of chlorthalidone, ie, inhibition of platelet function, which in turn may contribute to this drug’s beneficial effect on cardiovascular outcomes.⁹

Pharmacokinetic differences

Hydrochlorothiazide and chlorthalidone have important differences in their pharmacokinetic properties (Table 1).¹¹

Hydrochlorothiazide has its onset of action in about 2 hours, and it reaches its peak in 4 to 6 hours. Though its duration of action is short—up to 12 hours—its pharmacodynamic response can be much longer than predicted by its kinetics, allowing once-daily dosing.⁸

Chlorthalidone has a longer duration of action than hydrochlorothiazide. This may be because it has a very high volume of distribution, since it is taken up into red blood cells and is bound to carbonic anhydrase.¹² This may result in a “drug reservoir” that keeps drug levels higher for a longer time.¹³ Its long duration of action makes it a favorable choice for patients who have difficulty adhering to medication instructions. In addition, a missed dose is unlikely to have a “rebound” effect like that seen with some other antihypertensive agents. However, both chlorthalidone and hydrochlorothiazide are effective if taken once daily.

BLOOD PRESSURE-LOWERING

Both hydrochlorothiazide and chlorthalidone are effective antihypertensive agents. Table 2 summarizes findings from studies that evaluated their blood pressure-lowering effect at various doses.^14–33 However, relatively few studies have directly compared these two agents’ effects on blood pressure.

Ernst et al,³⁴ in a small study (but probably the best one to address this issue), compared chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and hydrochlorothiazide 25 mg/day (force-titrated to 50 mg/day) in untreated hypertensive patients. After 8 weeks, ambulatory blood pressure monitoring indicated a greater reduction from baseline in systolic blood pressure with chlorthalidone 25 mg/day than with hydrochlorothiazide 50 mg/day (24-hour mean –12.4 vs –7.4 mm Hg, P = .05). Interestingly, the change in nighttime blood pressure was greater in the chlorthalidone group (–13.5 mm Hg) than in the hydrochlorothiazide group (–6.4 mm Hg; P = .009). These data suggest that at the doses studied, chlorthalidone is more effective than hydrochlorothiazide in lowering systolic blood pressure.

Bakris et al,³⁵ using a different study design, compared the single-pill combination of azilsartan medoxomil and chlorthalidone vs coadministration of azilsartan medoxomil and hydrochlorothiazide in participants with stage 2 primary hypertension (≥ 160/100 mm Hg). Systolic blood pressure, as measured in the clinic, declined more with the chlorthalidone combination (–35.1 mm Hg) than with the hydrochlorothiazide combination (–29.5 mm Hg, mean difference –5.6 mm Hg, P < .001).

Meta-analyses also support the conclusion that chlorthalidone is more potent than hydrochlorothiazide in lowering blood pressure.^35,36 Several studies have shown that chlorthalidone at the same dose is 1.5 to 2 times as potent as hydrochlorothiazide.^33,36,37 Therefore, for clinical purposes, it is reasonable to consider chlorthalidone 12.5 mg daily as similar to 25 mg of hydrochlorothiazide daily.

ADVERSE EFFECTS

Electrolyte disturbances are a common adverse effect of thiazide diuretics.

Hypokalemia. All thiazide diuretics cause potassium wasting. The frequency of hypokalemia depends on the dose, frequency of administration, diet, and other pharmacologic agents used.

Two large clinical trials, the Systolic Hypertension in the Elderly Program and ALLHAT, found that chlorthalidone caused hypokalemia requiring therapy in about 6% to 8% of patients.^38,39 Chlorthalidone therapy was associated with a lowering of serum potassium levels of 0.2 to 0.5 mmol/L.³⁶ In ALLHAT, chlorthalidone was associated with a reduction in potassium levels of approximately 0.2 mmol/L after 4 years.³⁸

All diuretics require monitoring of electrolytes, especially during the first 2 weeks of therapy. Once a steady state is reached, patients are not usually at risk of hypokalemia  unless the dose is increased, extrarenal losses of potassium increase, or dietary potassium is reduced.

Other electrolyte changes. Thiazide and thiazide-like diuretics can cause other metabolic and endocrine abnormalities such as hypochloremic alkalosis, hyponatremia, and hypercalcemia.^40,41 They can also cause photosensitivity and can precipitate gout.⁴²

Observational studies have suggested that metabolic adverse effects such as hypokalemia and hyperuricemia are more common with chlorthalidone than with hydrochlorothiazide.⁴³ It is prudent to monitor laboratory values periodically in patients on diuretic therapy.

DRUG INTERACTIONS

The drug interaction profiles of hydrochlorothiazide and chlorthalidone are also similar. The most common interactions are pharmacodynamic interactions resulting from potassium depletion caused by the diuretics.

Antiarrythymic drugs. Hypokalemia is a risk factor for arrhythmias such as torsades de pointes, and the risk is magnified with concomitant therapy with antiarrhythmic agents that prolong the QT interval independently of serum potassium concentration (eg, sotalol, dronedarone, ibutilide, propafenone). Therefore, combinations of drugs that can cause hypokalemia (eg, diuretics) and antiarrhythmic agents require vigilant monitoring of potassium and appropriate replenishment.⁴⁴

Dofetilide is a class III antiarrhythmic agent and, like other antiarrhythmic drugs, carries a risk of QT prolongation and torsades de pointes, which is magnified by hypokalemia.⁴⁵ In addition, dofetilide undergoes active tubular secretion in the kidney via the cation transport system, which is inhibited by hydrochlorothiazide.⁴⁵ The resulting increase in plasma concentrations of dofetilide may magnify the risk of arrhythmias. Chlorthalidone has not been specifically studied in combination with dofetilide, but thiazide diuretics in general are thought to have a similar effect on tubular secretion and, therefore, should be considered similar to hydrochlorothiazide in this regard.

Digoxin. Similarly, digoxin toxicity may be enhanced in hypokalemia. As with antiarrhythmic agents, serum potassium should be carefully monitored and replenished appropriately when diuretics are used in combination with digoxin.

Lithium is reabsorbed in the proximal tubule along with sodium. Diuretics including hydrochlorothiazide and chlorthalidone that alter sodium reabsorption can also alter lithium absorption.⁴⁶ When sodium reabsorption is decreased, lithium ion reabsorption is increased and may result in lithium toxicity. Although this combination is not contraindicated, monitoring of serum lithium concentrations and clinical signs and symptoms of lithium toxicity is recommended during initiation and dose adjustments of thiazide diuretics.

Nonsteroidal anti-inflammatory drugs can decrease the natriuretic, diuretic, and antihypertensive effects of both hydrochlorothiazide and chlorthalidone.⁴⁷

Renin-angiotensin-aldosterone system antagonists, ie, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and the renin inhibitor aliskiren, have potentially beneficial interactions with hydrochlorothiazide and chlorthalidone, producing additive decreases in blood pressure when coadministered with these diuretics. These effects may be particularly potent early in concomitant therapy and allow use of lower doses of diuretics, typically 12.5 mg of hydrochlorothiazide in combination therapy.

LONG-TERM EFFECTS ON CARDIOVASCULAR EVENTS

The long-term goal in treating hypertension is to lower the risk of cardiovascular disease. Therefore, the clinician needs to consider the effect of antihypertensive drug therapy on long-term clinical outcomes.

Antihypertensive drug therapy based on thiazide diuretics has been shown to lower cardiovascular risk when compared with placebo.⁴⁸ In addition, the effect of chlorthalidone-based antihypertensive therapy was similar to that of other antihypertensive drug classes in preventing most cardiovascular outcomes in ALLHAT.⁴

However, no study has directly compared hydrochlorothiazide and chlorthalidone with the primary outcome of reduction in long-term cardiovascular events. The data to date come from observational studies and meta-analyses. For example, in a retrospective analysis of the Multiple Risk Factor Intervention Trial, cardiovascular events were significantly fewer in those receiving chlorthalidone vs hydrochlorothiazide (P = .0016).⁴³

In a systematic review and meta-analysis, chlorthalidone was associated with a 23% lower risk of heart failure and a 21% lower risk of all cardiovascular events.⁴⁹

However, a Canadian observational study of 29,873 patients found no difference in the composite outcome of death or hospitalization for heart failure, stroke, or myocardial infarction between chlorthalidone recipients (3.2 events per 100 person-years) and hydrochlorothiazide recipients (3.4 events per 100 person-years; adjusted hazard ratio 0.93, 95% confidence interval 0.81–1.06).⁵⁰

In summary, it is unclear whether chlorthalidone or hydrochlorothiazide is superior in preventing cardiovascular events.

SUMMARY

Thiazide and thiazidelike diuretics play an important role in managing hypertension in most patients. The eighth Joint National Committee guidelines do not recommend either hydrochlorothiazide or chlorthalidone over the other. The target dose recommendations are hydrochlorothiazide 25 to 50 mg or chlorthalidone 12.5 to 25 mg daily, with lower doses considered for the elderly.

There are important differences between hydrochlorothiazide and chlorthalidone in pharmacology, potency, and frequency of metabolic side effects. Clinicians should consider these factors to tailor the choice of thiazide diuretic therapy in hypertensive patients.

The thiazide diuretic hydrochlorothiazide and the thiazidelike diuretic chlorthalidone are two old drugs that are still useful. Although similar, they differ in important ways still not fully appreciated more than a half century after they were introduced.

Most hypertension guidelines recommend thiazide diuretics as one of the classes of agents that can be used either as initial antihypertensive drug therapy or as part of combination therapy.^1–3

In the United States, hydrochlorothiazide is used more often than chlorthalidone, but many clinical trials of antihypertensive therapy have used chlorthalidone.^4,5 In recent years, particularly after the publication of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), interest in chlorthalidone has been increasing, and new data are now available comparing these two diuretics.⁶ While current US guidelines do not recommend one over the other, British guidelines prefer chlorthalidone.⁷

This review summarizes the data comparing the two drugs’ pharmacology, antihypertensive effect, and impact on clinical outcomes to help guide clinicians in choosing antihypertensive drug therapy.

PHARMACOLOGY AND MECHANISM OF ACTION

Many of the differences in effectiveness and adverse effects of hydrochlorothiazide and chlorthalidone are thought to be due to their different pharmacodynamic and pharmacokinetic effects.

Pharmacodynamic effects

Hydrochlorothiazide and chlorthalidone differ significantly in chemical structure (Figure 1), but both contain a sulfonamide group that inhibits carbonic anhydrase activity, which may be associated with lower vascular contractility. Both drugs are concentrated in the kidney and secreted into the tubular lumen⁸; therefore, their therapeutic diuretic effects are often achieved with relatively low plasma concentrations.

Both drugs inhibit the sodium-chloride cotransporter in the luminal membrane of the distal convoluted tubule of the ascending loop of Henle, leading to a modest natriuresis and diuresis. The exact mechanism by which they lower blood pressure is not known: while the initial response is from diuresis and volume changes, long-term reduction in blood pressure is through uncertain mechanisms. In addition, chlorthalidone may have beneficial effects on endothelial function and oxidative stress.^9,10

Both drugs also increase secretion of potassium and hydrogen ions and promote increased reabsorption of calcium through increased expression of a sodium-calcium exchange channel.⁸ Chlorthalidone may cause more inhibition of carbonic anhydrase than hydrochlorothiazide, which can lead to lower intracellular pH and cell volume. This effect may in part explain a pleiotropic effect of chlorthalidone, ie, inhibition of platelet function, which in turn may contribute to this drug’s beneficial effect on cardiovascular outcomes.⁹

Pharmacokinetic differences

Hydrochlorothiazide and chlorthalidone have important differences in their pharmacokinetic properties (Table 1).¹¹

Hydrochlorothiazide has its onset of action in about 2 hours, and it reaches its peak in 4 to 6 hours. Though its duration of action is short—up to 12 hours—its pharmacodynamic response can be much longer than predicted by its kinetics, allowing once-daily dosing.⁸

Chlorthalidone has a longer duration of action than hydrochlorothiazide. This may be because it has a very high volume of distribution, since it is taken up into red blood cells and is bound to carbonic anhydrase.¹² This may result in a “drug reservoir” that keeps drug levels higher for a longer time.¹³ Its long duration of action makes it a favorable choice for patients who have difficulty adhering to medication instructions. In addition, a missed dose is unlikely to have a “rebound” effect like that seen with some other antihypertensive agents. However, both chlorthalidone and hydrochlorothiazide are effective if taken once daily.

BLOOD PRESSURE-LOWERING

Both hydrochlorothiazide and chlorthalidone are effective antihypertensive agents. Table 2 summarizes findings from studies that evaluated their blood pressure-lowering effect at various doses.^14–33 However, relatively few studies have directly compared these two agents’ effects on blood pressure.

Ernst et al,³⁴ in a small study (but probably the best one to address this issue), compared chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and hydrochlorothiazide 25 mg/day (force-titrated to 50 mg/day) in untreated hypertensive patients. After 8 weeks, ambulatory blood pressure monitoring indicated a greater reduction from baseline in systolic blood pressure with chlorthalidone 25 mg/day than with hydrochlorothiazide 50 mg/day (24-hour mean –12.4 vs –7.4 mm Hg, P = .05). Interestingly, the change in nighttime blood pressure was greater in the chlorthalidone group (–13.5 mm Hg) than in the hydrochlorothiazide group (–6.4 mm Hg; P = .009). These data suggest that at the doses studied, chlorthalidone is more effective than hydrochlorothiazide in lowering systolic blood pressure.

Bakris et al,³⁵ using a different study design, compared the single-pill combination of azilsartan medoxomil and chlorthalidone vs coadministration of azilsartan medoxomil and hydrochlorothiazide in participants with stage 2 primary hypertension (≥ 160/100 mm Hg). Systolic blood pressure, as measured in the clinic, declined more with the chlorthalidone combination (–35.1 mm Hg) than with the hydrochlorothiazide combination (–29.5 mm Hg, mean difference –5.6 mm Hg, P < .001).

Meta-analyses also support the conclusion that chlorthalidone is more potent than hydrochlorothiazide in lowering blood pressure.^35,36 Several studies have shown that chlorthalidone at the same dose is 1.5 to 2 times as potent as hydrochlorothiazide.^33,36,37 Therefore, for clinical purposes, it is reasonable to consider chlorthalidone 12.5 mg daily as similar to 25 mg of hydrochlorothiazide daily.

ADVERSE EFFECTS

Electrolyte disturbances are a common adverse effect of thiazide diuretics.

Hypokalemia. All thiazide diuretics cause potassium wasting. The frequency of hypokalemia depends on the dose, frequency of administration, diet, and other pharmacologic agents used.

Two large clinical trials, the Systolic Hypertension in the Elderly Program and ALLHAT, found that chlorthalidone caused hypokalemia requiring therapy in about 6% to 8% of patients.^38,39 Chlorthalidone therapy was associated with a lowering of serum potassium levels of 0.2 to 0.5 mmol/L.³⁶ In ALLHAT, chlorthalidone was associated with a reduction in potassium levels of approximately 0.2 mmol/L after 4 years.³⁸

All diuretics require monitoring of electrolytes, especially during the first 2 weeks of therapy. Once a steady state is reached, patients are not usually at risk of hypokalemia  unless the dose is increased, extrarenal losses of potassium increase, or dietary potassium is reduced.

Other electrolyte changes. Thiazide and thiazide-like diuretics can cause other metabolic and endocrine abnormalities such as hypochloremic alkalosis, hyponatremia, and hypercalcemia.^40,41 They can also cause photosensitivity and can precipitate gout.⁴²

Observational studies have suggested that metabolic adverse effects such as hypokalemia and hyperuricemia are more common with chlorthalidone than with hydrochlorothiazide.⁴³ It is prudent to monitor laboratory values periodically in patients on diuretic therapy.

DRUG INTERACTIONS

The drug interaction profiles of hydrochlorothiazide and chlorthalidone are also similar. The most common interactions are pharmacodynamic interactions resulting from potassium depletion caused by the diuretics.

Antiarrythymic drugs. Hypokalemia is a risk factor for arrhythmias such as torsades de pointes, and the risk is magnified with concomitant therapy with antiarrhythmic agents that prolong the QT interval independently of serum potassium concentration (eg, sotalol, dronedarone, ibutilide, propafenone). Therefore, combinations of drugs that can cause hypokalemia (eg, diuretics) and antiarrhythmic agents require vigilant monitoring of potassium and appropriate replenishment.⁴⁴

Dofetilide is a class III antiarrhythmic agent and, like other antiarrhythmic drugs, carries a risk of QT prolongation and torsades de pointes, which is magnified by hypokalemia.⁴⁵ In addition, dofetilide undergoes active tubular secretion in the kidney via the cation transport system, which is inhibited by hydrochlorothiazide.⁴⁵ The resulting increase in plasma concentrations of dofetilide may magnify the risk of arrhythmias. Chlorthalidone has not been specifically studied in combination with dofetilide, but thiazide diuretics in general are thought to have a similar effect on tubular secretion and, therefore, should be considered similar to hydrochlorothiazide in this regard.

Digoxin. Similarly, digoxin toxicity may be enhanced in hypokalemia. As with antiarrhythmic agents, serum potassium should be carefully monitored and replenished appropriately when diuretics are used in combination with digoxin.

Lithium is reabsorbed in the proximal tubule along with sodium. Diuretics including hydrochlorothiazide and chlorthalidone that alter sodium reabsorption can also alter lithium absorption.⁴⁶ When sodium reabsorption is decreased, lithium ion reabsorption is increased and may result in lithium toxicity. Although this combination is not contraindicated, monitoring of serum lithium concentrations and clinical signs and symptoms of lithium toxicity is recommended during initiation and dose adjustments of thiazide diuretics.

Nonsteroidal anti-inflammatory drugs can decrease the natriuretic, diuretic, and antihypertensive effects of both hydrochlorothiazide and chlorthalidone.⁴⁷

Renin-angiotensin-aldosterone system antagonists, ie, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and the renin inhibitor aliskiren, have potentially beneficial interactions with hydrochlorothiazide and chlorthalidone, producing additive decreases in blood pressure when coadministered with these diuretics. These effects may be particularly potent early in concomitant therapy and allow use of lower doses of diuretics, typically 12.5 mg of hydrochlorothiazide in combination therapy.

LONG-TERM EFFECTS ON CARDIOVASCULAR EVENTS

The long-term goal in treating hypertension is to lower the risk of cardiovascular disease. Therefore, the clinician needs to consider the effect of antihypertensive drug therapy on long-term clinical outcomes.

Antihypertensive drug therapy based on thiazide diuretics has been shown to lower cardiovascular risk when compared with placebo.⁴⁸ In addition, the effect of chlorthalidone-based antihypertensive therapy was similar to that of other antihypertensive drug classes in preventing most cardiovascular outcomes in ALLHAT.⁴

However, no study has directly compared hydrochlorothiazide and chlorthalidone with the primary outcome of reduction in long-term cardiovascular events. The data to date come from observational studies and meta-analyses. For example, in a retrospective analysis of the Multiple Risk Factor Intervention Trial, cardiovascular events were significantly fewer in those receiving chlorthalidone vs hydrochlorothiazide (P = .0016).⁴³

In a systematic review and meta-analysis, chlorthalidone was associated with a 23% lower risk of heart failure and a 21% lower risk of all cardiovascular events.⁴⁹

However, a Canadian observational study of 29,873 patients found no difference in the composite outcome of death or hospitalization for heart failure, stroke, or myocardial infarction between chlorthalidone recipients (3.2 events per 100 person-years) and hydrochlorothiazide recipients (3.4 events per 100 person-years; adjusted hazard ratio 0.93, 95% confidence interval 0.81–1.06).⁵⁰

In summary, it is unclear whether chlorthalidone or hydrochlorothiazide is superior in preventing cardiovascular events.

SUMMARY

Thiazide and thiazidelike diuretics play an important role in managing hypertension in most patients. The eighth Joint National Committee guidelines do not recommend either hydrochlorothiazide or chlorthalidone over the other. The target dose recommendations are hydrochlorothiazide 25 to 50 mg or chlorthalidone 12.5 to 25 mg daily, with lower doses considered for the elderly.

There are important differences between hydrochlorothiazide and chlorthalidone in pharmacology, potency, and frequency of metabolic side effects. Clinicians should consider these factors to tailor the choice of thiazide diuretic therapy in hypertensive patients.

Patients with loss of bladder control experience discomfort, embarrassment, personal care and health issues, and, often, significant pain, all with a decidedly negative impact on quality of life. Although some patients may find lifestyle modifications, drug therapy, and self-catheterization acceptable and effective, there is a clear need for more options.

Botulinum toxin, or onabotulinumtoxinA, is currently approved by the US Food and Drug Administration (FDA) for neurogenic detrusor overactivity and overactive bladder refractory to drug therapy. Studies so far have shown botulinum toxin injection to be safe and effective for these conditions, and these results have led to interest in off-label uses, eg, for detrusor external sphincter dyssynergia (DESD), motor and sensory urgency, and painful bladder syndrome/interstitial cystitis (Table 1).

Although more data from clinical trials are needed, botulinum toxin injection offers patients a much-needed treatment option.

HOW BOTULINUM TOXIN WORKS

Seven serotypes identified

Discovered in 1897, botulinum toxin is a neurotoxin produced by the gram-positive, rod-shaped anaerobic bacterium Clostridium botulinum¹ and is the most poisonous naturally occurring toxin known.² Seven immunologically distinct antigenic serotypes have been identified (A, B, C1, D, E, F, and G),¹ but only types A and B are available for clinical use.

Most research into potential therapeutic uses has focused on type A, which has the longest duration of action, a clinical advantage.³ Recently, work has been done to further characterize other serotypes and to isolate additional variants of botulinum toxin. For example, serotype E, the predominant serotype associated with foodborne botulism, is being studied in an effort to prevent future outbreaks.⁴

Our discussion focuses on clinical uses of the serotype A botulinum toxin preparation, which we will refer to simply as botulinum toxin.

Studies exploring how it works

Botulinum toxin exerts its effects by binding to peripheral cholinergic terminals, inhibiting release of acetylcholine at the neuromuscular junction. Flaccid paralysis ensues as a result.

Results of animal studies have shed additional light on the specific actions of botulinum toxin A:

• It may alter levels of nerve growth factor and transient receptor potential vanilloid 1 in rats, and this may provide an additional mechanism of reducing bladder detrusor overactivity.⁵
• In addition to blocking acetylcholine release from motor neurons, it inhibits the release of neurotransmitters involved in bladder sensory afferent pathways.⁶
• It inhibits the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.^6,7
• It promotes apoptosis in prostatic tissue; however, this effect has not been shown in the bladder.³

The time necessary to recover function after botulinum toxin paralysis depends on the subtype of botulinum toxin as well as on the type of nerve terminal. Chemodenervation lasts from 3 to 6 months when the toxin is injected into the neuromuscular junction of skeletal muscle, and considerably longer (up to 1 year) when injected into the autonomic neurons of smooth muscle.^2,6

TREATMENT OF NEUROGENIC DETRUSOR OVERACTIVITY

Neurogenic detrusor overactivity involves involuntary contractions of the bladder resulting from spinal cord injury, multiple sclerosis, and other neurologic conditions. An estimated 273,000 people in the United States have a spinal cord injury, and 81% of them have urologic symptoms ranging from areflexia to overactivity.⁸ From 75% to 100% of patients with multiple sclerosis have urologic symptoms, and detrusor overactivity is the most common.⁹

Detrusor overactivity can cause urinary urgency, urinary frequency, and urgency incontinence, significantly affecting quality of life and leading to skin breakdown, sacral ulcerations, and challenges with personal care.

Anticholinergic drugs have been the mainstay of therapy. If drug therapy failed, the next option was reconstructive surgery, often augmentation cystoplasty. Thus, botulinum toxin injection is an important advance in treatment options.

Studies that showed effectiveness

Botulinum toxin for neurogenic detrusor overactivity was first studied by Schurch et al.¹⁰ In their study, 200 U or 300 U was injected into the trigone of 21 patients with spinal cord injury and urgency incontinence managed with intermittent self-catheterization.¹⁰ At 6 weeks after injection, 17 of the 19 patients seen at follow-up visits were completely continent. Urodynamic evaluation revealed significant increases in maximum cystometric capacity and in volume at first involuntary detrusor contraction, and a decrease in detrusor voiding pressure. Of the 11 patients available for follow-up at 16 and 36 weeks, improvements in measures of incontinence and urodynamic function persisted.

In addition, two small randomized controlled trials^11,12 showed significant increases in cystometric bladder capacity, significant improvement in quality-of-life measures, and reduction in episodes of urgency incontinence.

In 2011 and 2012, two multicenter double-blind randomized controlled trials reported on patients with multiple sclerosis and spinal cord injury with neurogenic detrusor overactivity inadequately managed with drug therapy. The patients were randomized to botulinum toxin injection (200 U or 300 U) or placebo injection.^13,14 The primary end point for both studies was the change from baseline in episodes of urinary incontinence per week at week 6. Secondary end points were maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and score on the Incontinence Quality of Life scale.¹⁵

In both studies, the mean number of urinary incontinence episodes per week was 33 at baseline. At week 6, Cruz et al¹⁴ found that patients who received botulinum toxin injection had significantly fewer episodes per week (21.8 fewer with 200 U, 19.4 fewer with 300 U) than those in the placebo group, who had 13.2 fewer episodes per week (P < .01). Ginsberg et al¹³ reported decreases in the mean number of episodes of urinary incontinence of 21, 23, and 9 episodes per week in the 200 U, 300 U, and placebo groups, respectively (P < .001). The patients who received botulinum toxin had statistically significant improvements in maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and Incontinence Quality of Life scores compared with placebo (P < .001). Thirty-eight percent of patients in the treatment group were fully continent.^13,14

Safety and adverse effects

The most frequently reported adverse events were urinary tract infection (24% of patients)^13,14 and urinary retention requiring initiation of clean intermittent catheterization. In the study by Cruz et al,¹⁴ these were reported in 30% with 200 U, 42% with 300 U, and 12% with placebo, while in the study by Ginsberg et al¹³ they were reported in 35% with 200 U, 42% with 300 U, and 10% with placebo.

In a study of long-term safety and efficacy of botulinum toxin injection in patients with neurogenic detrusor overactivity, Kennelly et al¹⁶ found that patients undergoing repeat injections had sustained reductions in episodes of incontinence and increases in the maximum cystometric capacity and quality of life scores, with no increase in adverse events over time.¹⁶

But is it cost-effective?

While botulinum toxin injection may be safe and effective for neurogenic detrusor overactivity, is it cost-effective?

Carlson et al¹⁷ used a Markov State Transition model to assess the cost of refractory neurogenic detrusor overactivity in patients receiving botulinum toxin vs best supportive care (incontinence pads, medications, intermittent self-catheterization).¹⁷ They found that the injections were more expensive than supportive care but were cost-effective when considering the reduction in episodes of incontinence, the reduced need for incontinence products, and improvement in measures of quality of life.

What the evidence indicates

Trials of botulinum toxin injection for neurogenic detrusor overactivity have shown that it improves continence, maximum cystometric capacity, detrusor pressures, and quality of life. The main adverse effects are urinary tract infection and urinary retention requiring intermittent self-catheterization.

Although many patients with this condition are already self-catheterizing, the physician must discuss this before botulinum toxin therapy to ensure that the patient or a family member is able to perform catheterization. Studies have shown that patients have an increase in urinary tract infections after botulinum injections. But in these studies, a urinary tract infection was defined as 100,000 colony-forming units or the presence of leukocytosis with or without symptoms. It is important to remember that patients on intermittent catheterization have bacteriuria and should be treated only for symptomatic, not asymptomatic, bacteriuria.

TREATMENT OF IDIOPATHIC OVERACTIVE BLADDER

Patients with idiopathic overactive bladder have urinary urgency accompanied by urgency incontinence, nocturia, or urinary frequency.¹⁸ The prevalence of this condition has been reported to range from 1.7% to 13.3% in men age 30 and older and 7% to 30.3% in women of similar ages. About one-third of women with overactive bladder also have detrusor overactivity.¹⁹ Overactive bladder presents a significant economic and medical burden on the healthcare system, as well as having a negative impact on quality of life.

The FDA approved botulinum toxin injection for treatment of idiopathic overactive bladder in January 2013.

Evidence of effectiveness

Two multicenter randomized controlled trials^20,21 of botulinum toxin 100 U enrolled patients age 18 and older who had more than three episodes of urinary urgency incontinence in a 3-day period or more than eight micturitions per day inadequately managed by anticholinergic drug therapy. Primary end points were the change from baseline in the number of episodes of urinary incontinence per day and the proportion of patients with a positive response on the Treatment Benefit Scale²² at week 12. Secondary end points included episodes of urinary urgency incontinence, micturition, urgency, and nocturia, and scores on health-related quality of life questionnaires (Incontinence Quality of Life scale, King’s Health Questionnaire).

In both studies, patients receiving botulinum toxin had significantly fewer episodes of incontinence compared with placebo (−2.65 vs −0.87; P < .001 and −2.95 vs −1.03; P < .001).^20,21 Reductions from baseline in all other symptoms of overactive bladder, a positive treatment response on the treatment benefit scale, and improvements in quality-of-life scores were also significantly greater with botulinum toxin injection than with placebo (P ≤ .01).

As in the studies of neurogenic detrusor overactivity, the most common adverse effects were urinary tract infection (occurring in 15.5%²⁰ and 24.1%²¹ of patients) and urinary retention requiring self-catheterization (5.4%²⁰ and 6.9%²¹).

The largest study to date of anticholinergic therapy vs botulinum toxin injection²³ in women with urinary urgency incontinence, published in 2012, studied nearly 250 women who had five or more episodes of idiopathic urgency incontinence in a 3-day period. They were randomized either to daily oral therapy (solifenacin 5 mg with possible escalation to 10 mg and, if necessary, a subsequent switch to extended-release trospium 60 mg) plus one intradetrusor injection of saline, or to a daily oral placebo plus one injection of botulinum toxin 100 U.²³

The dropout rate was low in both groups, with 93% of patients in both groups completing the 6-month protocol. Women experienced a mean reduction in urgency incontinence episodes of 3.4 per day (baseline 5) in the anticholinergic group vs 3.3 episodes in the botulinum toxin group (P = .81). However, more patients achieved complete resolution of urinary urgency incontinence in the botulinum toxin group than in the anticholinergic therapy group (27% vs 13%; P = .003). Quality of life improved in both groups without a significant difference between the groups. The botulinum toxin group had higher rates of initiation of self-catheterization (5% vs 0%, P = .01) and urinary tract infection (33% vs 13%, P < .001).²³

Botulinum toxin as a third-line therapy

In May 2014, the American Urological Association updated its guidelines on idiopathic overactive bladder²⁴ to include botulinum toxin injection as standard third-line therapy for patients in whom behavioral and medical management (ie, anticholinergics and beta-3-agonists) failed.

Interpreting the evidence to date

Overall, studies in idiopathic overactive bladder have shown a reduction in episodes of urgency incontinence and other symptoms, with some data also demonstrating a corresponding improvement in quality of life.

As in neurogenic detrusor overactivity, the main risks associated with botulinum toxin injection are urinary tract infection and the need to initiate self-catheterization. Although 94% of patients studied did not require self-catheterization after injection, the patient’s ability to perform self-catheterization should be determined before proceeding with botulinum toxin injections.

DETRUSOR EXTERNAL SPHINCTER DYSSYNERGIA

Botulinum toxin has been used not only to improve bladder storage but also to facilitate bladder emptying, as in patients with DESD, a lack of coordination between the bladder and the urinary sphincter. Normal voiding involves relaxation of the urinary sphincter and contraction of the bladder; in DESD the sphincter contracts and works against the bladder’s ability to empty. This leads not only to difficulty emptying the bladder but also to elevated bladder pressure, which can cause renal damage if untreated.

DESD can be seen after injury between the pontine micturition center, which coordinates activity between the bladder and the sphincter, and the caudal spinal cord. This can occur in spinal cord injury, multiple sclerosis, myelomeningocele, and transverse myelitis and can cause significant morbidity for the patient.

Treatment options include drug therapy, injection of botulinum toxin into the sphincter, clean intermittent catheterization, indwelling catheterization, urethral stenting, sphincterotomy, and reconstructive surgery such as urinary diversion.²⁵

The goals of therapy are to avoid the need for clean intermittent catheterization in patients who have difficulty with manual dexterity, and to avoid the need for surgical procedures such as sphincterotomy and urinary diversion. The efficacy of urethral stenting is low, and medical management can be limited.²⁶

DESD leads to difficulty emptying the bladder, elevated bladder pressure, and, if untreated, renal damage

In the first published report on botulinum toxin for DESD (in 1988),²⁷ of 11 patients with spinal cord injury and DESD who received botulinum toxin injected into the external urethral sphincter, 10 showed signs of sphincter denervation on electromyography and reductions in urethral pressure profiles and postvoid residual volumes. Schurch et al²⁸ and de Sèze et al²⁹ also reported reductions in postvoid residual volume and maximal urethral pressures in patients with spinal cord injury and DESD.

In 2005, Gallien et al³⁰ reported what is still the largest multicenter randomized controlled trial of botulinum toxin injection in DESD. Eighty-six patients with multiple sclerosis, DESD, and chronic urinary retention were randomized to receive either a single transperineal botulinum toxin injection of 100 U plus the alpha-1-blocker alfuzosin, or a placebo injection plus alfuzosin. Botulinum toxin treatment was associated with significantly increased voided volumes and reduced premicturition and maximal detrusor pressures, but no significant decrease in postvoid residual volume.³⁰

More study needed

Despite these findings, a Cochrane Review concluded that, given the limited experience with intrasphincteric injection of botulinum toxin, data from larger randomized controlled trials are needed before making definitive recommendations.²⁵ In the meantime, the clinician must weigh the low morbidity of the procedure against the limited options in the treatment of these patients.

OFF-LABEL UROLOGIC INDICATIONS

Botulinum toxin injection has been studied off-label for painful bladder syndrome/interstitial cystitis and for chronic prostatic pain. Patients with these conditions often describe pain with filling of the bladder, which leads to urinary frequency in an attempt to relieve the pain.

These pain syndromes can be difficult to treat and can have a devastating impact on quality of life. Treatment options include pain management, stress management, physical therapy, intravesical therapies, cystoscopy with hydrodistention, neuromodulation, cyclosporine, urinary diversion surgery, and botulinum toxin injection (an off-label use).³¹

In painful bladder syndrome/interstitial cystitis, botulinum toxin is thought to act on sensory afferent pathways, as well as to inhibit the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.⁶ In animal studies,³² botulinum toxin was found to inhibit the afferent neural response by inhibiting mechanoreceptor-mediated release of adenosine triphosphate and by causing a decrease in calcitonin gene-related peptide, which helps regulate micturition and mediates painful bladder sensation.

Clinical studies to date in pelvic pain syndromes

Data from clinical studies of botulinum toxin injection for pelvic pain syndromes are limited. Zermann et al³³ performed transurethral perisphincteric injection in 11 men with chronic prostatic pain, 9 of whom reported subjective pain relief, with an average decrease from 7.2 to 1.6 on a visual analogue scale. Postinjection urodynamic studies showed a decrease in functional urethral length, urethral closure pressure, and postvoid residual volume, and an increase in the peak and average flow rates.³³

Abbott et al³⁴ evaluated the effect of botulinum toxin injection into the levator ani in 12 women with chronic pelvic pain and pelvic floor hypertonicity. Pelvic floor manometry showed significant reduction in resting muscle pressures and improvements in dyspareunia and nonmenstrual pain. There were also improvements in quality of life and dyschezia, but these were not statistically significant.

Smith et al³⁵ injected botulinum toxin into the detrusor of 13 women with refractory painful bladder syndrome and interstitial cystitis,³⁵ and 9 women (69%) noted statistically significant improvements in the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index, daytime frequency, nocturia, pain, and urodynamic parameters (volume at first desire to void, and maximum cystometric capacity).

In a prospective randomized study of patients with refractory painful bladder syndrome and interstitial cystitis, Kuo and Chancellor³⁶ compared suburothelial injection of 200 U or 100 U of botulinum toxin plus hydrodistention against hydrodistention alone.Patients who received botulinum toxin had increased bladder capacity and improved long-term pain relief, but no difference was noted between 200 U and 100 U, and more adverse effects were seen with the higher dose.³⁶

Pinto et al³⁷ treated 16 women with refractory painful bladder syndrome and interstitial cystitis with intratrigonal injections of botulinum toxin and reported improvements in pain scores, symptom scores, urinary frequency, and quality-of-life measures. The effect lasted 9.9 months (± 2.4 months) and persisted with successive injections.³⁷

More study needed

Although these studies show that botulinum toxin injection for pelvic pain syndromes has the potential to improve pain, urinary frequency, bladder sensation, bladder capacity, and quality of life, larger randomized controlled trials are needed.

Again, the treatment options are limited for refractory painful bladder syndrome and interstitial cystitis. Patients may be desperate for relief from their symptoms. Practitioners must manage expectations and properly inform patients of the potential risks of treatments, especially with patients who will easily agree to further treatment with the smallest hope of relief.

INJECTION TECHNIQUES

For general points about the procedure to discuss with patients, see “What to tell patients.”

Cystoscopic detrusor injection

This procedure is usually done on an outpatient basis (eg, office, ambulatory surgery center). With the patient in the lithotomy position, 100 mL of 2% lidocaine is instilled into the bladder and is allowed 15 to 20 minutes to take effect. A flexible or rigid cystoscope can be used. Depending on the indication, the bladder is injected with 100 U to 300 U of botulinum toxin. The ideal depth of injection is 2 mm in the detrusor muscle, with each injection spaced about 1 cm apart. The recommended administration for 100 U is to inject 20 sites with 0.5 U per mL of saline and, for 200 U, to inject 30 sites with about 0.67 U per mL of saline.³⁸ The location of the injections into the detrusor can vary, as long as adequate spacing is assured.

Injection sites vary. Proponents of injecting the trigone argue that as it is an area of greater nerve density, patients will have a better clinical response. Opponents argue that trigonal injection could result in distal ureteral paralysis and subsequent ureteral reflux. However, this theoretical concern has not been observed clinically.

Urethral injection (off-label use)

The urethra can be injected cystoscopically or periurethrally. Cystoscopic injection involves localization of the external sphincter using the rigid cystoscope and collagen needle; a total of 100 U is injected into the sphincter under direct vision, typically at the 3 o’clock and 9 o’clock positions.³⁵ The periurethral technique is an option in women and involves a spinal needle with 100 U to 200 U of botulinum toxin injected into the external sphincter muscle at the 2 o’clock and 10 o’clock positions.

ADVERSE EFFECTS AND CONTRAINDICATIONS

Adverse effects are rare for urologic applications. The injections are localized, with little systemic absorption, and the doses are 1/1,000th of the theorized lethal dose in a 70-kg male.² The maximum recommended dose for a 3-month period is 360 U.

Generalized muscle weakness has been reported in a paraplegic patient and in a tetraplegic patient after detrusor injections.² Interestingly, both patients had return of bladder spasticity within 2 months, prompting speculation about diffusion of botulinum toxin through the bladder wall.²

Repeat injections can cause an immune response in up to 5% of patients.⁶ Patients undergoing repeat injections are at risk of forming neutralizing antibodies that can interfere with the efficacy of botulinum toxin.⁶ In a study by Schulte-Baukloh et al, all patients with antibodies to botulinum toxin had a history of recurrent urinary tract infection.³⁹

Botulinum toxin injection is contraindicated in patients with preexisting neuromuscular disease, such as myasthenia gravis, Eaton-Lambert syndrome, and amyotrophic lateral sclerosis. It should also be avoided in patients who are breastfeeding, pregnant, or using agents that potentiate neuromuscular weakness, such as aminoglycosides.

Patients should be informed that some formulations of botulinum toxin include a stabilizer such as albumin derived from human blood, as this may be of religious or cultural significance.

Patients with loss of bladder control experience discomfort, embarrassment, personal care and health issues, and, often, significant pain, all with a decidedly negative impact on quality of life. Although some patients may find lifestyle modifications, drug therapy, and self-catheterization acceptable and effective, there is a clear need for more options.

Botulinum toxin, or onabotulinumtoxinA, is currently approved by the US Food and Drug Administration (FDA) for neurogenic detrusor overactivity and overactive bladder refractory to drug therapy. Studies so far have shown botulinum toxin injection to be safe and effective for these conditions, and these results have led to interest in off-label uses, eg, for detrusor external sphincter dyssynergia (DESD), motor and sensory urgency, and painful bladder syndrome/interstitial cystitis (Table 1).

Although more data from clinical trials are needed, botulinum toxin injection offers patients a much-needed treatment option.

HOW BOTULINUM TOXIN WORKS

Seven serotypes identified

Discovered in 1897, botulinum toxin is a neurotoxin produced by the gram-positive, rod-shaped anaerobic bacterium Clostridium botulinum¹ and is the most poisonous naturally occurring toxin known.² Seven immunologically distinct antigenic serotypes have been identified (A, B, C1, D, E, F, and G),¹ but only types A and B are available for clinical use.

Most research into potential therapeutic uses has focused on type A, which has the longest duration of action, a clinical advantage.³ Recently, work has been done to further characterize other serotypes and to isolate additional variants of botulinum toxin. For example, serotype E, the predominant serotype associated with foodborne botulism, is being studied in an effort to prevent future outbreaks.⁴

Our discussion focuses on clinical uses of the serotype A botulinum toxin preparation, which we will refer to simply as botulinum toxin.

Studies exploring how it works

Botulinum toxin exerts its effects by binding to peripheral cholinergic terminals, inhibiting release of acetylcholine at the neuromuscular junction. Flaccid paralysis ensues as a result.

Results of animal studies have shed additional light on the specific actions of botulinum toxin A:

• It may alter levels of nerve growth factor and transient receptor potential vanilloid 1 in rats, and this may provide an additional mechanism of reducing bladder detrusor overactivity.⁵
• In addition to blocking acetylcholine release from motor neurons, it inhibits the release of neurotransmitters involved in bladder sensory afferent pathways.⁶
• It inhibits the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.^6,7
• It promotes apoptosis in prostatic tissue; however, this effect has not been shown in the bladder.³

The time necessary to recover function after botulinum toxin paralysis depends on the subtype of botulinum toxin as well as on the type of nerve terminal. Chemodenervation lasts from 3 to 6 months when the toxin is injected into the neuromuscular junction of skeletal muscle, and considerably longer (up to 1 year) when injected into the autonomic neurons of smooth muscle.^2,6

TREATMENT OF NEUROGENIC DETRUSOR OVERACTIVITY

Neurogenic detrusor overactivity involves involuntary contractions of the bladder resulting from spinal cord injury, multiple sclerosis, and other neurologic conditions. An estimated 273,000 people in the United States have a spinal cord injury, and 81% of them have urologic symptoms ranging from areflexia to overactivity.⁸ From 75% to 100% of patients with multiple sclerosis have urologic symptoms, and detrusor overactivity is the most common.⁹

Detrusor overactivity can cause urinary urgency, urinary frequency, and urgency incontinence, significantly affecting quality of life and leading to skin breakdown, sacral ulcerations, and challenges with personal care.

Anticholinergic drugs have been the mainstay of therapy. If drug therapy failed, the next option was reconstructive surgery, often augmentation cystoplasty. Thus, botulinum toxin injection is an important advance in treatment options.

Studies that showed effectiveness

Botulinum toxin for neurogenic detrusor overactivity was first studied by Schurch et al.¹⁰ In their study, 200 U or 300 U was injected into the trigone of 21 patients with spinal cord injury and urgency incontinence managed with intermittent self-catheterization.¹⁰ At 6 weeks after injection, 17 of the 19 patients seen at follow-up visits were completely continent. Urodynamic evaluation revealed significant increases in maximum cystometric capacity and in volume at first involuntary detrusor contraction, and a decrease in detrusor voiding pressure. Of the 11 patients available for follow-up at 16 and 36 weeks, improvements in measures of incontinence and urodynamic function persisted.

In addition, two small randomized controlled trials^11,12 showed significant increases in cystometric bladder capacity, significant improvement in quality-of-life measures, and reduction in episodes of urgency incontinence.

In 2011 and 2012, two multicenter double-blind randomized controlled trials reported on patients with multiple sclerosis and spinal cord injury with neurogenic detrusor overactivity inadequately managed with drug therapy. The patients were randomized to botulinum toxin injection (200 U or 300 U) or placebo injection.^13,14 The primary end point for both studies was the change from baseline in episodes of urinary incontinence per week at week 6. Secondary end points were maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and score on the Incontinence Quality of Life scale.¹⁵

In both studies, the mean number of urinary incontinence episodes per week was 33 at baseline. At week 6, Cruz et al¹⁴ found that patients who received botulinum toxin injection had significantly fewer episodes per week (21.8 fewer with 200 U, 19.4 fewer with 300 U) than those in the placebo group, who had 13.2 fewer episodes per week (P < .01). Ginsberg et al¹³ reported decreases in the mean number of episodes of urinary incontinence of 21, 23, and 9 episodes per week in the 200 U, 300 U, and placebo groups, respectively (P < .001). The patients who received botulinum toxin had statistically significant improvements in maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and Incontinence Quality of Life scores compared with placebo (P < .001). Thirty-eight percent of patients in the treatment group were fully continent.^13,14

Safety and adverse effects

The most frequently reported adverse events were urinary tract infection (24% of patients)^13,14 and urinary retention requiring initiation of clean intermittent catheterization. In the study by Cruz et al,¹⁴ these were reported in 30% with 200 U, 42% with 300 U, and 12% with placebo, while in the study by Ginsberg et al¹³ they were reported in 35% with 200 U, 42% with 300 U, and 10% with placebo.

In a study of long-term safety and efficacy of botulinum toxin injection in patients with neurogenic detrusor overactivity, Kennelly et al¹⁶ found that patients undergoing repeat injections had sustained reductions in episodes of incontinence and increases in the maximum cystometric capacity and quality of life scores, with no increase in adverse events over time.¹⁶

But is it cost-effective?

While botulinum toxin injection may be safe and effective for neurogenic detrusor overactivity, is it cost-effective?

Carlson et al¹⁷ used a Markov State Transition model to assess the cost of refractory neurogenic detrusor overactivity in patients receiving botulinum toxin vs best supportive care (incontinence pads, medications, intermittent self-catheterization).¹⁷ They found that the injections were more expensive than supportive care but were cost-effective when considering the reduction in episodes of incontinence, the reduced need for incontinence products, and improvement in measures of quality of life.

What the evidence indicates

Trials of botulinum toxin injection for neurogenic detrusor overactivity have shown that it improves continence, maximum cystometric capacity, detrusor pressures, and quality of life. The main adverse effects are urinary tract infection and urinary retention requiring intermittent self-catheterization.

Although many patients with this condition are already self-catheterizing, the physician must discuss this before botulinum toxin therapy to ensure that the patient or a family member is able to perform catheterization. Studies have shown that patients have an increase in urinary tract infections after botulinum injections. But in these studies, a urinary tract infection was defined as 100,000 colony-forming units or the presence of leukocytosis with or without symptoms. It is important to remember that patients on intermittent catheterization have bacteriuria and should be treated only for symptomatic, not asymptomatic, bacteriuria.

TREATMENT OF IDIOPATHIC OVERACTIVE BLADDER

Patients with idiopathic overactive bladder have urinary urgency accompanied by urgency incontinence, nocturia, or urinary frequency.¹⁸ The prevalence of this condition has been reported to range from 1.7% to 13.3% in men age 30 and older and 7% to 30.3% in women of similar ages. About one-third of women with overactive bladder also have detrusor overactivity.¹⁹ Overactive bladder presents a significant economic and medical burden on the healthcare system, as well as having a negative impact on quality of life.

The FDA approved botulinum toxin injection for treatment of idiopathic overactive bladder in January 2013.

Evidence of effectiveness

Two multicenter randomized controlled trials^20,21 of botulinum toxin 100 U enrolled patients age 18 and older who had more than three episodes of urinary urgency incontinence in a 3-day period or more than eight micturitions per day inadequately managed by anticholinergic drug therapy. Primary end points were the change from baseline in the number of episodes of urinary incontinence per day and the proportion of patients with a positive response on the Treatment Benefit Scale²² at week 12. Secondary end points included episodes of urinary urgency incontinence, micturition, urgency, and nocturia, and scores on health-related quality of life questionnaires (Incontinence Quality of Life scale, King’s Health Questionnaire).

In both studies, patients receiving botulinum toxin had significantly fewer episodes of incontinence compared with placebo (−2.65 vs −0.87; P < .001 and −2.95 vs −1.03; P < .001).^20,21 Reductions from baseline in all other symptoms of overactive bladder, a positive treatment response on the treatment benefit scale, and improvements in quality-of-life scores were also significantly greater with botulinum toxin injection than with placebo (P ≤ .01).

As in the studies of neurogenic detrusor overactivity, the most common adverse effects were urinary tract infection (occurring in 15.5%²⁰ and 24.1%²¹ of patients) and urinary retention requiring self-catheterization (5.4%²⁰ and 6.9%²¹).

The largest study to date of anticholinergic therapy vs botulinum toxin injection²³ in women with urinary urgency incontinence, published in 2012, studied nearly 250 women who had five or more episodes of idiopathic urgency incontinence in a 3-day period. They were randomized either to daily oral therapy (solifenacin 5 mg with possible escalation to 10 mg and, if necessary, a subsequent switch to extended-release trospium 60 mg) plus one intradetrusor injection of saline, or to a daily oral placebo plus one injection of botulinum toxin 100 U.²³

The dropout rate was low in both groups, with 93% of patients in both groups completing the 6-month protocol. Women experienced a mean reduction in urgency incontinence episodes of 3.4 per day (baseline 5) in the anticholinergic group vs 3.3 episodes in the botulinum toxin group (P = .81). However, more patients achieved complete resolution of urinary urgency incontinence in the botulinum toxin group than in the anticholinergic therapy group (27% vs 13%; P = .003). Quality of life improved in both groups without a significant difference between the groups. The botulinum toxin group had higher rates of initiation of self-catheterization (5% vs 0%, P = .01) and urinary tract infection (33% vs 13%, P < .001).²³

Botulinum toxin as a third-line therapy

In May 2014, the American Urological Association updated its guidelines on idiopathic overactive bladder²⁴ to include botulinum toxin injection as standard third-line therapy for patients in whom behavioral and medical management (ie, anticholinergics and beta-3-agonists) failed.

Interpreting the evidence to date

Overall, studies in idiopathic overactive bladder have shown a reduction in episodes of urgency incontinence and other symptoms, with some data also demonstrating a corresponding improvement in quality of life.

As in neurogenic detrusor overactivity, the main risks associated with botulinum toxin injection are urinary tract infection and the need to initiate self-catheterization. Although 94% of patients studied did not require self-catheterization after injection, the patient’s ability to perform self-catheterization should be determined before proceeding with botulinum toxin injections.

DETRUSOR EXTERNAL SPHINCTER DYSSYNERGIA

Botulinum toxin has been used not only to improve bladder storage but also to facilitate bladder emptying, as in patients with DESD, a lack of coordination between the bladder and the urinary sphincter. Normal voiding involves relaxation of the urinary sphincter and contraction of the bladder; in DESD the sphincter contracts and works against the bladder’s ability to empty. This leads not only to difficulty emptying the bladder but also to elevated bladder pressure, which can cause renal damage if untreated.

DESD can be seen after injury between the pontine micturition center, which coordinates activity between the bladder and the sphincter, and the caudal spinal cord. This can occur in spinal cord injury, multiple sclerosis, myelomeningocele, and transverse myelitis and can cause significant morbidity for the patient.

Treatment options include drug therapy, injection of botulinum toxin into the sphincter, clean intermittent catheterization, indwelling catheterization, urethral stenting, sphincterotomy, and reconstructive surgery such as urinary diversion.²⁵

The goals of therapy are to avoid the need for clean intermittent catheterization in patients who have difficulty with manual dexterity, and to avoid the need for surgical procedures such as sphincterotomy and urinary diversion. The efficacy of urethral stenting is low, and medical management can be limited.²⁶

DESD leads to difficulty emptying the bladder, elevated bladder pressure, and, if untreated, renal damage

In the first published report on botulinum toxin for DESD (in 1988),²⁷ of 11 patients with spinal cord injury and DESD who received botulinum toxin injected into the external urethral sphincter, 10 showed signs of sphincter denervation on electromyography and reductions in urethral pressure profiles and postvoid residual volumes. Schurch et al²⁸ and de Sèze et al²⁹ also reported reductions in postvoid residual volume and maximal urethral pressures in patients with spinal cord injury and DESD.

In 2005, Gallien et al³⁰ reported what is still the largest multicenter randomized controlled trial of botulinum toxin injection in DESD. Eighty-six patients with multiple sclerosis, DESD, and chronic urinary retention were randomized to receive either a single transperineal botulinum toxin injection of 100 U plus the alpha-1-blocker alfuzosin, or a placebo injection plus alfuzosin. Botulinum toxin treatment was associated with significantly increased voided volumes and reduced premicturition and maximal detrusor pressures, but no significant decrease in postvoid residual volume.³⁰

More study needed

Despite these findings, a Cochrane Review concluded that, given the limited experience with intrasphincteric injection of botulinum toxin, data from larger randomized controlled trials are needed before making definitive recommendations.²⁵ In the meantime, the clinician must weigh the low morbidity of the procedure against the limited options in the treatment of these patients.

OFF-LABEL UROLOGIC INDICATIONS

Botulinum toxin injection has been studied off-label for painful bladder syndrome/interstitial cystitis and for chronic prostatic pain. Patients with these conditions often describe pain with filling of the bladder, which leads to urinary frequency in an attempt to relieve the pain.

These pain syndromes can be difficult to treat and can have a devastating impact on quality of life. Treatment options include pain management, stress management, physical therapy, intravesical therapies, cystoscopy with hydrodistention, neuromodulation, cyclosporine, urinary diversion surgery, and botulinum toxin injection (an off-label use).³¹

In painful bladder syndrome/interstitial cystitis, botulinum toxin is thought to act on sensory afferent pathways, as well as to inhibit the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.⁶ In animal studies,³² botulinum toxin was found to inhibit the afferent neural response by inhibiting mechanoreceptor-mediated release of adenosine triphosphate and by causing a decrease in calcitonin gene-related peptide, which helps regulate micturition and mediates painful bladder sensation.

Clinical studies to date in pelvic pain syndromes

Data from clinical studies of botulinum toxin injection for pelvic pain syndromes are limited. Zermann et al³³ performed transurethral perisphincteric injection in 11 men with chronic prostatic pain, 9 of whom reported subjective pain relief, with an average decrease from 7.2 to 1.6 on a visual analogue scale. Postinjection urodynamic studies showed a decrease in functional urethral length, urethral closure pressure, and postvoid residual volume, and an increase in the peak and average flow rates.³³

Abbott et al³⁴ evaluated the effect of botulinum toxin injection into the levator ani in 12 women with chronic pelvic pain and pelvic floor hypertonicity. Pelvic floor manometry showed significant reduction in resting muscle pressures and improvements in dyspareunia and nonmenstrual pain. There were also improvements in quality of life and dyschezia, but these were not statistically significant.

Smith et al³⁵ injected botulinum toxin into the detrusor of 13 women with refractory painful bladder syndrome and interstitial cystitis,³⁵ and 9 women (69%) noted statistically significant improvements in the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index, daytime frequency, nocturia, pain, and urodynamic parameters (volume at first desire to void, and maximum cystometric capacity).

In a prospective randomized study of patients with refractory painful bladder syndrome and interstitial cystitis, Kuo and Chancellor³⁶ compared suburothelial injection of 200 U or 100 U of botulinum toxin plus hydrodistention against hydrodistention alone.Patients who received botulinum toxin had increased bladder capacity and improved long-term pain relief, but no difference was noted between 200 U and 100 U, and more adverse effects were seen with the higher dose.³⁶

Pinto et al³⁷ treated 16 women with refractory painful bladder syndrome and interstitial cystitis with intratrigonal injections of botulinum toxin and reported improvements in pain scores, symptom scores, urinary frequency, and quality-of-life measures. The effect lasted 9.9 months (± 2.4 months) and persisted with successive injections.³⁷

More study needed

Although these studies show that botulinum toxin injection for pelvic pain syndromes has the potential to improve pain, urinary frequency, bladder sensation, bladder capacity, and quality of life, larger randomized controlled trials are needed.

Again, the treatment options are limited for refractory painful bladder syndrome and interstitial cystitis. Patients may be desperate for relief from their symptoms. Practitioners must manage expectations and properly inform patients of the potential risks of treatments, especially with patients who will easily agree to further treatment with the smallest hope of relief.

INJECTION TECHNIQUES

For general points about the procedure to discuss with patients, see “What to tell patients.”

Cystoscopic detrusor injection

This procedure is usually done on an outpatient basis (eg, office, ambulatory surgery center). With the patient in the lithotomy position, 100 mL of 2% lidocaine is instilled into the bladder and is allowed 15 to 20 minutes to take effect. A flexible or rigid cystoscope can be used. Depending on the indication, the bladder is injected with 100 U to 300 U of botulinum toxin. The ideal depth of injection is 2 mm in the detrusor muscle, with each injection spaced about 1 cm apart. The recommended administration for 100 U is to inject 20 sites with 0.5 U per mL of saline and, for 200 U, to inject 30 sites with about 0.67 U per mL of saline.³⁸ The location of the injections into the detrusor can vary, as long as adequate spacing is assured.

Injection sites vary. Proponents of injecting the trigone argue that as it is an area of greater nerve density, patients will have a better clinical response. Opponents argue that trigonal injection could result in distal ureteral paralysis and subsequent ureteral reflux. However, this theoretical concern has not been observed clinically.

Urethral injection (off-label use)

The urethra can be injected cystoscopically or periurethrally. Cystoscopic injection involves localization of the external sphincter using the rigid cystoscope and collagen needle; a total of 100 U is injected into the sphincter under direct vision, typically at the 3 o’clock and 9 o’clock positions.³⁵ The periurethral technique is an option in women and involves a spinal needle with 100 U to 200 U of botulinum toxin injected into the external sphincter muscle at the 2 o’clock and 10 o’clock positions.

ADVERSE EFFECTS AND CONTRAINDICATIONS

Adverse effects are rare for urologic applications. The injections are localized, with little systemic absorption, and the doses are 1/1,000th of the theorized lethal dose in a 70-kg male.² The maximum recommended dose for a 3-month period is 360 U.

Generalized muscle weakness has been reported in a paraplegic patient and in a tetraplegic patient after detrusor injections.² Interestingly, both patients had return of bladder spasticity within 2 months, prompting speculation about diffusion of botulinum toxin through the bladder wall.²

Repeat injections can cause an immune response in up to 5% of patients.⁶ Patients undergoing repeat injections are at risk of forming neutralizing antibodies that can interfere with the efficacy of botulinum toxin.⁶ In a study by Schulte-Baukloh et al, all patients with antibodies to botulinum toxin had a history of recurrent urinary tract infection.³⁹

Botulinum toxin injection is contraindicated in patients with preexisting neuromuscular disease, such as myasthenia gravis, Eaton-Lambert syndrome, and amyotrophic lateral sclerosis. It should also be avoided in patients who are breastfeeding, pregnant, or using agents that potentiate neuromuscular weakness, such as aminoglycosides.

Patients should be informed that some formulations of botulinum toxin include a stabilizer such as albumin derived from human blood, as this may be of religious or cultural significance.

Patients with loss of bladder control experience discomfort, embarrassment, personal care and health issues, and, often, significant pain, all with a decidedly negative impact on quality of life. Although some patients may find lifestyle modifications, drug therapy, and self-catheterization acceptable and effective, there is a clear need for more options.

Botulinum toxin, or onabotulinumtoxinA, is currently approved by the US Food and Drug Administration (FDA) for neurogenic detrusor overactivity and overactive bladder refractory to drug therapy. Studies so far have shown botulinum toxin injection to be safe and effective for these conditions, and these results have led to interest in off-label uses, eg, for detrusor external sphincter dyssynergia (DESD), motor and sensory urgency, and painful bladder syndrome/interstitial cystitis (Table 1).

Although more data from clinical trials are needed, botulinum toxin injection offers patients a much-needed treatment option.

HOW BOTULINUM TOXIN WORKS

Seven serotypes identified

Discovered in 1897, botulinum toxin is a neurotoxin produced by the gram-positive, rod-shaped anaerobic bacterium Clostridium botulinum¹ and is the most poisonous naturally occurring toxin known.² Seven immunologically distinct antigenic serotypes have been identified (A, B, C1, D, E, F, and G),¹ but only types A and B are available for clinical use.

Most research into potential therapeutic uses has focused on type A, which has the longest duration of action, a clinical advantage.³ Recently, work has been done to further characterize other serotypes and to isolate additional variants of botulinum toxin. For example, serotype E, the predominant serotype associated with foodborne botulism, is being studied in an effort to prevent future outbreaks.⁴

Our discussion focuses on clinical uses of the serotype A botulinum toxin preparation, which we will refer to simply as botulinum toxin.

Studies exploring how it works

Botulinum toxin exerts its effects by binding to peripheral cholinergic terminals, inhibiting release of acetylcholine at the neuromuscular junction. Flaccid paralysis ensues as a result.

Results of animal studies have shed additional light on the specific actions of botulinum toxin A:

• It may alter levels of nerve growth factor and transient receptor potential vanilloid 1 in rats, and this may provide an additional mechanism of reducing bladder detrusor overactivity.⁵
• In addition to blocking acetylcholine release from motor neurons, it inhibits the release of neurotransmitters involved in bladder sensory afferent pathways.⁶
• It inhibits the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.^6,7
• It promotes apoptosis in prostatic tissue; however, this effect has not been shown in the bladder.³

The time necessary to recover function after botulinum toxin paralysis depends on the subtype of botulinum toxin as well as on the type of nerve terminal. Chemodenervation lasts from 3 to 6 months when the toxin is injected into the neuromuscular junction of skeletal muscle, and considerably longer (up to 1 year) when injected into the autonomic neurons of smooth muscle.^2,6

TREATMENT OF NEUROGENIC DETRUSOR OVERACTIVITY

Neurogenic detrusor overactivity involves involuntary contractions of the bladder resulting from spinal cord injury, multiple sclerosis, and other neurologic conditions. An estimated 273,000 people in the United States have a spinal cord injury, and 81% of them have urologic symptoms ranging from areflexia to overactivity.⁸ From 75% to 100% of patients with multiple sclerosis have urologic symptoms, and detrusor overactivity is the most common.⁹

Detrusor overactivity can cause urinary urgency, urinary frequency, and urgency incontinence, significantly affecting quality of life and leading to skin breakdown, sacral ulcerations, and challenges with personal care.

Anticholinergic drugs have been the mainstay of therapy. If drug therapy failed, the next option was reconstructive surgery, often augmentation cystoplasty. Thus, botulinum toxin injection is an important advance in treatment options.

Studies that showed effectiveness

Botulinum toxin for neurogenic detrusor overactivity was first studied by Schurch et al.¹⁰ In their study, 200 U or 300 U was injected into the trigone of 21 patients with spinal cord injury and urgency incontinence managed with intermittent self-catheterization.¹⁰ At 6 weeks after injection, 17 of the 19 patients seen at follow-up visits were completely continent. Urodynamic evaluation revealed significant increases in maximum cystometric capacity and in volume at first involuntary detrusor contraction, and a decrease in detrusor voiding pressure. Of the 11 patients available for follow-up at 16 and 36 weeks, improvements in measures of incontinence and urodynamic function persisted.

In addition, two small randomized controlled trials^11,12 showed significant increases in cystometric bladder capacity, significant improvement in quality-of-life measures, and reduction in episodes of urgency incontinence.

In 2011 and 2012, two multicenter double-blind randomized controlled trials reported on patients with multiple sclerosis and spinal cord injury with neurogenic detrusor overactivity inadequately managed with drug therapy. The patients were randomized to botulinum toxin injection (200 U or 300 U) or placebo injection.^13,14 The primary end point for both studies was the change from baseline in episodes of urinary incontinence per week at week 6. Secondary end points were maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and score on the Incontinence Quality of Life scale.¹⁵

In both studies, the mean number of urinary incontinence episodes per week was 33 at baseline. At week 6, Cruz et al¹⁴ found that patients who received botulinum toxin injection had significantly fewer episodes per week (21.8 fewer with 200 U, 19.4 fewer with 300 U) than those in the placebo group, who had 13.2 fewer episodes per week (P < .01). Ginsberg et al¹³ reported decreases in the mean number of episodes of urinary incontinence of 21, 23, and 9 episodes per week in the 200 U, 300 U, and placebo groups, respectively (P < .001). The patients who received botulinum toxin had statistically significant improvements in maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and Incontinence Quality of Life scores compared with placebo (P < .001). Thirty-eight percent of patients in the treatment group were fully continent.^13,14

Safety and adverse effects

The most frequently reported adverse events were urinary tract infection (24% of patients)^13,14 and urinary retention requiring initiation of clean intermittent catheterization. In the study by Cruz et al,¹⁴ these were reported in 30% with 200 U, 42% with 300 U, and 12% with placebo, while in the study by Ginsberg et al¹³ they were reported in 35% with 200 U, 42% with 300 U, and 10% with placebo.

In a study of long-term safety and efficacy of botulinum toxin injection in patients with neurogenic detrusor overactivity, Kennelly et al¹⁶ found that patients undergoing repeat injections had sustained reductions in episodes of incontinence and increases in the maximum cystometric capacity and quality of life scores, with no increase in adverse events over time.¹⁶

But is it cost-effective?

While botulinum toxin injection may be safe and effective for neurogenic detrusor overactivity, is it cost-effective?

Carlson et al¹⁷ used a Markov State Transition model to assess the cost of refractory neurogenic detrusor overactivity in patients receiving botulinum toxin vs best supportive care (incontinence pads, medications, intermittent self-catheterization).¹⁷ They found that the injections were more expensive than supportive care but were cost-effective when considering the reduction in episodes of incontinence, the reduced need for incontinence products, and improvement in measures of quality of life.

What the evidence indicates

Trials of botulinum toxin injection for neurogenic detrusor overactivity have shown that it improves continence, maximum cystometric capacity, detrusor pressures, and quality of life. The main adverse effects are urinary tract infection and urinary retention requiring intermittent self-catheterization.

Although many patients with this condition are already self-catheterizing, the physician must discuss this before botulinum toxin therapy to ensure that the patient or a family member is able to perform catheterization. Studies have shown that patients have an increase in urinary tract infections after botulinum injections. But in these studies, a urinary tract infection was defined as 100,000 colony-forming units or the presence of leukocytosis with or without symptoms. It is important to remember that patients on intermittent catheterization have bacteriuria and should be treated only for symptomatic, not asymptomatic, bacteriuria.

TREATMENT OF IDIOPATHIC OVERACTIVE BLADDER

Patients with idiopathic overactive bladder have urinary urgency accompanied by urgency incontinence, nocturia, or urinary frequency.¹⁸ The prevalence of this condition has been reported to range from 1.7% to 13.3% in men age 30 and older and 7% to 30.3% in women of similar ages. About one-third of women with overactive bladder also have detrusor overactivity.¹⁹ Overactive bladder presents a significant economic and medical burden on the healthcare system, as well as having a negative impact on quality of life.

The FDA approved botulinum toxin injection for treatment of idiopathic overactive bladder in January 2013.

Evidence of effectiveness

Two multicenter randomized controlled trials^20,21 of botulinum toxin 100 U enrolled patients age 18 and older who had more than three episodes of urinary urgency incontinence in a 3-day period or more than eight micturitions per day inadequately managed by anticholinergic drug therapy. Primary end points were the change from baseline in the number of episodes of urinary incontinence per day and the proportion of patients with a positive response on the Treatment Benefit Scale²² at week 12. Secondary end points included episodes of urinary urgency incontinence, micturition, urgency, and nocturia, and scores on health-related quality of life questionnaires (Incontinence Quality of Life scale, King’s Health Questionnaire).

In both studies, patients receiving botulinum toxin had significantly fewer episodes of incontinence compared with placebo (−2.65 vs −0.87; P < .001 and −2.95 vs −1.03; P < .001).^20,21 Reductions from baseline in all other symptoms of overactive bladder, a positive treatment response on the treatment benefit scale, and improvements in quality-of-life scores were also significantly greater with botulinum toxin injection than with placebo (P ≤ .01).

As in the studies of neurogenic detrusor overactivity, the most common adverse effects were urinary tract infection (occurring in 15.5%²⁰ and 24.1%²¹ of patients) and urinary retention requiring self-catheterization (5.4%²⁰ and 6.9%²¹).

The largest study to date of anticholinergic therapy vs botulinum toxin injection²³ in women with urinary urgency incontinence, published in 2012, studied nearly 250 women who had five or more episodes of idiopathic urgency incontinence in a 3-day period. They were randomized either to daily oral therapy (solifenacin 5 mg with possible escalation to 10 mg and, if necessary, a subsequent switch to extended-release trospium 60 mg) plus one intradetrusor injection of saline, or to a daily oral placebo plus one injection of botulinum toxin 100 U.²³

The dropout rate was low in both groups, with 93% of patients in both groups completing the 6-month protocol. Women experienced a mean reduction in urgency incontinence episodes of 3.4 per day (baseline 5) in the anticholinergic group vs 3.3 episodes in the botulinum toxin group (P = .81). However, more patients achieved complete resolution of urinary urgency incontinence in the botulinum toxin group than in the anticholinergic therapy group (27% vs 13%; P = .003). Quality of life improved in both groups without a significant difference between the groups. The botulinum toxin group had higher rates of initiation of self-catheterization (5% vs 0%, P = .01) and urinary tract infection (33% vs 13%, P < .001).²³

Botulinum toxin as a third-line therapy

In May 2014, the American Urological Association updated its guidelines on idiopathic overactive bladder²⁴ to include botulinum toxin injection as standard third-line therapy for patients in whom behavioral and medical management (ie, anticholinergics and beta-3-agonists) failed.

Interpreting the evidence to date

Overall, studies in idiopathic overactive bladder have shown a reduction in episodes of urgency incontinence and other symptoms, with some data also demonstrating a corresponding improvement in quality of life.

As in neurogenic detrusor overactivity, the main risks associated with botulinum toxin injection are urinary tract infection and the need to initiate self-catheterization. Although 94% of patients studied did not require self-catheterization after injection, the patient’s ability to perform self-catheterization should be determined before proceeding with botulinum toxin injections.

DETRUSOR EXTERNAL SPHINCTER DYSSYNERGIA

Botulinum toxin has been used not only to improve bladder storage but also to facilitate bladder emptying, as in patients with DESD, a lack of coordination between the bladder and the urinary sphincter. Normal voiding involves relaxation of the urinary sphincter and contraction of the bladder; in DESD the sphincter contracts and works against the bladder’s ability to empty. This leads not only to difficulty emptying the bladder but also to elevated bladder pressure, which can cause renal damage if untreated.

DESD can be seen after injury between the pontine micturition center, which coordinates activity between the bladder and the sphincter, and the caudal spinal cord. This can occur in spinal cord injury, multiple sclerosis, myelomeningocele, and transverse myelitis and can cause significant morbidity for the patient.

Treatment options include drug therapy, injection of botulinum toxin into the sphincter, clean intermittent catheterization, indwelling catheterization, urethral stenting, sphincterotomy, and reconstructive surgery such as urinary diversion.²⁵

The goals of therapy are to avoid the need for clean intermittent catheterization in patients who have difficulty with manual dexterity, and to avoid the need for surgical procedures such as sphincterotomy and urinary diversion. The efficacy of urethral stenting is low, and medical management can be limited.²⁶

DESD leads to difficulty emptying the bladder, elevated bladder pressure, and, if untreated, renal damage

In the first published report on botulinum toxin for DESD (in 1988),²⁷ of 11 patients with spinal cord injury and DESD who received botulinum toxin injected into the external urethral sphincter, 10 showed signs of sphincter denervation on electromyography and reductions in urethral pressure profiles and postvoid residual volumes. Schurch et al²⁸ and de Sèze et al²⁹ also reported reductions in postvoid residual volume and maximal urethral pressures in patients with spinal cord injury and DESD.

In 2005, Gallien et al³⁰ reported what is still the largest multicenter randomized controlled trial of botulinum toxin injection in DESD. Eighty-six patients with multiple sclerosis, DESD, and chronic urinary retention were randomized to receive either a single transperineal botulinum toxin injection of 100 U plus the alpha-1-blocker alfuzosin, or a placebo injection plus alfuzosin. Botulinum toxin treatment was associated with significantly increased voided volumes and reduced premicturition and maximal detrusor pressures, but no significant decrease in postvoid residual volume.³⁰

More study needed

Despite these findings, a Cochrane Review concluded that, given the limited experience with intrasphincteric injection of botulinum toxin, data from larger randomized controlled trials are needed before making definitive recommendations.²⁵ In the meantime, the clinician must weigh the low morbidity of the procedure against the limited options in the treatment of these patients.

OFF-LABEL UROLOGIC INDICATIONS

Botulinum toxin injection has been studied off-label for painful bladder syndrome/interstitial cystitis and for chronic prostatic pain. Patients with these conditions often describe pain with filling of the bladder, which leads to urinary frequency in an attempt to relieve the pain.

These pain syndromes can be difficult to treat and can have a devastating impact on quality of life. Treatment options include pain management, stress management, physical therapy, intravesical therapies, cystoscopy with hydrodistention, neuromodulation, cyclosporine, urinary diversion surgery, and botulinum toxin injection (an off-label use).³¹

In painful bladder syndrome/interstitial cystitis, botulinum toxin is thought to act on sensory afferent pathways, as well as to inhibit the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.⁶ In animal studies,³² botulinum toxin was found to inhibit the afferent neural response by inhibiting mechanoreceptor-mediated release of adenosine triphosphate and by causing a decrease in calcitonin gene-related peptide, which helps regulate micturition and mediates painful bladder sensation.

Clinical studies to date in pelvic pain syndromes

Data from clinical studies of botulinum toxin injection for pelvic pain syndromes are limited. Zermann et al³³ performed transurethral perisphincteric injection in 11 men with chronic prostatic pain, 9 of whom reported subjective pain relief, with an average decrease from 7.2 to 1.6 on a visual analogue scale. Postinjection urodynamic studies showed a decrease in functional urethral length, urethral closure pressure, and postvoid residual volume, and an increase in the peak and average flow rates.³³

Abbott et al³⁴ evaluated the effect of botulinum toxin injection into the levator ani in 12 women with chronic pelvic pain and pelvic floor hypertonicity. Pelvic floor manometry showed significant reduction in resting muscle pressures and improvements in dyspareunia and nonmenstrual pain. There were also improvements in quality of life and dyschezia, but these were not statistically significant.

Smith et al³⁵ injected botulinum toxin into the detrusor of 13 women with refractory painful bladder syndrome and interstitial cystitis,³⁵ and 9 women (69%) noted statistically significant improvements in the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index, daytime frequency, nocturia, pain, and urodynamic parameters (volume at first desire to void, and maximum cystometric capacity).

In a prospective randomized study of patients with refractory painful bladder syndrome and interstitial cystitis, Kuo and Chancellor³⁶ compared suburothelial injection of 200 U or 100 U of botulinum toxin plus hydrodistention against hydrodistention alone.Patients who received botulinum toxin had increased bladder capacity and improved long-term pain relief, but no difference was noted between 200 U and 100 U, and more adverse effects were seen with the higher dose.³⁶

Pinto et al³⁷ treated 16 women with refractory painful bladder syndrome and interstitial cystitis with intratrigonal injections of botulinum toxin and reported improvements in pain scores, symptom scores, urinary frequency, and quality-of-life measures. The effect lasted 9.9 months (± 2.4 months) and persisted with successive injections.³⁷

More study needed

Although these studies show that botulinum toxin injection for pelvic pain syndromes has the potential to improve pain, urinary frequency, bladder sensation, bladder capacity, and quality of life, larger randomized controlled trials are needed.

Again, the treatment options are limited for refractory painful bladder syndrome and interstitial cystitis. Patients may be desperate for relief from their symptoms. Practitioners must manage expectations and properly inform patients of the potential risks of treatments, especially with patients who will easily agree to further treatment with the smallest hope of relief.

INJECTION TECHNIQUES

For general points about the procedure to discuss with patients, see “What to tell patients.”

Cystoscopic detrusor injection

This procedure is usually done on an outpatient basis (eg, office, ambulatory surgery center). With the patient in the lithotomy position, 100 mL of 2% lidocaine is instilled into the bladder and is allowed 15 to 20 minutes to take effect. A flexible or rigid cystoscope can be used. Depending on the indication, the bladder is injected with 100 U to 300 U of botulinum toxin. The ideal depth of injection is 2 mm in the detrusor muscle, with each injection spaced about 1 cm apart. The recommended administration for 100 U is to inject 20 sites with 0.5 U per mL of saline and, for 200 U, to inject 30 sites with about 0.67 U per mL of saline.³⁸ The location of the injections into the detrusor can vary, as long as adequate spacing is assured.

Injection sites vary. Proponents of injecting the trigone argue that as it is an area of greater nerve density, patients will have a better clinical response. Opponents argue that trigonal injection could result in distal ureteral paralysis and subsequent ureteral reflux. However, this theoretical concern has not been observed clinically.

Urethral injection (off-label use)

The urethra can be injected cystoscopically or periurethrally. Cystoscopic injection involves localization of the external sphincter using the rigid cystoscope and collagen needle; a total of 100 U is injected into the sphincter under direct vision, typically at the 3 o’clock and 9 o’clock positions.³⁵ The periurethral technique is an option in women and involves a spinal needle with 100 U to 200 U of botulinum toxin injected into the external sphincter muscle at the 2 o’clock and 10 o’clock positions.

ADVERSE EFFECTS AND CONTRAINDICATIONS

Adverse effects are rare for urologic applications. The injections are localized, with little systemic absorption, and the doses are 1/1,000th of the theorized lethal dose in a 70-kg male.² The maximum recommended dose for a 3-month period is 360 U.

Generalized muscle weakness has been reported in a paraplegic patient and in a tetraplegic patient after detrusor injections.² Interestingly, both patients had return of bladder spasticity within 2 months, prompting speculation about diffusion of botulinum toxin through the bladder wall.²

Repeat injections can cause an immune response in up to 5% of patients.⁶ Patients undergoing repeat injections are at risk of forming neutralizing antibodies that can interfere with the efficacy of botulinum toxin.⁶ In a study by Schulte-Baukloh et al, all patients with antibodies to botulinum toxin had a history of recurrent urinary tract infection.³⁹

Botulinum toxin injection is contraindicated in patients with preexisting neuromuscular disease, such as myasthenia gravis, Eaton-Lambert syndrome, and amyotrophic lateral sclerosis. It should also be avoided in patients who are breastfeeding, pregnant, or using agents that potentiate neuromuscular weakness, such as aminoglycosides.

Patients should be informed that some formulations of botulinum toxin include a stabilizer such as albumin derived from human blood, as this may be of religious or cultural significance.

Ceftaroline fosamil (Teflaro), introduced to the US market in October 2010, is the first beta-lactam agent with clinically useful activity against methicillin-resistant Staphylococcus aureus (MRSA). Currently, it is approved by the US Food and Drug Administration (FDA) to treat acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia caused by susceptible microorganisms.

In an era of increasing drug resistance and limited numbers of antimicrobials in the drug-production pipeline, ceftaroline is a step forward in fulfilling the Infectious Diseases Society of America’s “10 × ’20 Initiative” to increase support for drug research and manufacturing, with the goal of producing 10 new antimicrobial drugs by the year 2020.¹ Ceftaroline was the first of several antibiotics to receive FDA approval in response to this initiative. It was followed by dalbavancin (May 2014), tedizolid phosphate (June 2014), oritavancin (August 2014), ceftolozane-tazobactam (December 2014), and ceftazidime-avibactam (February 2015). These antibiotic agents are aimed at treating infections caused by drug-resistant gram-positive and gram-negative microorganisms. It is important to understand and optimize the use of these new antibiotic agents in order to decrease the risk of emerging antibiotic resistance and superinfections (eg, Clostridium difficile infection) caused by antibiotic overuse or misuse.

This article provides an overview of ceftaroline’s mechanisms of action and resistance, spectrum of activity, pharmacokinetic properties, adverse effects, and current place in therapy.

AN ERA OF MULTIDRUG-RESISTANT MICROORGANISMS

Increasing rates of antimicrobial resistance threaten the efficacy of antimicrobial drugs in the daily practice of medicine. The World Health Organization has labeled antimicrobial resistance one of the three greatest threats to human health. Global efforts are under way to stimulate development of new antimicrobial agents and to decrease rates of antimicrobial resistance.

Staphylococcus aureus: A threat, even with vancomycin

Between 1998 and 2005, S aureus was one of the most common inpatient and outpatient isolates reported by clinical laboratories throughout the United States.²

Treatment of S aureus infection is complicated by a variety of resistance mechanisms that have evolved over time. In fact, the first resistant isolate of S aureus emerged not long after penicillin’s debut into clinical practice, and now the majority of strains are resistant to penicillin.

Methicillin was designed to overcome this beta-lactamase resistance and became the treatment of choice for penicillin-resistant S aureus isolates. However, MRSA isolates soon emerged because of the organism’s acquisition of penicillin-binding protein PBP2a via the mecA gene, leading to decreased binding affinity of methicillin.³

Since then, several agents active against MRSA (vancomycin, daptomycin, linezolid, tigecycline) have been introduced and continue to be widely used. While vancomycin is considered the first-line option for a variety of MRSA infections, its use has been threatened because of the emergence of vancomycin-intermediate-resistant S aureus (VISA), S aureus strains displaying vancomycin heteroresistance (hVISA), and vancomycin-resistant S aureus (VRSA) strains.⁴

VISA and hVISA isolates emerged through sequential mutations that lead to autolytic activity and cell-wall thickening. In contrast, the mechanism of resistance in VRSA is by acquisition of the vanA resistance gene, which alters the binding site of vancomycin from d-alanine-d-alanine to d-alanine-d-lactate.⁵

Streptococcus pneumoniae resistance: A continuing problem

The prevalence of drug resistance in S pneumoniae has risen since the late 1990s. A 2013 report from the SENTRY Antimicrobial Surveillance Program stated that almost 20% of S pneumoniae isolates were resistant to amoxicillin-clavulanate, and similar trends have been observed for penicillin (14.8%) and ceftriaxone (11.7%).⁶

S pneumoniae resistance is acquired through modifications of the penicillin-binding proteins, namely PBP1a, PBP2b, PBP2x, and, less frequently, PBP2a. These modifications lead to decreased binding affinity for most beta-lactams.⁷

Clinical impact of multidrug-resistant S aureus and S pneumoniae

In 2011, the US Centers for Disease Control and Prevention reported an estimated 80,000 severe MRSA infections and 11,000 MRSA-related deaths in the United States.⁸ In the same report, drug-resistant S pneumoniae was estimated to be responsible for almost 1.2 million illnesses and 7,000 deaths per year, leading to upwards of $96 million in related medical costs.

While invasive drug-resistant S pneumoniae infections usually affect patients at the extremes of age (under age 5 and over age 65), they have had a serious impact on patients of all ages.⁸

In light of the increasing prevalence of multidrug-resistant organisms, newer antimicrobial agents with novel mechanisms of action are needed.

CEFTAROLINE: A BETA-LACTAM WITH ANTI-MRSA ACTIVITY

The cephalosporins, a class of beta-lactam antibiotics, were originally derived from the fungus Cephalosporium (now called Acremonium). There are now many agents in this class, each containing a nucleus consisting of a beta-lactam ring fused to a six-member dihydrothiazine ring, and two side chains that can be modified to affect antibacterial activity and pharmacokinetic properties.

Cephalosporins are typically categorized into “generations.” With some exceptions, the first- and second-generation agents have good activity against gram-positive microorganisms, including methicillin-susceptible S aureus—but not against MRSA. The third- and fourth-generation cephalosporins have better gram-negative activity, with many agents having activity against the gram-negative bacterium Pseudomonas aeruginosa.

Enterococcal isolates are intrinsically resistant to cephalosporins. Additionally, cephalosporins are not active against anaerobic bacteria, except for a subset of structurally unique second-generation cephalosporins, ie, cefotetan and cefoxitin.

Ceftaroline was synthesized with specific manipulations of the side chains to provide enhanced activity against MRSA and multidrug-resistant S pneumoniae isolates, making it the first available beta-lactam with this ability.

Mechanism of action

Ceftaroline binds to penicillin-binding proteins, inhibiting transpeptidation. This interaction blocks the final stage of peptidoglycan synthesis and inhibits bacterial cell wall formation, ultimately leading to cellular autolysis and microorganism death. Ceftaroline binds with high affinity to PBP2a and PBP2x, expanding its activity to encompass MRSA and penicillin-resistant S pneumoniae isolates.⁹

Spectrum of activity

Ceftaroline has in vitro activity against many gram-positive and gram-negative bacteria,^10–13 including (Table 1):

• Methicillin-susceptible and methicillin-resistant staphylococci
• VISA, VRSA, and hVISA
• Daptomycin-nonsusceptible S aureus
• Streptococcal species, including penicillin-resistant S pneumoniae
• Enterobacteriaceae, including Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Citrobacter koseri, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Morganella morganii, and Proteus mirabilis.

Of note, ceftaroline is not active against Pseudomonas species, Enterococcus species, or Bacteroides fragilis. In addition, it is not active against the “atypical” respiratory pathogens Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila.

Ceftaroline resistance

Gram-negative organisms appear to develop resistance to ceftaroline at rates similar to those observed with the other oxyimino-cephalosporins (eg, ceftriaxone). Ceftaroline is inactive against gram-negative organisms producing extended-spectrum beta-lactamases, including K pneumoniae carbapenemase and metallo-beta-lactamases.¹⁴ In addition, it induces the expression of AmpC beta-lactamases.

Although currently uncommon, resistance to ceftaroline has also been reported in S aureus strains.¹⁵ The mechanism of resistance is decreased binding affinity for PBP2a due to amino acid substitutions on the nonpenicillin-binding domains.¹⁵

Pharmacokinetic profile

An understanding of pharmacokinetics is key in optimizing the dose of antimicrobials so that the drugs are used most effectively and pathogens do not develop resistance to them.

Ceftaroline fosamil is a prodrug that, upon intravenous administration, is rapidly converted by phosphatase enzymes to its active moiety, ceftaroline. Its pharmacokinetic profile is summarized in Table 2.^16,17 Its volume of distribution is similar to that of the fourth-generation cephalosporin cefepime.

Ceftaroline is then hydrolyzed into its inactive metabolite, ceftaroline M-1. It undergoes little hepatic metabolism and lacks properties to make it a substrate, inhibitor, or inducer of the CYP450 enzyme system and therefore is not likely to cause notable CYP450-related drug-drug interactions.

Like most other beta-lactams, ceftaroline is primarily excreted by the kidneys. Furthermore, an estimated 21% of a dose is eliminated with each intermittent hemodialysis session. Therefore, renal and intermittent hemodialysis dose adjustments are necessary. The estimated elimination half-life is 2.6 hours, necessitating dosing two to three times daily, depending on the indication and infectious inoculum.

Ceftaroline dosing

Ceftaroline is available only in a parenteral preparation and is typically given at a dose of 600 mg every 12 hours.¹⁰ The intravenous infusion is given over 1 hour.

The current stability data require reconstituted ceftaroline to be used within 6 hours at room temperature and within 24 hours if refrigerated.¹⁰

Ceftaroline requires dosing adjustments for patients with renal insufficiency. Per the manufacturer, renal dosing adjustments are based on the creatinine clearance rate, as estimated by the Cockroft-Gault formula:

• Creatinine clearance > 50 mL/min: no dosage adjustment necessary
• Creatinine clearance > 30 to ≤ 50 mL/min: give 400 mg every 12 hours
• Creatinine clearance ≥ 15 to ≤ 30 mL/min: give 300 mg every 12 hours
• Creatinine clearance < 15 mL/min or on intermittent dialysis: give 200 mg every 12 hours.

Ongoing clinical trials are investigating a higher-dosing strategy of 600 mg every 8 hours for patients with community-acquired bacterial pneumonia at risk of MRSA bacteremia.¹⁸

CLINICAL TRIALS LEADING TO CEFTAROLINE’S APPROVAL

Ceftaroline was approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections due to susceptible pathogens on the basis of phase 3 comparator trials.

Community-acquired bacterial pneumonia: The FOCUS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of community-acquired bacterial pneumonia was studied in two randomized, double-blind, noninferiority trials, known as Ceftaroline Community-acquired Pneumonia vs Ceftriaxone (FOCUS) 1 and FOCUS 2.^19,20

Patients were adults and not critically ill, as was reflected by their being in Pneumonia Outcomes Research Team (PORT) risk class III or IV (with class V indicating the highest risk of death). Therefore, the results may not be completely applicable to critically ill patients or those not admitted to the hospital. Of note, patients were excluded from the trials if they had infections known or thought to be due to MRSA or to atypical organisms.²¹ Baseline characteristics and patient demographics were similar between study groups in both trials.

A bacterial pathogen was identified in 26.1% of the patients included in the modified intent-to-treat analysis of the pooled data of the trials; the most common pathogens were S pneumoniae, methicillin-sensitive S aureus, Haemophilus influenzae, K pneumoniae, and E coli.²¹

Treatment. Patients received either ceftaroline 600 mg every 12 hours (or a lower dose based on renal function) or ceftriaxone 1 g every 24 hours. In addition, in the FOCUS 1 trial, patients in both treatment groups received clarithromycin 500 mg every 12 hours for the first day.¹⁹

Results. In both trials and in the integrated analysis, ceftaroline was noninferior to ceftriaxone (Table 3).²² In the integrated analysis of both trials, compared with the ceftriaxone group, the ceftaroline group had a higher clinical cure rate among patients classified as PORT risk class III (86.8% vs 79.2%, weighted treatment difference 12.6%, 95% confidence interval [CI] 1.3–13.8) and among patients who had not received prior antibiotic treatment (85.5% vs 74.9%, weighted treatment difference 11.2%, 95% CI 4.5–18.0).²¹

Acute bacterial skin and skin-structure infections: The CANVAS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of complicated acute bacterial skin and skin-structure infections was studied in two randomized, double-blind trials: Ceftaroline Versus Vancomycin in Skin and Skin Structure Infections (CANVAS) 1 and CANVAS 2.^23,24

Patients. Adult patients with a diagnosis of community-acquired skin and skin-structure infections warranting at least 5 days of intravenous antimicrobial therapy were included in the trials. Important protocol exclusions were patients with diabetic foot ulcers, decubitus ulcers, burns, ulcers associated with peripheral vascular disease accompanied by osteomyelitis, and suspected P aeruginosa infections.²⁵ This limits the external validity of ceftaroline use in the aforementioned excluded patient populations.

Patients in each treatment group of the trials had similar demographic characteristics. The most common infections were cellulitis, major abscess requiring surgical intervention, wound infection, and infected ulcer. Bacteremia was present in 4.2% of patients in the ceftaroline group and in 3.8% of patients in the vancomycin-aztreonam group. The most common pathogen was S aureus. Methicillin resistance was present in 40% of the ceftaroline group and 34% of the control group.

Treatment. Patients received either ceftaroline 600 mg every 12 hours or the combination of vancomycin 1 g plus aztreonam 1 g given 12 hours, for 5 to 14 days.

Results. As assessed at a “test-of-cure” visit 8 to 15 days after the last dose of study medication, the efficacy of ceftaroline was similar to that of vancomycin-aztreonam, meeting the set noninferiority goal (Table 4).²⁵ Moreover, if assessed on day 2 or 3 (a new end point recommended by the FDA), the rate of cessation of erythema spread and absence of fever was higher in the ceftaroline group than in the vancomycin-aztreonam group.²⁶ However, this end point was not in the original trial protocol.

CEFTAROLINE FOR OTHER INDICATIONS

As noted, ceftaroline has been approved for treating community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections. In addition, it has been used in several studies in animals, and case reports of non-FDA approved indications including endocarditis and osteomyelitis have been published. Clinical trials are evaluating its use in pediatric patients, as well as for community-acquired bacterial pneumonia with risk for MRSA and for MRSA bacteremia.

Endocarditis

Animal studies have demonstrated ceftaroline to have bactericidal activity against MRSA and hVISA in endocarditis.²⁷

A few case series have been published describing ceftaroline’s use as salvage therapy for persistent MRSA bacteremia and endocarditis. For example, Ho et al²⁸ reported using it in three patients who had endocarditis as a source of their persistent bacteremia. All three patients had resolution of their MRSA bloodstream infection following ceftaroline therapy. The dosage was 600 mg every 8 hours, which is higher than in the manufacturer’s prescribing information.

Lin et al²⁹ reported using ceftaroline in five patients with either possible or probable endocarditis. Three of the five patients had clinical cure as defined by resolution or improvement of all signs and symptoms of infection, and not requiring further antimicrobial therapy.²⁹

More data from clinical trials would be beneficial in defining ceftaroline’s role in treating endocarditis caused by susceptible microorganisms.

Osteomyelitis

In animal studies of osteomyelitis, ceftaroline exhibited activity against MRSA in infected bone and joint fluid. Compared with vancomycin and linezolid, ceftaroline was associated with more significant decreases in bacterial load in the infected joint fluid, bone marrow, and bone.³⁰

Lin et al²⁹ gave ceftaroline to two patients with bone and joint infections, both of whom had received other therapies that had failed. The doses of ceftaroline were higher than those recommended in the prescribing information; clinical cure was noted in both cases following the switch.

These data come from case series, and more study of ceftaroline’s role in the treatment of osteomyelitis infections is warranted.

Meningitis

The use of ceftaroline in meningitis has been studied in rabbits. While ceftaroline penetrated into the cerebrospinal fluid in only negligible amounts in healthy rabbits (3% penetration), its penetration improved to 15% in animals with inflamed meninges. Ceftaroline cerebrospinal fluid levels in inflamed meninges were sufficient to provide bactericidal activity against penicillin-sensitive and resistant S pneumoniae strains as well as K pneumoniae and E coli strains.^31,32

REPORTED ADVERSE EFFECTS OF CEFTAROLINE

Overall, ceftaroline was well tolerated in clinical trials, and its safety profile was similar to those of the comparator agents (ceftriaxone and vancomycin-aztreonam).

As with the other cephalosporins, hypersensitivity reactions have been reported with ceftaroline. In the clinical trials, 3% of patients developed a rash with ceftaroline.^33,34 Patients with a history of beta-lactam allergy were excluded from the trials, so the rate of cross-reactivity with penicillins and with other cephalosporins is unknown.

In the phase 3 clinical trials, gastrointestinal side effects including diarrhea (5%), nausea (4%), and vomiting (2%) were reported with ceftaroline. C difficile-associated diarrhea has also been reported.³³

As with other cephalosporins, ceftaroline can cause a false-positive result on the Coombs test. Approximately 11% of ceftaroline-treated patients in phase 3 clinical trials had a positive Coombs test, but hemolytic anemia did not occur in any patients.^33,34

Discontinuation of ceftaroline due to an adverse reaction was reported in 2.7% of patients receiving the drug during phase 3 trials, compared with 3.7% with comparator agents.

WHEN SHOULD CEFTAROLINE BE USED IN DAILY PRACTICE?

Ceftaroline has been shown to be at least as effective as ceftriaxone in treating community-acquired bacterial pneumonia, and at least as effective as vancomycin-aztreonam in treating acute bacterial skin and skin-structure infections. The 2014 Infectious Diseases Society of America’s guidelines for the diagnosis and management of skin and soft-tissue infections recommend ceftaroline as an option for empiric therapy for purulent skin and soft-tissue infections.³⁵

The guidelines on community-acquired pneumonia have not been updated since 2007, which was before ceftaroline was approved. However, these guidelines are currently undergoing revision and may provide insight on ceftaroline’s place in the treatment of community-acquired bacterial pneumonia.³⁶

Currently, ceftaroline’s routine use for these indications should be balanced by its higher cost ($150 for a 600-mg dose) compared with ceftriaxone ($5 for a 1-g dose) or vancomycin ($25 for a 1-g dose). The drug’s in vitro activity against drug-resistant pneumococci and S aureus, including MRSA, hVISA, and VISA may help fill an unmet need or provide a safer and more tolerable alternative to currently available therapies.

However, ceftaroline’s lack of activity against P aeruginosa and carbapenem-resistant Enterobacteriaceae does not meet the public health threat needs stemming from these multidrug-resistant microorganisms. Ongoing clinical trials in patients with more serious MRSA infections will provide important information about ceftaroline’s role as an anti-MRSA agent.

While the discovery of antimicrobials has had one of the greatest impacts on medicine, continued antibiotic use is threatened by the emergence of drug-resistant pathogens. Therefore, it is as important as ever to be good stewards of our currently available antimicrobials. Developing usage and dosing criteria for antimicrobials based on available data and literature is a step forward in optimizing the use of antibiotics—a precious medical resource.

Ceftaroline fosamil (Teflaro), introduced to the US market in October 2010, is the first beta-lactam agent with clinically useful activity against methicillin-resistant Staphylococcus aureus (MRSA). Currently, it is approved by the US Food and Drug Administration (FDA) to treat acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia caused by susceptible microorganisms.

In an era of increasing drug resistance and limited numbers of antimicrobials in the drug-production pipeline, ceftaroline is a step forward in fulfilling the Infectious Diseases Society of America’s “10 × ’20 Initiative” to increase support for drug research and manufacturing, with the goal of producing 10 new antimicrobial drugs by the year 2020.¹ Ceftaroline was the first of several antibiotics to receive FDA approval in response to this initiative. It was followed by dalbavancin (May 2014), tedizolid phosphate (June 2014), oritavancin (August 2014), ceftolozane-tazobactam (December 2014), and ceftazidime-avibactam (February 2015). These antibiotic agents are aimed at treating infections caused by drug-resistant gram-positive and gram-negative microorganisms. It is important to understand and optimize the use of these new antibiotic agents in order to decrease the risk of emerging antibiotic resistance and superinfections (eg, Clostridium difficile infection) caused by antibiotic overuse or misuse.

This article provides an overview of ceftaroline’s mechanisms of action and resistance, spectrum of activity, pharmacokinetic properties, adverse effects, and current place in therapy.

AN ERA OF MULTIDRUG-RESISTANT MICROORGANISMS

Increasing rates of antimicrobial resistance threaten the efficacy of antimicrobial drugs in the daily practice of medicine. The World Health Organization has labeled antimicrobial resistance one of the three greatest threats to human health. Global efforts are under way to stimulate development of new antimicrobial agents and to decrease rates of antimicrobial resistance.

Staphylococcus aureus: A threat, even with vancomycin

Between 1998 and 2005, S aureus was one of the most common inpatient and outpatient isolates reported by clinical laboratories throughout the United States.²

Treatment of S aureus infection is complicated by a variety of resistance mechanisms that have evolved over time. In fact, the first resistant isolate of S aureus emerged not long after penicillin’s debut into clinical practice, and now the majority of strains are resistant to penicillin.

Methicillin was designed to overcome this beta-lactamase resistance and became the treatment of choice for penicillin-resistant S aureus isolates. However, MRSA isolates soon emerged because of the organism’s acquisition of penicillin-binding protein PBP2a via the mecA gene, leading to decreased binding affinity of methicillin.³

Since then, several agents active against MRSA (vancomycin, daptomycin, linezolid, tigecycline) have been introduced and continue to be widely used. While vancomycin is considered the first-line option for a variety of MRSA infections, its use has been threatened because of the emergence of vancomycin-intermediate-resistant S aureus (VISA), S aureus strains displaying vancomycin heteroresistance (hVISA), and vancomycin-resistant S aureus (VRSA) strains.⁴

VISA and hVISA isolates emerged through sequential mutations that lead to autolytic activity and cell-wall thickening. In contrast, the mechanism of resistance in VRSA is by acquisition of the vanA resistance gene, which alters the binding site of vancomycin from d-alanine-d-alanine to d-alanine-d-lactate.⁵

Streptococcus pneumoniae resistance: A continuing problem

The prevalence of drug resistance in S pneumoniae has risen since the late 1990s. A 2013 report from the SENTRY Antimicrobial Surveillance Program stated that almost 20% of S pneumoniae isolates were resistant to amoxicillin-clavulanate, and similar trends have been observed for penicillin (14.8%) and ceftriaxone (11.7%).⁶

S pneumoniae resistance is acquired through modifications of the penicillin-binding proteins, namely PBP1a, PBP2b, PBP2x, and, less frequently, PBP2a. These modifications lead to decreased binding affinity for most beta-lactams.⁷

Clinical impact of multidrug-resistant S aureus and S pneumoniae

In 2011, the US Centers for Disease Control and Prevention reported an estimated 80,000 severe MRSA infections and 11,000 MRSA-related deaths in the United States.⁸ In the same report, drug-resistant S pneumoniae was estimated to be responsible for almost 1.2 million illnesses and 7,000 deaths per year, leading to upwards of $96 million in related medical costs.

While invasive drug-resistant S pneumoniae infections usually affect patients at the extremes of age (under age 5 and over age 65), they have had a serious impact on patients of all ages.⁸

In light of the increasing prevalence of multidrug-resistant organisms, newer antimicrobial agents with novel mechanisms of action are needed.

CEFTAROLINE: A BETA-LACTAM WITH ANTI-MRSA ACTIVITY

The cephalosporins, a class of beta-lactam antibiotics, were originally derived from the fungus Cephalosporium (now called Acremonium). There are now many agents in this class, each containing a nucleus consisting of a beta-lactam ring fused to a six-member dihydrothiazine ring, and two side chains that can be modified to affect antibacterial activity and pharmacokinetic properties.

Cephalosporins are typically categorized into “generations.” With some exceptions, the first- and second-generation agents have good activity against gram-positive microorganisms, including methicillin-susceptible S aureus—but not against MRSA. The third- and fourth-generation cephalosporins have better gram-negative activity, with many agents having activity against the gram-negative bacterium Pseudomonas aeruginosa.

Enterococcal isolates are intrinsically resistant to cephalosporins. Additionally, cephalosporins are not active against anaerobic bacteria, except for a subset of structurally unique second-generation cephalosporins, ie, cefotetan and cefoxitin.

Ceftaroline was synthesized with specific manipulations of the side chains to provide enhanced activity against MRSA and multidrug-resistant S pneumoniae isolates, making it the first available beta-lactam with this ability.

Mechanism of action

Ceftaroline binds to penicillin-binding proteins, inhibiting transpeptidation. This interaction blocks the final stage of peptidoglycan synthesis and inhibits bacterial cell wall formation, ultimately leading to cellular autolysis and microorganism death. Ceftaroline binds with high affinity to PBP2a and PBP2x, expanding its activity to encompass MRSA and penicillin-resistant S pneumoniae isolates.⁹

Spectrum of activity

Ceftaroline has in vitro activity against many gram-positive and gram-negative bacteria,^10–13 including (Table 1):

• Methicillin-susceptible and methicillin-resistant staphylococci
• VISA, VRSA, and hVISA
• Daptomycin-nonsusceptible S aureus
• Streptococcal species, including penicillin-resistant S pneumoniae
• Enterobacteriaceae, including Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Citrobacter koseri, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Morganella morganii, and Proteus mirabilis.

Of note, ceftaroline is not active against Pseudomonas species, Enterococcus species, or Bacteroides fragilis. In addition, it is not active against the “atypical” respiratory pathogens Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila.

Ceftaroline resistance

Gram-negative organisms appear to develop resistance to ceftaroline at rates similar to those observed with the other oxyimino-cephalosporins (eg, ceftriaxone). Ceftaroline is inactive against gram-negative organisms producing extended-spectrum beta-lactamases, including K pneumoniae carbapenemase and metallo-beta-lactamases.¹⁴ In addition, it induces the expression of AmpC beta-lactamases.

Although currently uncommon, resistance to ceftaroline has also been reported in S aureus strains.¹⁵ The mechanism of resistance is decreased binding affinity for PBP2a due to amino acid substitutions on the nonpenicillin-binding domains.¹⁵

Pharmacokinetic profile

An understanding of pharmacokinetics is key in optimizing the dose of antimicrobials so that the drugs are used most effectively and pathogens do not develop resistance to them.

Ceftaroline fosamil is a prodrug that, upon intravenous administration, is rapidly converted by phosphatase enzymes to its active moiety, ceftaroline. Its pharmacokinetic profile is summarized in Table 2.^16,17 Its volume of distribution is similar to that of the fourth-generation cephalosporin cefepime.

Ceftaroline is then hydrolyzed into its inactive metabolite, ceftaroline M-1. It undergoes little hepatic metabolism and lacks properties to make it a substrate, inhibitor, or inducer of the CYP450 enzyme system and therefore is not likely to cause notable CYP450-related drug-drug interactions.

Like most other beta-lactams, ceftaroline is primarily excreted by the kidneys. Furthermore, an estimated 21% of a dose is eliminated with each intermittent hemodialysis session. Therefore, renal and intermittent hemodialysis dose adjustments are necessary. The estimated elimination half-life is 2.6 hours, necessitating dosing two to three times daily, depending on the indication and infectious inoculum.

Ceftaroline dosing

Ceftaroline is available only in a parenteral preparation and is typically given at a dose of 600 mg every 12 hours.¹⁰ The intravenous infusion is given over 1 hour.

The current stability data require reconstituted ceftaroline to be used within 6 hours at room temperature and within 24 hours if refrigerated.¹⁰

Ceftaroline requires dosing adjustments for patients with renal insufficiency. Per the manufacturer, renal dosing adjustments are based on the creatinine clearance rate, as estimated by the Cockroft-Gault formula:

• Creatinine clearance > 50 mL/min: no dosage adjustment necessary
• Creatinine clearance > 30 to ≤ 50 mL/min: give 400 mg every 12 hours
• Creatinine clearance ≥ 15 to ≤ 30 mL/min: give 300 mg every 12 hours
• Creatinine clearance < 15 mL/min or on intermittent dialysis: give 200 mg every 12 hours.

Ongoing clinical trials are investigating a higher-dosing strategy of 600 mg every 8 hours for patients with community-acquired bacterial pneumonia at risk of MRSA bacteremia.¹⁸

CLINICAL TRIALS LEADING TO CEFTAROLINE’S APPROVAL

Ceftaroline was approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections due to susceptible pathogens on the basis of phase 3 comparator trials.

Community-acquired bacterial pneumonia: The FOCUS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of community-acquired bacterial pneumonia was studied in two randomized, double-blind, noninferiority trials, known as Ceftaroline Community-acquired Pneumonia vs Ceftriaxone (FOCUS) 1 and FOCUS 2.^19,20

Patients were adults and not critically ill, as was reflected by their being in Pneumonia Outcomes Research Team (PORT) risk class III or IV (with class V indicating the highest risk of death). Therefore, the results may not be completely applicable to critically ill patients or those not admitted to the hospital. Of note, patients were excluded from the trials if they had infections known or thought to be due to MRSA or to atypical organisms.²¹ Baseline characteristics and patient demographics were similar between study groups in both trials.

A bacterial pathogen was identified in 26.1% of the patients included in the modified intent-to-treat analysis of the pooled data of the trials; the most common pathogens were S pneumoniae, methicillin-sensitive S aureus, Haemophilus influenzae, K pneumoniae, and E coli.²¹

Treatment. Patients received either ceftaroline 600 mg every 12 hours (or a lower dose based on renal function) or ceftriaxone 1 g every 24 hours. In addition, in the FOCUS 1 trial, patients in both treatment groups received clarithromycin 500 mg every 12 hours for the first day.¹⁹

Results. In both trials and in the integrated analysis, ceftaroline was noninferior to ceftriaxone (Table 3).²² In the integrated analysis of both trials, compared with the ceftriaxone group, the ceftaroline group had a higher clinical cure rate among patients classified as PORT risk class III (86.8% vs 79.2%, weighted treatment difference 12.6%, 95% confidence interval [CI] 1.3–13.8) and among patients who had not received prior antibiotic treatment (85.5% vs 74.9%, weighted treatment difference 11.2%, 95% CI 4.5–18.0).²¹

Acute bacterial skin and skin-structure infections: The CANVAS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of complicated acute bacterial skin and skin-structure infections was studied in two randomized, double-blind trials: Ceftaroline Versus Vancomycin in Skin and Skin Structure Infections (CANVAS) 1 and CANVAS 2.^23,24

Patients. Adult patients with a diagnosis of community-acquired skin and skin-structure infections warranting at least 5 days of intravenous antimicrobial therapy were included in the trials. Important protocol exclusions were patients with diabetic foot ulcers, decubitus ulcers, burns, ulcers associated with peripheral vascular disease accompanied by osteomyelitis, and suspected P aeruginosa infections.²⁵ This limits the external validity of ceftaroline use in the aforementioned excluded patient populations.

Patients in each treatment group of the trials had similar demographic characteristics. The most common infections were cellulitis, major abscess requiring surgical intervention, wound infection, and infected ulcer. Bacteremia was present in 4.2% of patients in the ceftaroline group and in 3.8% of patients in the vancomycin-aztreonam group. The most common pathogen was S aureus. Methicillin resistance was present in 40% of the ceftaroline group and 34% of the control group.

Treatment. Patients received either ceftaroline 600 mg every 12 hours or the combination of vancomycin 1 g plus aztreonam 1 g given 12 hours, for 5 to 14 days.

Results. As assessed at a “test-of-cure” visit 8 to 15 days after the last dose of study medication, the efficacy of ceftaroline was similar to that of vancomycin-aztreonam, meeting the set noninferiority goal (Table 4).²⁵ Moreover, if assessed on day 2 or 3 (a new end point recommended by the FDA), the rate of cessation of erythema spread and absence of fever was higher in the ceftaroline group than in the vancomycin-aztreonam group.²⁶ However, this end point was not in the original trial protocol.

CEFTAROLINE FOR OTHER INDICATIONS

As noted, ceftaroline has been approved for treating community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections. In addition, it has been used in several studies in animals, and case reports of non-FDA approved indications including endocarditis and osteomyelitis have been published. Clinical trials are evaluating its use in pediatric patients, as well as for community-acquired bacterial pneumonia with risk for MRSA and for MRSA bacteremia.

Endocarditis

Animal studies have demonstrated ceftaroline to have bactericidal activity against MRSA and hVISA in endocarditis.²⁷

A few case series have been published describing ceftaroline’s use as salvage therapy for persistent MRSA bacteremia and endocarditis. For example, Ho et al²⁸ reported using it in three patients who had endocarditis as a source of their persistent bacteremia. All three patients had resolution of their MRSA bloodstream infection following ceftaroline therapy. The dosage was 600 mg every 8 hours, which is higher than in the manufacturer’s prescribing information.

Lin et al²⁹ reported using ceftaroline in five patients with either possible or probable endocarditis. Three of the five patients had clinical cure as defined by resolution or improvement of all signs and symptoms of infection, and not requiring further antimicrobial therapy.²⁹

More data from clinical trials would be beneficial in defining ceftaroline’s role in treating endocarditis caused by susceptible microorganisms.

Osteomyelitis

In animal studies of osteomyelitis, ceftaroline exhibited activity against MRSA in infected bone and joint fluid. Compared with vancomycin and linezolid, ceftaroline was associated with more significant decreases in bacterial load in the infected joint fluid, bone marrow, and bone.³⁰

Lin et al²⁹ gave ceftaroline to two patients with bone and joint infections, both of whom had received other therapies that had failed. The doses of ceftaroline were higher than those recommended in the prescribing information; clinical cure was noted in both cases following the switch.

These data come from case series, and more study of ceftaroline’s role in the treatment of osteomyelitis infections is warranted.

Meningitis

The use of ceftaroline in meningitis has been studied in rabbits. While ceftaroline penetrated into the cerebrospinal fluid in only negligible amounts in healthy rabbits (3% penetration), its penetration improved to 15% in animals with inflamed meninges. Ceftaroline cerebrospinal fluid levels in inflamed meninges were sufficient to provide bactericidal activity against penicillin-sensitive and resistant S pneumoniae strains as well as K pneumoniae and E coli strains.^31,32

REPORTED ADVERSE EFFECTS OF CEFTAROLINE

Overall, ceftaroline was well tolerated in clinical trials, and its safety profile was similar to those of the comparator agents (ceftriaxone and vancomycin-aztreonam).

As with the other cephalosporins, hypersensitivity reactions have been reported with ceftaroline. In the clinical trials, 3% of patients developed a rash with ceftaroline.^33,34 Patients with a history of beta-lactam allergy were excluded from the trials, so the rate of cross-reactivity with penicillins and with other cephalosporins is unknown.

In the phase 3 clinical trials, gastrointestinal side effects including diarrhea (5%), nausea (4%), and vomiting (2%) were reported with ceftaroline. C difficile-associated diarrhea has also been reported.³³

As with other cephalosporins, ceftaroline can cause a false-positive result on the Coombs test. Approximately 11% of ceftaroline-treated patients in phase 3 clinical trials had a positive Coombs test, but hemolytic anemia did not occur in any patients.^33,34

Discontinuation of ceftaroline due to an adverse reaction was reported in 2.7% of patients receiving the drug during phase 3 trials, compared with 3.7% with comparator agents.

WHEN SHOULD CEFTAROLINE BE USED IN DAILY PRACTICE?

Ceftaroline has been shown to be at least as effective as ceftriaxone in treating community-acquired bacterial pneumonia, and at least as effective as vancomycin-aztreonam in treating acute bacterial skin and skin-structure infections. The 2014 Infectious Diseases Society of America’s guidelines for the diagnosis and management of skin and soft-tissue infections recommend ceftaroline as an option for empiric therapy for purulent skin and soft-tissue infections.³⁵

The guidelines on community-acquired pneumonia have not been updated since 2007, which was before ceftaroline was approved. However, these guidelines are currently undergoing revision and may provide insight on ceftaroline’s place in the treatment of community-acquired bacterial pneumonia.³⁶

Currently, ceftaroline’s routine use for these indications should be balanced by its higher cost ($150 for a 600-mg dose) compared with ceftriaxone ($5 for a 1-g dose) or vancomycin ($25 for a 1-g dose). The drug’s in vitro activity against drug-resistant pneumococci and S aureus, including MRSA, hVISA, and VISA may help fill an unmet need or provide a safer and more tolerable alternative to currently available therapies.

However, ceftaroline’s lack of activity against P aeruginosa and carbapenem-resistant Enterobacteriaceae does not meet the public health threat needs stemming from these multidrug-resistant microorganisms. Ongoing clinical trials in patients with more serious MRSA infections will provide important information about ceftaroline’s role as an anti-MRSA agent.

While the discovery of antimicrobials has had one of the greatest impacts on medicine, continued antibiotic use is threatened by the emergence of drug-resistant pathogens. Therefore, it is as important as ever to be good stewards of our currently available antimicrobials. Developing usage and dosing criteria for antimicrobials based on available data and literature is a step forward in optimizing the use of antibiotics—a precious medical resource.

Ceftaroline fosamil (Teflaro), introduced to the US market in October 2010, is the first beta-lactam agent with clinically useful activity against methicillin-resistant Staphylococcus aureus (MRSA). Currently, it is approved by the US Food and Drug Administration (FDA) to treat acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia caused by susceptible microorganisms.

In an era of increasing drug resistance and limited numbers of antimicrobials in the drug-production pipeline, ceftaroline is a step forward in fulfilling the Infectious Diseases Society of America’s “10 × ’20 Initiative” to increase support for drug research and manufacturing, with the goal of producing 10 new antimicrobial drugs by the year 2020.¹ Ceftaroline was the first of several antibiotics to receive FDA approval in response to this initiative. It was followed by dalbavancin (May 2014), tedizolid phosphate (June 2014), oritavancin (August 2014), ceftolozane-tazobactam (December 2014), and ceftazidime-avibactam (February 2015). These antibiotic agents are aimed at treating infections caused by drug-resistant gram-positive and gram-negative microorganisms. It is important to understand and optimize the use of these new antibiotic agents in order to decrease the risk of emerging antibiotic resistance and superinfections (eg, Clostridium difficile infection) caused by antibiotic overuse or misuse.

This article provides an overview of ceftaroline’s mechanisms of action and resistance, spectrum of activity, pharmacokinetic properties, adverse effects, and current place in therapy.

AN ERA OF MULTIDRUG-RESISTANT MICROORGANISMS

Increasing rates of antimicrobial resistance threaten the efficacy of antimicrobial drugs in the daily practice of medicine. The World Health Organization has labeled antimicrobial resistance one of the three greatest threats to human health. Global efforts are under way to stimulate development of new antimicrobial agents and to decrease rates of antimicrobial resistance.

Staphylococcus aureus: A threat, even with vancomycin

Between 1998 and 2005, S aureus was one of the most common inpatient and outpatient isolates reported by clinical laboratories throughout the United States.²

Treatment of S aureus infection is complicated by a variety of resistance mechanisms that have evolved over time. In fact, the first resistant isolate of S aureus emerged not long after penicillin’s debut into clinical practice, and now the majority of strains are resistant to penicillin.

Methicillin was designed to overcome this beta-lactamase resistance and became the treatment of choice for penicillin-resistant S aureus isolates. However, MRSA isolates soon emerged because of the organism’s acquisition of penicillin-binding protein PBP2a via the mecA gene, leading to decreased binding affinity of methicillin.³

Since then, several agents active against MRSA (vancomycin, daptomycin, linezolid, tigecycline) have been introduced and continue to be widely used. While vancomycin is considered the first-line option for a variety of MRSA infections, its use has been threatened because of the emergence of vancomycin-intermediate-resistant S aureus (VISA), S aureus strains displaying vancomycin heteroresistance (hVISA), and vancomycin-resistant S aureus (VRSA) strains.⁴

VISA and hVISA isolates emerged through sequential mutations that lead to autolytic activity and cell-wall thickening. In contrast, the mechanism of resistance in VRSA is by acquisition of the vanA resistance gene, which alters the binding site of vancomycin from d-alanine-d-alanine to d-alanine-d-lactate.⁵

Streptococcus pneumoniae resistance: A continuing problem

The prevalence of drug resistance in S pneumoniae has risen since the late 1990s. A 2013 report from the SENTRY Antimicrobial Surveillance Program stated that almost 20% of S pneumoniae isolates were resistant to amoxicillin-clavulanate, and similar trends have been observed for penicillin (14.8%) and ceftriaxone (11.7%).⁶

S pneumoniae resistance is acquired through modifications of the penicillin-binding proteins, namely PBP1a, PBP2b, PBP2x, and, less frequently, PBP2a. These modifications lead to decreased binding affinity for most beta-lactams.⁷

Clinical impact of multidrug-resistant S aureus and S pneumoniae

In 2011, the US Centers for Disease Control and Prevention reported an estimated 80,000 severe MRSA infections and 11,000 MRSA-related deaths in the United States.⁸ In the same report, drug-resistant S pneumoniae was estimated to be responsible for almost 1.2 million illnesses and 7,000 deaths per year, leading to upwards of $96 million in related medical costs.

While invasive drug-resistant S pneumoniae infections usually affect patients at the extremes of age (under age 5 and over age 65), they have had a serious impact on patients of all ages.⁸

In light of the increasing prevalence of multidrug-resistant organisms, newer antimicrobial agents with novel mechanisms of action are needed.

CEFTAROLINE: A BETA-LACTAM WITH ANTI-MRSA ACTIVITY

The cephalosporins, a class of beta-lactam antibiotics, were originally derived from the fungus Cephalosporium (now called Acremonium). There are now many agents in this class, each containing a nucleus consisting of a beta-lactam ring fused to a six-member dihydrothiazine ring, and two side chains that can be modified to affect antibacterial activity and pharmacokinetic properties.

Cephalosporins are typically categorized into “generations.” With some exceptions, the first- and second-generation agents have good activity against gram-positive microorganisms, including methicillin-susceptible S aureus—but not against MRSA. The third- and fourth-generation cephalosporins have better gram-negative activity, with many agents having activity against the gram-negative bacterium Pseudomonas aeruginosa.

Enterococcal isolates are intrinsically resistant to cephalosporins. Additionally, cephalosporins are not active against anaerobic bacteria, except for a subset of structurally unique second-generation cephalosporins, ie, cefotetan and cefoxitin.

Ceftaroline was synthesized with specific manipulations of the side chains to provide enhanced activity against MRSA and multidrug-resistant S pneumoniae isolates, making it the first available beta-lactam with this ability.

Mechanism of action

Ceftaroline binds to penicillin-binding proteins, inhibiting transpeptidation. This interaction blocks the final stage of peptidoglycan synthesis and inhibits bacterial cell wall formation, ultimately leading to cellular autolysis and microorganism death. Ceftaroline binds with high affinity to PBP2a and PBP2x, expanding its activity to encompass MRSA and penicillin-resistant S pneumoniae isolates.⁹

Spectrum of activity

Ceftaroline has in vitro activity against many gram-positive and gram-negative bacteria,^10–13 including (Table 1):

• Methicillin-susceptible and methicillin-resistant staphylococci
• VISA, VRSA, and hVISA
• Daptomycin-nonsusceptible S aureus
• Streptococcal species, including penicillin-resistant S pneumoniae
• Enterobacteriaceae, including Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Citrobacter koseri, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Morganella morganii, and Proteus mirabilis.

Of note, ceftaroline is not active against Pseudomonas species, Enterococcus species, or Bacteroides fragilis. In addition, it is not active against the “atypical” respiratory pathogens Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila.

Ceftaroline resistance

Gram-negative organisms appear to develop resistance to ceftaroline at rates similar to those observed with the other oxyimino-cephalosporins (eg, ceftriaxone). Ceftaroline is inactive against gram-negative organisms producing extended-spectrum beta-lactamases, including K pneumoniae carbapenemase and metallo-beta-lactamases.¹⁴ In addition, it induces the expression of AmpC beta-lactamases.

Although currently uncommon, resistance to ceftaroline has also been reported in S aureus strains.¹⁵ The mechanism of resistance is decreased binding affinity for PBP2a due to amino acid substitutions on the nonpenicillin-binding domains.¹⁵

Pharmacokinetic profile

An understanding of pharmacokinetics is key in optimizing the dose of antimicrobials so that the drugs are used most effectively and pathogens do not develop resistance to them.

Ceftaroline fosamil is a prodrug that, upon intravenous administration, is rapidly converted by phosphatase enzymes to its active moiety, ceftaroline. Its pharmacokinetic profile is summarized in Table 2.^16,17 Its volume of distribution is similar to that of the fourth-generation cephalosporin cefepime.

Ceftaroline is then hydrolyzed into its inactive metabolite, ceftaroline M-1. It undergoes little hepatic metabolism and lacks properties to make it a substrate, inhibitor, or inducer of the CYP450 enzyme system and therefore is not likely to cause notable CYP450-related drug-drug interactions.

Like most other beta-lactams, ceftaroline is primarily excreted by the kidneys. Furthermore, an estimated 21% of a dose is eliminated with each intermittent hemodialysis session. Therefore, renal and intermittent hemodialysis dose adjustments are necessary. The estimated elimination half-life is 2.6 hours, necessitating dosing two to three times daily, depending on the indication and infectious inoculum.

Ceftaroline dosing

Ceftaroline is available only in a parenteral preparation and is typically given at a dose of 600 mg every 12 hours.¹⁰ The intravenous infusion is given over 1 hour.

The current stability data require reconstituted ceftaroline to be used within 6 hours at room temperature and within 24 hours if refrigerated.¹⁰

Ceftaroline requires dosing adjustments for patients with renal insufficiency. Per the manufacturer, renal dosing adjustments are based on the creatinine clearance rate, as estimated by the Cockroft-Gault formula:

• Creatinine clearance > 50 mL/min: no dosage adjustment necessary
• Creatinine clearance > 30 to ≤ 50 mL/min: give 400 mg every 12 hours
• Creatinine clearance ≥ 15 to ≤ 30 mL/min: give 300 mg every 12 hours
• Creatinine clearance < 15 mL/min or on intermittent dialysis: give 200 mg every 12 hours.

Ongoing clinical trials are investigating a higher-dosing strategy of 600 mg every 8 hours for patients with community-acquired bacterial pneumonia at risk of MRSA bacteremia.¹⁸

CLINICAL TRIALS LEADING TO CEFTAROLINE’S APPROVAL

Ceftaroline was approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections due to susceptible pathogens on the basis of phase 3 comparator trials.

Community-acquired bacterial pneumonia: The FOCUS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of community-acquired bacterial pneumonia was studied in two randomized, double-blind, noninferiority trials, known as Ceftaroline Community-acquired Pneumonia vs Ceftriaxone (FOCUS) 1 and FOCUS 2.^19,20

Patients were adults and not critically ill, as was reflected by their being in Pneumonia Outcomes Research Team (PORT) risk class III or IV (with class V indicating the highest risk of death). Therefore, the results may not be completely applicable to critically ill patients or those not admitted to the hospital. Of note, patients were excluded from the trials if they had infections known or thought to be due to MRSA or to atypical organisms.²¹ Baseline characteristics and patient demographics were similar between study groups in both trials.

A bacterial pathogen was identified in 26.1% of the patients included in the modified intent-to-treat analysis of the pooled data of the trials; the most common pathogens were S pneumoniae, methicillin-sensitive S aureus, Haemophilus influenzae, K pneumoniae, and E coli.²¹

Treatment. Patients received either ceftaroline 600 mg every 12 hours (or a lower dose based on renal function) or ceftriaxone 1 g every 24 hours. In addition, in the FOCUS 1 trial, patients in both treatment groups received clarithromycin 500 mg every 12 hours for the first day.¹⁹

Results. In both trials and in the integrated analysis, ceftaroline was noninferior to ceftriaxone (Table 3).²² In the integrated analysis of both trials, compared with the ceftriaxone group, the ceftaroline group had a higher clinical cure rate among patients classified as PORT risk class III (86.8% vs 79.2%, weighted treatment difference 12.6%, 95% confidence interval [CI] 1.3–13.8) and among patients who had not received prior antibiotic treatment (85.5% vs 74.9%, weighted treatment difference 11.2%, 95% CI 4.5–18.0).²¹

Acute bacterial skin and skin-structure infections: The CANVAS 1 and 2 trials

The efficacy and safety of ceftaroline in the treatment of complicated acute bacterial skin and skin-structure infections was studied in two randomized, double-blind trials: Ceftaroline Versus Vancomycin in Skin and Skin Structure Infections (CANVAS) 1 and CANVAS 2.^23,24

Patients. Adult patients with a diagnosis of community-acquired skin and skin-structure infections warranting at least 5 days of intravenous antimicrobial therapy were included in the trials. Important protocol exclusions were patients with diabetic foot ulcers, decubitus ulcers, burns, ulcers associated with peripheral vascular disease accompanied by osteomyelitis, and suspected P aeruginosa infections.²⁵ This limits the external validity of ceftaroline use in the aforementioned excluded patient populations.

Patients in each treatment group of the trials had similar demographic characteristics. The most common infections were cellulitis, major abscess requiring surgical intervention, wound infection, and infected ulcer. Bacteremia was present in 4.2% of patients in the ceftaroline group and in 3.8% of patients in the vancomycin-aztreonam group. The most common pathogen was S aureus. Methicillin resistance was present in 40% of the ceftaroline group and 34% of the control group.

Treatment. Patients received either ceftaroline 600 mg every 12 hours or the combination of vancomycin 1 g plus aztreonam 1 g given 12 hours, for 5 to 14 days.

Results. As assessed at a “test-of-cure” visit 8 to 15 days after the last dose of study medication, the efficacy of ceftaroline was similar to that of vancomycin-aztreonam, meeting the set noninferiority goal (Table 4).²⁵ Moreover, if assessed on day 2 or 3 (a new end point recommended by the FDA), the rate of cessation of erythema spread and absence of fever was higher in the ceftaroline group than in the vancomycin-aztreonam group.²⁶ However, this end point was not in the original trial protocol.

CEFTAROLINE FOR OTHER INDICATIONS

As noted, ceftaroline has been approved for treating community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections. In addition, it has been used in several studies in animals, and case reports of non-FDA approved indications including endocarditis and osteomyelitis have been published. Clinical trials are evaluating its use in pediatric patients, as well as for community-acquired bacterial pneumonia with risk for MRSA and for MRSA bacteremia.

Endocarditis

Animal studies have demonstrated ceftaroline to have bactericidal activity against MRSA and hVISA in endocarditis.²⁷

A few case series have been published describing ceftaroline’s use as salvage therapy for persistent MRSA bacteremia and endocarditis. For example, Ho et al²⁸ reported using it in three patients who had endocarditis as a source of their persistent bacteremia. All three patients had resolution of their MRSA bloodstream infection following ceftaroline therapy. The dosage was 600 mg every 8 hours, which is higher than in the manufacturer’s prescribing information.

Lin et al²⁹ reported using ceftaroline in five patients with either possible or probable endocarditis. Three of the five patients had clinical cure as defined by resolution or improvement of all signs and symptoms of infection, and not requiring further antimicrobial therapy.²⁹

More data from clinical trials would be beneficial in defining ceftaroline’s role in treating endocarditis caused by susceptible microorganisms.

Osteomyelitis

In animal studies of osteomyelitis, ceftaroline exhibited activity against MRSA in infected bone and joint fluid. Compared with vancomycin and linezolid, ceftaroline was associated with more significant decreases in bacterial load in the infected joint fluid, bone marrow, and bone.³⁰

Lin et al²⁹ gave ceftaroline to two patients with bone and joint infections, both of whom had received other therapies that had failed. The doses of ceftaroline were higher than those recommended in the prescribing information; clinical cure was noted in both cases following the switch.

These data come from case series, and more study of ceftaroline’s role in the treatment of osteomyelitis infections is warranted.

Meningitis

The use of ceftaroline in meningitis has been studied in rabbits. While ceftaroline penetrated into the cerebrospinal fluid in only negligible amounts in healthy rabbits (3% penetration), its penetration improved to 15% in animals with inflamed meninges. Ceftaroline cerebrospinal fluid levels in inflamed meninges were sufficient to provide bactericidal activity against penicillin-sensitive and resistant S pneumoniae strains as well as K pneumoniae and E coli strains.^31,32

REPORTED ADVERSE EFFECTS OF CEFTAROLINE

Overall, ceftaroline was well tolerated in clinical trials, and its safety profile was similar to those of the comparator agents (ceftriaxone and vancomycin-aztreonam).

As with the other cephalosporins, hypersensitivity reactions have been reported with ceftaroline. In the clinical trials, 3% of patients developed a rash with ceftaroline.^33,34 Patients with a history of beta-lactam allergy were excluded from the trials, so the rate of cross-reactivity with penicillins and with other cephalosporins is unknown.

In the phase 3 clinical trials, gastrointestinal side effects including diarrhea (5%), nausea (4%), and vomiting (2%) were reported with ceftaroline. C difficile-associated diarrhea has also been reported.³³

As with other cephalosporins, ceftaroline can cause a false-positive result on the Coombs test. Approximately 11% of ceftaroline-treated patients in phase 3 clinical trials had a positive Coombs test, but hemolytic anemia did not occur in any patients.^33,34

Discontinuation of ceftaroline due to an adverse reaction was reported in 2.7% of patients receiving the drug during phase 3 trials, compared with 3.7% with comparator agents.

WHEN SHOULD CEFTAROLINE BE USED IN DAILY PRACTICE?

Ceftaroline has been shown to be at least as effective as ceftriaxone in treating community-acquired bacterial pneumonia, and at least as effective as vancomycin-aztreonam in treating acute bacterial skin and skin-structure infections. The 2014 Infectious Diseases Society of America’s guidelines for the diagnosis and management of skin and soft-tissue infections recommend ceftaroline as an option for empiric therapy for purulent skin and soft-tissue infections.³⁵

The guidelines on community-acquired pneumonia have not been updated since 2007, which was before ceftaroline was approved. However, these guidelines are currently undergoing revision and may provide insight on ceftaroline’s place in the treatment of community-acquired bacterial pneumonia.³⁶

Currently, ceftaroline’s routine use for these indications should be balanced by its higher cost ($150 for a 600-mg dose) compared with ceftriaxone ($5 for a 1-g dose) or vancomycin ($25 for a 1-g dose). The drug’s in vitro activity against drug-resistant pneumococci and S aureus, including MRSA, hVISA, and VISA may help fill an unmet need or provide a safer and more tolerable alternative to currently available therapies.

However, ceftaroline’s lack of activity against P aeruginosa and carbapenem-resistant Enterobacteriaceae does not meet the public health threat needs stemming from these multidrug-resistant microorganisms. Ongoing clinical trials in patients with more serious MRSA infections will provide important information about ceftaroline’s role as an anti-MRSA agent.

While the discovery of antimicrobials has had one of the greatest impacts on medicine, continued antibiotic use is threatened by the emergence of drug-resistant pathogens. Therefore, it is as important as ever to be good stewards of our currently available antimicrobials. Developing usage and dosing criteria for antimicrobials based on available data and literature is a step forward in optimizing the use of antibiotics—a precious medical resource.

A 49-year-old woman with a history of depression, bipolar disorder, and chronic back pain was brought to the emergency department unresponsive after having taken an unknown quantity of amitriptyline tablets.

On arrival, she was comatose, with a score of 3 (the lowest possible score) on the 15-point Glasgow Coma Scale. Her blood pressure was 65/22 mm Hg, heart rate 121 beats per minute, respiratory rate 14 per minute, and oxygen saturation 88% on room air. The rest of the initial physical examination was normal.

She was immediately intubated, put on mechanical ventilation, and given an infusion of a 1-L bolus of normal saline and 50 mmol (1 mmol/kg) of sodium bicarbonate. Norepinephrine infusion was started. Gastric lavage was not done.

Results of initial laboratory testing showed a serum potassium of 2.9 mmol/L (reference range 3.5–5.0) and a serum magnesium of 1.6 mmol/L (1.7–2.6), which were corrected with infusion of 60 mmol of potassium chloride and 2 g of magnesium sulfate. The serum amitriptyline measurement was ordered at the time of her presentation to the emergency department.

Arterial blood gas analysis showed:

• pH 7.15 (normal range 7.35–7.45)
• Paco₂ 66 mm Hg (34–46)
• Pao₂ 229 mm Hg (85–95)
• Bicarbonate 22 mmol/L (22–26).

The initial electrocardiogram (ECG) (Figure 1) showed regular wide-complex tachycardia with no definite right or left bundle branch block morphology, no discernible P waves, a QRS duration of 198 msec, right axis deviation, and no Brugada criteria to suggest ventricular tachycardia.

She remained hypotensive, with regular wide-complex tachycardia on the ECG. She was given an additional 1-L bolus of normal saline and 100 mmol (2 mmol/kg) of sodium bicarbonate, and within 1 minute the wide-complex tachycardia resolved to narrow-complex sinus tachycardia (Figure 2). At this point, an infusion of 150 mmol/L of sodium bicarbonate in dextrose 5% in water was started, with serial ECGs to monitor the QRS duration and serial arterial blood gas monitoring to maintain the pH between 7.45 and 7.55.

TRANSFER TO THE ICU

She was then transferred to the intensive care unit (ICU), where she remained for 2 weeks. While in the ICU, she had a single recurrence of wide-complex tachycardia that resolved immediately with an infusion of 100 mmol of sodium bicarbonate. A urine toxicology screen was negative, and the serum amitriptyline measurement, returned from the laboratory 48 hours after her initial presentation, was 594 ng/mL (reference range 100–250 ng/mL). She was eventually weaned off the norepinephrine infusion after 20 hours, the sodium bicarbonate infusion was discontinued after 4 days, and she was taken off mechanical ventilation after 10 days. Also during her ICU stay, she had seizures on day 3 and developed aspiration pneumonia.

From the ICU, she was transferred to a regular floor, where she stayed for another week and then was transferred to a rehabilitation center. This patient was known to have clinical depression and to have attempted suicide once before. She had recently been under additional psychosocial stresses, which likely prompted this second attempt.

She reportedly had no neurologic or cardiovascular sequelae after her discharge from the hospital.

AMITRIPTYLINE OVERDOSE

Amitriptyline causes a relatively high number of fatal overdoses, at 34 per 1 million prescriptions.¹ Death is usually from hypotension and ventricular arrhythmia caused by blockage of cardiac fast sodium channels leading to disturbances of cardiac conduction such as wide-complex tachycardia.

Other manifestations of amitriptyline overdose include seizures, sedation, and anticholinergic toxicity from variable blockade of gamma-aminobutyric acid receptors, histamine 1 receptors, and alpha receptors.²

In amitriptyline overdose, sinus tachycardia is the most common finding on ECG

Of the various changes on ECG described with amitriptyline overdose, sinus tachycardia is the most common. A QRS duration greater than 100 msec, right to extreme-right axis deviation with negative QRS complexes in leads I and aVL, and an R-wave amplitude greater than 3 mm in lead aVR are indications for sodium bicarbonate infusion, especially in hemodynamically unstable patients.³ Sodium bicarbonate increases the serum concentration of sodium and thereby overcomes the sodium channel blockade. It also alkalinizes the serum, favoring an electrically neutral form of amitriptyline that binds less to receptors and binds more to alpha-1-acid glycoprotein, decreasing the fraction of free drug available for toxicity.⁴

In patients with amitriptyline overdose, wide-complex tachycardia and hypotension refractory to sodium bicarbonate infusion can be treated with lidocaine, magnesium sulfate, direct-current cardioversion, and lipid resuscitation.^5,6 Treatment with class IA, IC, and III antiarrhythmics is contraindicated, as they block sodium channels and thus can worsen conduction disturbances.

A 49-year-old woman with a history of depression, bipolar disorder, and chronic back pain was brought to the emergency department unresponsive after having taken an unknown quantity of amitriptyline tablets.

On arrival, she was comatose, with a score of 3 (the lowest possible score) on the 15-point Glasgow Coma Scale. Her blood pressure was 65/22 mm Hg, heart rate 121 beats per minute, respiratory rate 14 per minute, and oxygen saturation 88% on room air. The rest of the initial physical examination was normal.

She was immediately intubated, put on mechanical ventilation, and given an infusion of a 1-L bolus of normal saline and 50 mmol (1 mmol/kg) of sodium bicarbonate. Norepinephrine infusion was started. Gastric lavage was not done.

Results of initial laboratory testing showed a serum potassium of 2.9 mmol/L (reference range 3.5–5.0) and a serum magnesium of 1.6 mmol/L (1.7–2.6), which were corrected with infusion of 60 mmol of potassium chloride and 2 g of magnesium sulfate. The serum amitriptyline measurement was ordered at the time of her presentation to the emergency department.

Arterial blood gas analysis showed:

• pH 7.15 (normal range 7.35–7.45)
• Paco₂ 66 mm Hg (34–46)
• Pao₂ 229 mm Hg (85–95)
• Bicarbonate 22 mmol/L (22–26).

The initial electrocardiogram (ECG) (Figure 1) showed regular wide-complex tachycardia with no definite right or left bundle branch block morphology, no discernible P waves, a QRS duration of 198 msec, right axis deviation, and no Brugada criteria to suggest ventricular tachycardia.

She remained hypotensive, with regular wide-complex tachycardia on the ECG. She was given an additional 1-L bolus of normal saline and 100 mmol (2 mmol/kg) of sodium bicarbonate, and within 1 minute the wide-complex tachycardia resolved to narrow-complex sinus tachycardia (Figure 2). At this point, an infusion of 150 mmol/L of sodium bicarbonate in dextrose 5% in water was started, with serial ECGs to monitor the QRS duration and serial arterial blood gas monitoring to maintain the pH between 7.45 and 7.55.

TRANSFER TO THE ICU

She was then transferred to the intensive care unit (ICU), where she remained for 2 weeks. While in the ICU, she had a single recurrence of wide-complex tachycardia that resolved immediately with an infusion of 100 mmol of sodium bicarbonate. A urine toxicology screen was negative, and the serum amitriptyline measurement, returned from the laboratory 48 hours after her initial presentation, was 594 ng/mL (reference range 100–250 ng/mL). She was eventually weaned off the norepinephrine infusion after 20 hours, the sodium bicarbonate infusion was discontinued after 4 days, and she was taken off mechanical ventilation after 10 days. Also during her ICU stay, she had seizures on day 3 and developed aspiration pneumonia.

From the ICU, she was transferred to a regular floor, where she stayed for another week and then was transferred to a rehabilitation center. This patient was known to have clinical depression and to have attempted suicide once before. She had recently been under additional psychosocial stresses, which likely prompted this second attempt.

She reportedly had no neurologic or cardiovascular sequelae after her discharge from the hospital.

AMITRIPTYLINE OVERDOSE

Amitriptyline causes a relatively high number of fatal overdoses, at 34 per 1 million prescriptions.¹ Death is usually from hypotension and ventricular arrhythmia caused by blockage of cardiac fast sodium channels leading to disturbances of cardiac conduction such as wide-complex tachycardia.

Other manifestations of amitriptyline overdose include seizures, sedation, and anticholinergic toxicity from variable blockade of gamma-aminobutyric acid receptors, histamine 1 receptors, and alpha receptors.²

In amitriptyline overdose, sinus tachycardia is the most common finding on ECG

Of the various changes on ECG described with amitriptyline overdose, sinus tachycardia is the most common. A QRS duration greater than 100 msec, right to extreme-right axis deviation with negative QRS complexes in leads I and aVL, and an R-wave amplitude greater than 3 mm in lead aVR are indications for sodium bicarbonate infusion, especially in hemodynamically unstable patients.³ Sodium bicarbonate increases the serum concentration of sodium and thereby overcomes the sodium channel blockade. It also alkalinizes the serum, favoring an electrically neutral form of amitriptyline that binds less to receptors and binds more to alpha-1-acid glycoprotein, decreasing the fraction of free drug available for toxicity.⁴

In patients with amitriptyline overdose, wide-complex tachycardia and hypotension refractory to sodium bicarbonate infusion can be treated with lidocaine, magnesium sulfate, direct-current cardioversion, and lipid resuscitation.^5,6 Treatment with class IA, IC, and III antiarrhythmics is contraindicated, as they block sodium channels and thus can worsen conduction disturbances.

A 49-year-old woman with a history of depression, bipolar disorder, and chronic back pain was brought to the emergency department unresponsive after having taken an unknown quantity of amitriptyline tablets.

On arrival, she was comatose, with a score of 3 (the lowest possible score) on the 15-point Glasgow Coma Scale. Her blood pressure was 65/22 mm Hg, heart rate 121 beats per minute, respiratory rate 14 per minute, and oxygen saturation 88% on room air. The rest of the initial physical examination was normal.

She was immediately intubated, put on mechanical ventilation, and given an infusion of a 1-L bolus of normal saline and 50 mmol (1 mmol/kg) of sodium bicarbonate. Norepinephrine infusion was started. Gastric lavage was not done.

Results of initial laboratory testing showed a serum potassium of 2.9 mmol/L (reference range 3.5–5.0) and a serum magnesium of 1.6 mmol/L (1.7–2.6), which were corrected with infusion of 60 mmol of potassium chloride and 2 g of magnesium sulfate. The serum amitriptyline measurement was ordered at the time of her presentation to the emergency department.

Arterial blood gas analysis showed:

• pH 7.15 (normal range 7.35–7.45)
• Paco₂ 66 mm Hg (34–46)
• Pao₂ 229 mm Hg (85–95)
• Bicarbonate 22 mmol/L (22–26).

The initial electrocardiogram (ECG) (Figure 1) showed regular wide-complex tachycardia with no definite right or left bundle branch block morphology, no discernible P waves, a QRS duration of 198 msec, right axis deviation, and no Brugada criteria to suggest ventricular tachycardia.

She remained hypotensive, with regular wide-complex tachycardia on the ECG. She was given an additional 1-L bolus of normal saline and 100 mmol (2 mmol/kg) of sodium bicarbonate, and within 1 minute the wide-complex tachycardia resolved to narrow-complex sinus tachycardia (Figure 2). At this point, an infusion of 150 mmol/L of sodium bicarbonate in dextrose 5% in water was started, with serial ECGs to monitor the QRS duration and serial arterial blood gas monitoring to maintain the pH between 7.45 and 7.55.

TRANSFER TO THE ICU

She was then transferred to the intensive care unit (ICU), where she remained for 2 weeks. While in the ICU, she had a single recurrence of wide-complex tachycardia that resolved immediately with an infusion of 100 mmol of sodium bicarbonate. A urine toxicology screen was negative, and the serum amitriptyline measurement, returned from the laboratory 48 hours after her initial presentation, was 594 ng/mL (reference range 100–250 ng/mL). She was eventually weaned off the norepinephrine infusion after 20 hours, the sodium bicarbonate infusion was discontinued after 4 days, and she was taken off mechanical ventilation after 10 days. Also during her ICU stay, she had seizures on day 3 and developed aspiration pneumonia.

From the ICU, she was transferred to a regular floor, where she stayed for another week and then was transferred to a rehabilitation center. This patient was known to have clinical depression and to have attempted suicide once before. She had recently been under additional psychosocial stresses, which likely prompted this second attempt.

She reportedly had no neurologic or cardiovascular sequelae after her discharge from the hospital.

AMITRIPTYLINE OVERDOSE

Amitriptyline causes a relatively high number of fatal overdoses, at 34 per 1 million prescriptions.¹ Death is usually from hypotension and ventricular arrhythmia caused by blockage of cardiac fast sodium channels leading to disturbances of cardiac conduction such as wide-complex tachycardia.

Other manifestations of amitriptyline overdose include seizures, sedation, and anticholinergic toxicity from variable blockade of gamma-aminobutyric acid receptors, histamine 1 receptors, and alpha receptors.²

In amitriptyline overdose, sinus tachycardia is the most common finding on ECG

Of the various changes on ECG described with amitriptyline overdose, sinus tachycardia is the most common. A QRS duration greater than 100 msec, right to extreme-right axis deviation with negative QRS complexes in leads I and aVL, and an R-wave amplitude greater than 3 mm in lead aVR are indications for sodium bicarbonate infusion, especially in hemodynamically unstable patients.³ Sodium bicarbonate increases the serum concentration of sodium and thereby overcomes the sodium channel blockade. It also alkalinizes the serum, favoring an electrically neutral form of amitriptyline that binds less to receptors and binds more to alpha-1-acid glycoprotein, decreasing the fraction of free drug available for toxicity.⁴

In patients with amitriptyline overdose, wide-complex tachycardia and hypotension refractory to sodium bicarbonate infusion can be treated with lidocaine, magnesium sulfate, direct-current cardioversion, and lipid resuscitation.^5,6 Treatment with class IA, IC, and III antiarrhythmics is contraindicated, as they block sodium channels and thus can worsen conduction disturbances.

The art of medicine includes picking the right drug for the right patient, especially when we can choose between different classes of efficacious therapies. But, in view of our growing understanding of the human genome, can science replace art?

That question is part of the promise of pharmacogenetics, the study of how inter-individual genetic differences influence a patient’s response to a specific drug. A patient’s genome dictates the expression of specific enzymes that metabolize a drug with various efficiencies: variant alleles may result in slightly different proteins that express different enzymatic activity, ie, different substrate affinities for a drug resulting in more or less efficient metabolism. Genomic differences may also dictate whether a specific biochemical pathway is dominant in generating a specific pathophysiologic response, in which case drugs that affect that pathway may be strikingly effective. This may partly explain the various responses to different antihypertensive drugs.

Another less well-understood example of pharmacogenetics is the link between specific HLA haplotypes and a dramatic increase in allergic reactions to specific medications, such as the link between HLA-B*57:01 and abacavir hypersensitivity.

In this issue of the Journal, DiPiero et al discuss thiopurine methyltransferase (TPMT), an enzyme responsible for the degradation of azathioprine, and how knowing the genetically determined relative activity of this enzyme should influence our initial dosing of this and related drugs. Patients with certain variant alleles of TPMT degrade azathioprine more slowly, and these patients are at higher risk of myelosuppressive toxicity from the drug when it is given at the full weight-based dose. The TPMT test is expensive but not prohibitively so, and it would seem that genomic testing is a reasonable clinical and cost-effective option.

As in the abacavir scenario noted above, genomic-based dosing of azathioprine makes scientific sense and offers proof of principle for the validity of pharmacogenomics. But is it truly a clinical game-changer?

The answer depends in part on how the prescribing physician doses the drug, which depends in part on what disease is being treated, how fast the drug needs to be at full dose, and whether there are equally effective alternatives. Recommendations have been offered that state if TPMT activity is normal, we can start at the usual maintenance dose of 1.5 to 2 mg/kg/day (or occasionally more). But if the patient is heterozygous for the wild-type gene and thus is a slower drug metabolizer, then initial dosing “should” be reduced to 25 to 50 mg/day, with close observation of the white blood cell count as the dose is slowly increased to the target. The very rare patient who is homozygous for a non–wild-type allele should not be given the drug.

My usual practice has been to start patients on 50 mg or less daily and slowly titrate up, asking them how they are tolerating the drug and watching the white count—notably, the same approach to be taken if I had done genotyping before starting the drug and had found the patient to be heterozygous for the TPMT gene.

Interestingly, one pragmatic clinical trial tested whether genotyping patients before starting azathioprine—with subsequent suggested dosing of the drug based on the genotype as above—was safer and cheaper than letting physicians dose as they chose.¹ It turned out that physicians participating in this study still dosed their patients conservatively. Even knowing that they might be able to give full doses from the start in patients with normal TPMT activity, many chose not to. I assume that many of those physicians felt as I do that there was no urgency in reaching the presumed-to-be-effective full weight-based therapeutic dose. (We don’t have a good clinical marker of azathioprine’s efficacy). At 4 months, the maintenance dose was about the same in all groups.

We have robust evidence to support the role of pharmacogenetics in informing the dosing of several medications, more than just the ones I have mentioned here. And in the right settings, we should use pharmacogenetic testing to limit toxicity and perhaps enhance efficacy in our drug selection. As the field moves rapidly forward, we will have many opportunities to improve clinical care by using our patients’ genomic information.

But like it or bemoan it, even when we have science in the house, the art of medicine still plays a role in our clinical decisions.

The art of medicine includes picking the right drug for the right patient, especially when we can choose between different classes of efficacious therapies. But, in view of our growing understanding of the human genome, can science replace art?

That question is part of the promise of pharmacogenetics, the study of how inter-individual genetic differences influence a patient’s response to a specific drug. A patient’s genome dictates the expression of specific enzymes that metabolize a drug with various efficiencies: variant alleles may result in slightly different proteins that express different enzymatic activity, ie, different substrate affinities for a drug resulting in more or less efficient metabolism. Genomic differences may also dictate whether a specific biochemical pathway is dominant in generating a specific pathophysiologic response, in which case drugs that affect that pathway may be strikingly effective. This may partly explain the various responses to different antihypertensive drugs.

Another less well-understood example of pharmacogenetics is the link between specific HLA haplotypes and a dramatic increase in allergic reactions to specific medications, such as the link between HLA-B*57:01 and abacavir hypersensitivity.

In this issue of the Journal, DiPiero et al discuss thiopurine methyltransferase (TPMT), an enzyme responsible for the degradation of azathioprine, and how knowing the genetically determined relative activity of this enzyme should influence our initial dosing of this and related drugs. Patients with certain variant alleles of TPMT degrade azathioprine more slowly, and these patients are at higher risk of myelosuppressive toxicity from the drug when it is given at the full weight-based dose. The TPMT test is expensive but not prohibitively so, and it would seem that genomic testing is a reasonable clinical and cost-effective option.

As in the abacavir scenario noted above, genomic-based dosing of azathioprine makes scientific sense and offers proof of principle for the validity of pharmacogenomics. But is it truly a clinical game-changer?

The answer depends in part on how the prescribing physician doses the drug, which depends in part on what disease is being treated, how fast the drug needs to be at full dose, and whether there are equally effective alternatives. Recommendations have been offered that state if TPMT activity is normal, we can start at the usual maintenance dose of 1.5 to 2 mg/kg/day (or occasionally more). But if the patient is heterozygous for the wild-type gene and thus is a slower drug metabolizer, then initial dosing “should” be reduced to 25 to 50 mg/day, with close observation of the white blood cell count as the dose is slowly increased to the target. The very rare patient who is homozygous for a non–wild-type allele should not be given the drug.

My usual practice has been to start patients on 50 mg or less daily and slowly titrate up, asking them how they are tolerating the drug and watching the white count—notably, the same approach to be taken if I had done genotyping before starting the drug and had found the patient to be heterozygous for the TPMT gene.

Interestingly, one pragmatic clinical trial tested whether genotyping patients before starting azathioprine—with subsequent suggested dosing of the drug based on the genotype as above—was safer and cheaper than letting physicians dose as they chose.¹ It turned out that physicians participating in this study still dosed their patients conservatively. Even knowing that they might be able to give full doses from the start in patients with normal TPMT activity, many chose not to. I assume that many of those physicians felt as I do that there was no urgency in reaching the presumed-to-be-effective full weight-based therapeutic dose. (We don’t have a good clinical marker of azathioprine’s efficacy). At 4 months, the maintenance dose was about the same in all groups.

We have robust evidence to support the role of pharmacogenetics in informing the dosing of several medications, more than just the ones I have mentioned here. And in the right settings, we should use pharmacogenetic testing to limit toxicity and perhaps enhance efficacy in our drug selection. As the field moves rapidly forward, we will have many opportunities to improve clinical care by using our patients’ genomic information.

But like it or bemoan it, even when we have science in the house, the art of medicine still plays a role in our clinical decisions.

The art of medicine includes picking the right drug for the right patient, especially when we can choose between different classes of efficacious therapies. But, in view of our growing understanding of the human genome, can science replace art?

That question is part of the promise of pharmacogenetics, the study of how inter-individual genetic differences influence a patient’s response to a specific drug. A patient’s genome dictates the expression of specific enzymes that metabolize a drug with various efficiencies: variant alleles may result in slightly different proteins that express different enzymatic activity, ie, different substrate affinities for a drug resulting in more or less efficient metabolism. Genomic differences may also dictate whether a specific biochemical pathway is dominant in generating a specific pathophysiologic response, in which case drugs that affect that pathway may be strikingly effective. This may partly explain the various responses to different antihypertensive drugs.

Another less well-understood example of pharmacogenetics is the link between specific HLA haplotypes and a dramatic increase in allergic reactions to specific medications, such as the link between HLA-B*57:01 and abacavir hypersensitivity.

In this issue of the Journal, DiPiero et al discuss thiopurine methyltransferase (TPMT), an enzyme responsible for the degradation of azathioprine, and how knowing the genetically determined relative activity of this enzyme should influence our initial dosing of this and related drugs. Patients with certain variant alleles of TPMT degrade azathioprine more slowly, and these patients are at higher risk of myelosuppressive toxicity from the drug when it is given at the full weight-based dose. The TPMT test is expensive but not prohibitively so, and it would seem that genomic testing is a reasonable clinical and cost-effective option.

As in the abacavir scenario noted above, genomic-based dosing of azathioprine makes scientific sense and offers proof of principle for the validity of pharmacogenomics. But is it truly a clinical game-changer?

The answer depends in part on how the prescribing physician doses the drug, which depends in part on what disease is being treated, how fast the drug needs to be at full dose, and whether there are equally effective alternatives. Recommendations have been offered that state if TPMT activity is normal, we can start at the usual maintenance dose of 1.5 to 2 mg/kg/day (or occasionally more). But if the patient is heterozygous for the wild-type gene and thus is a slower drug metabolizer, then initial dosing “should” be reduced to 25 to 50 mg/day, with close observation of the white blood cell count as the dose is slowly increased to the target. The very rare patient who is homozygous for a non–wild-type allele should not be given the drug.

My usual practice has been to start patients on 50 mg or less daily and slowly titrate up, asking them how they are tolerating the drug and watching the white count—notably, the same approach to be taken if I had done genotyping before starting the drug and had found the patient to be heterozygous for the TPMT gene.

Interestingly, one pragmatic clinical trial tested whether genotyping patients before starting azathioprine—with subsequent suggested dosing of the drug based on the genotype as above—was safer and cheaper than letting physicians dose as they chose.¹ It turned out that physicians participating in this study still dosed their patients conservatively. Even knowing that they might be able to give full doses from the start in patients with normal TPMT activity, many chose not to. I assume that many of those physicians felt as I do that there was no urgency in reaching the presumed-to-be-effective full weight-based therapeutic dose. (We don’t have a good clinical marker of azathioprine’s efficacy). At 4 months, the maintenance dose was about the same in all groups.

We have robust evidence to support the role of pharmacogenetics in informing the dosing of several medications, more than just the ones I have mentioned here. And in the right settings, we should use pharmacogenetic testing to limit toxicity and perhaps enhance efficacy in our drug selection. As the field moves rapidly forward, we will have many opportunities to improve clinical care by using our patients’ genomic information.

But like it or bemoan it, even when we have science in the house, the art of medicine still plays a role in our clinical decisions.

The thiopurines azathioprine, mercaptopurine, and thioguanine are prodrugs that are converted to active thioguanine nucleotide metabolites or methylated by thiopurine methyltransferase (TPMT) to compounds with less pharmacologic activity. In the absence of TPMT activity, patients are likely to have higher concentrations of thioguanine nucleotides, which can pose an increased risk of severe life-threatening myelosuppression. Determining TPMT activity, either directly by phenotyping or indirectly by determining the specific genetic allele (different alleles have different enzymatic activity), can help identify patients at greater risk of severe myelosuppression. Therefore, we recommend that TPMT testing be strongly considered before initiating therapy with a thiopurine.

THIOPURINES AND TPMT

Azathioprine, mercaptopurine, and thioguanine are used for treating autoimmune and inflammatory diseases^1–3 and certain types of cancer such as leukemias and lymphomas.^1,4–6 Typically, azathioprine is used to treat nonmalignant conditions, thioguanine is used to treat malignancies, and mercaptopurine can be used to treat both malignant and nonmalignant conditions.

Although the exact mechanism of action of these drugs has not been completely elucidated, the active thioguanine nucleotide metabolites are thought to be incorporated into the DNA of leukocytes, resulting in DNA damage that subsequently leads to cell death and myelosuppression.^7–9

Variants of the TPMT gene may alter the activity of the TPMT enzyme, resulting in individual variability in thiopurine metabolism. Compared with people with normal (high) TPMT activity, those with intermediate or low TPMT activity metabolize the drugs more slowly, and are likely to have higher thioguanine nucleotide concentrations and therefore an increased risk of myelosuppression.

One of the earliest correlations between TPMT activity and thiopurine-induced myelosuppression was described in a pediatric patient with acute lymphocytic leukemia.¹⁰ After being prescribed a conventional mercaptopurine dosage (75 mg/m² daily), the patient developed severe myelosuppression and was observed to have a thioguanine nucleotide metabolite concentration seven times the observed population median. TPMT phenotyping demonstrated that the patient had low TPMT activity. Reducing the mercaptopurine dose by approximately 90% resulted in normalization of thioguanine nucleotide metabolite concentrations, and the myelosuppression subsequently resolved.

Approximately 10% of the population has intermediate TPMT activity and 0.3% has low or absent TPMT activity, though these percentages vary depending on ancestry.¹ Research has demonstrated that approximately 30% to 60% of those with intermediate TPMT activity cannot tolerate a full thiopurine dose (eg, azathioprine 2–3 mg/kg/day or mercaptopurine 1.5 mg/kg/day).¹ Almost all patients with low TPMT activity will develop life-threating myelosuppression if prescribed a full thiopurine dose.¹

SHOULD TPMT ACTIVITY BE DETERMINED FOR EVERY PATIENT PRESCRIBED A THIOPURINE?

Although determining TPMT activity in thiopurine-naïve patients will assist clinicians in selecting a thiopurine starting dose or in deciding if an alternative agent is warranted, there are instances when a clinician may elect to not perform a TPMT genotype or phenotype test. For example, determining TPMT activity is not recommended for patients who previously tolerated thiopurine therapy at full steady-state doses.

The required starting dose of a thiopurine can influence the decision on whether or not to test for TPMT activity. TPMT genotyping or phenotyping may be of most benefit for patients requiring immediate full doses of a thiopurine.¹¹ Ideally, TPMT activity should be determined before prescribing immediate full doses of a thiopurine. This could be achieved by preemptively ordering a TPMT test in patients likely to require immunosuppression—for example, in patients diagnosed with inflammatory or autoimmune diseases. If therapy cannot be delayed and TPMT activity is unknown, ordering a TPMT test at the time of prescribing a full thiopurine dose is still of benefit. Depending on the clinical laboratory utilized for testing, TPMT phenotype results are usually reported in 3 to 5 days, and TPMT genotype results are usually reported in 5 to 7 days. Because most patients will not reach steady-state concentrations for 2 to 6 weeks, clinicians could initiate immediate full doses of a thiopurine and modify therapy based on TPMT test results before accumulation of thioguanine nucleotide metabolites occurs. Caution should be used with this approach, particularly in situations where the clinical laboratory may not return results in a timely manner.

For patients who are candidates for an initial low dose of a thiopurine, clinicians may choose to slowly titrate doses based on response and tolerability instead of determining TPMT activity.¹¹ Depending on the starting dose and how slowly titration occurs, initiating a thiopurine at a low dose and titrating based on response can be a feasible approach for patients with intermediate TPMT activity. Because drastic thiopurine dose reductions of approximately 10-fold are required for patients with low TPMT activity, which is a much smaller dosage than most clinicians will initially prescribe, the starting dosage will likely not be low enough to prevent myelosuppression in patients with low TPMT activity.^1,10

Determining TPMT activity can help clinicians establish an appropriate titration schedule. Patients with normal TPMT activity will usually reach thiopurine steady-state concentrations in 2 weeks, and the dosage can be titrated based on response.¹ Alterations in TPMT activity influence the pharmacokinetic parameters of thiopurines, and the time to reach steady-state is extended to 4 or 6 weeks for those with intermediate or low TPMT activity.¹ Increasing the thiopurine dosage before reaching steady state can lead to the prescribing of doses that will not be tolerated, resulting in myelosuppression.

Factors to consider when deciding if TPMT activity should be assessed include the disease state being treated and corresponding starting dose, the need for immediate full doses, and previous documented tolerance of thiopurines at steady-state doses. As with many aspects of medicine that have multiple options, coupled with an increase in patient access to healthcare information, the decision to test for TPMT activity may include shared decision-making between patients and providers. Although TPMT genotyping or phenotyping can help identify those at greatest risk of severe myelosuppression, such assays do not replace routine monitoring for myelosuppression, hepatotoxicity, or pancreatitis that may be caused by thiopurines.

WHAT TESTS ARE AVAILABLE TO DETERMINE TPMT ACTIVITY?

Patients with intermediate or low TPMT activity can be identified by either genotyping or phenotyping. There are considerations, though, that clinicians should be aware of before selecting a particular test.

TPMT genotyping

Four TPMT alleles, TPMT*2, *3A, *3B, and *3C, account for over 90% of inactivating polymorphisms.¹² Therefore, most reference laboratories only analyze for those genetic variants. Based on the reported test result, a predicted phenotype (eg, normal, intermediate, or low TPMT activity) can be assigned. Table 1 lists the predicted phenotypes for select genotyping results.

TPMT phenotyping

Phenotyping quantitates TPMT enzyme activity in erythrocytes, and based on the result, patients are classified as having normal, intermediate, or low TPMT activity. Because internal standards and other testing conditions may differ between reference laboratories, test results must be interpreted in the context of the laboratory that performed the assay.

Which test is right for my patient?

In most cases, either the genotype or the phenotype test provides sufficient information to guide thiopurine therapy. There are certain circumstances, though, in which the genotype or phenotype test is less informative.

TPMT genotyping, when performed using a blood specimen, is not recommended in those with a history of allogeneic bone marrow transplantation, as the result would reflect the donor’s genotype, not the patient’s. In such instances, monitoring of white blood cell counts and thiopurine metabolites may be more beneficial.

TPMT phenotyping may be inaccurate if performed within 30 to 90 days of an erythrocyte transfusion, as the test result may be influenced by donor erythrocytes. If a patient is receiving erythrocyte transfusions, TPMT genotyping is preferable to phenotyping.

Test cost may also be a consideration when determining if the genotype or phenotype test is best for your patient. Costs vary by laboratory, but phenotyping is generally less expensive than genotyping. The cost of genotyping, though, continues to decrease.¹³ The approximate commercial cost is $200 for phenotyping and $450 for genotyping, but laboratory fees may be substantially higher. Several insurance plans, including Medicare, cover TPMT testing, but reimbursement and copayments vary, depending on the patient’s specific plan.

There are conflicting data as to whether determining TPMT status is^11,14–18 or is not¹⁹ cost-effective. Multiple studies suggest that the cost of genotyping a sufficient number of patients to identify a single individual at high risk of myelosuppression is cheaper than the costs associated with treating an adverse event. Additional cost-benefit studies are needed, particularly studies that consider how bundled payments and outcomes-based reimbursement influence cost-effectiveness.

MODIFYING THIOPURINE THERAPY BASED ON TPMT ACTIVITY

There is a strong correlation between TPMT activity and tolerated thiopurine doses, with those having intermediate or low TPMT activity requiring lower doses.^10,20–23 Adjusting mercaptopurine doses based on TPMT activity to prevent hematopoietic toxicity has been successfully demonstrated in pediatric patients with acute lymphoblastic leukemia.²⁴ Furthermore, reducing initial thiopurine doses to avoid myelosuppression and titrating based on response has been shown to not compromise outcomes.^1,25,26 The Clinical Pharmacogenetic Implementation Consortium (CPIC) has developed an evidence-based guideline on how to adjust thiopurine doses based on TPMT activity,¹ summarized in Table 2. These dosing recommendations are classified as “strong.”

Patients with normal TPMT activity should be prescribed the usual thiopurine starting dose as indicated by disease-specific guidelines.

For those with intermediate TPMT activity, the CPIC guideline recommends reducing the initial targeted full dose of azathioprine and mercaptopurine by 30% to 70% and reducing the targeted full dose of thioguanine by 30% to 50%. The percentage of dose reduction depends on the targeted full dose. Siegel and Sands²⁷ suggested that for those who are diagnosed with inflammatory bowel disease and have intermediate TPMT activity, azathioprine should be initiated at a low dose and titrated to 1.25 mg/kg and mercaptopurine should be initiated at a low dose and titrated to 0.75 mg/kg. Based on these titration goals, if the targeted full dose for mercaptopurine is 1 mg/kg, then a dose reduction of approximately 30% would be more appropriate. If the targeted full dose is 1.5 mg/kg, a dose reduction of approximately 50% would be more appropriate. Thiopurine doses should be titrated based on response and disease-specific guidelines, allowing 2 to 4 weeks to reach steady state before dose titration.

For those with low TPMT activity, alternative therapy should be considered for nonmalignant conditions because of the risk of severe myelosuppression. For malignancy, or if a thiopurine is warranted for a nonmalignant condition, consider a 90% dose reduction and give the drug three times per week instead of daily. For example, acute lymphoblastic leukemia patients with low TPMT activity can be started on mercaptopurine 10 mg/m² three times per week instead of the usual starting dose.¹⁰ Thiopurine doses should be titrated based on response and disease-specific guidelines, allowing 4 to 6 weeks to reach steady state before dose titration.

RECOMMENDATIONS

Individuals with intermediate or low TPMT activity have an increased risk of myelosuppression. Because of the elevated risk for morbidity and death, especially for patients with low TPMT activity, multiple guidelines and regulatory agencies recommend TPMT genotyping or phenotyping if a thiopurine is prescribed.^25,28–32 Although additional cost-benefit analysis studies are needed, evidence suggests testing for TPMT activity may be cheaper than the costs associated with treating myelosuppression.

In view of treatment guidelines, the recommendations of regulatory agencies, cost-benefit analyses, and the availability of gene-based dosing recommendations, we consider the benefits of testing for TPMT activity to greatly outweigh any associated risks. Therefore, we recommend that TPMT testing be strongly considered before initiating therapy with a thiopurine.

The thiopurines azathioprine, mercaptopurine, and thioguanine are prodrugs that are converted to active thioguanine nucleotide metabolites or methylated by thiopurine methyltransferase (TPMT) to compounds with less pharmacologic activity. In the absence of TPMT activity, patients are likely to have higher concentrations of thioguanine nucleotides, which can pose an increased risk of severe life-threatening myelosuppression. Determining TPMT activity, either directly by phenotyping or indirectly by determining the specific genetic allele (different alleles have different enzymatic activity), can help identify patients at greater risk of severe myelosuppression. Therefore, we recommend that TPMT testing be strongly considered before initiating therapy with a thiopurine.

THIOPURINES AND TPMT

Azathioprine, mercaptopurine, and thioguanine are used for treating autoimmune and inflammatory diseases^1–3 and certain types of cancer such as leukemias and lymphomas.^1,4–6 Typically, azathioprine is used to treat nonmalignant conditions, thioguanine is used to treat malignancies, and mercaptopurine can be used to treat both malignant and nonmalignant conditions.

Although the exact mechanism of action of these drugs has not been completely elucidated, the active thioguanine nucleotide metabolites are thought to be incorporated into the DNA of leukocytes, resulting in DNA damage that subsequently leads to cell death and myelosuppression.^7–9

Variants of the TPMT gene may alter the activity of the TPMT enzyme, resulting in individual variability in thiopurine metabolism. Compared with people with normal (high) TPMT activity, those with intermediate or low TPMT activity metabolize the drugs more slowly, and are likely to have higher thioguanine nucleotide concentrations and therefore an increased risk of myelosuppression.

One of the earliest correlations between TPMT activity and thiopurine-induced myelosuppression was described in a pediatric patient with acute lymphocytic leukemia.¹⁰ After being prescribed a conventional mercaptopurine dosage (75 mg/m² daily), the patient developed severe myelosuppression and was observed to have a thioguanine nucleotide metabolite concentration seven times the observed population median. TPMT phenotyping demonstrated that the patient had low TPMT activity. Reducing the mercaptopurine dose by approximately 90% resulted in normalization of thioguanine nucleotide metabolite concentrations, and the myelosuppression subsequently resolved.

Approximately 10% of the population has intermediate TPMT activity and 0.3% has low or absent TPMT activity, though these percentages vary depending on ancestry.¹ Research has demonstrated that approximately 30% to 60% of those with intermediate TPMT activity cannot tolerate a full thiopurine dose (eg, azathioprine 2–3 mg/kg/day or mercaptopurine 1.5 mg/kg/day).¹ Almost all patients with low TPMT activity will develop life-threating myelosuppression if prescribed a full thiopurine dose.¹

SHOULD TPMT ACTIVITY BE DETERMINED FOR EVERY PATIENT PRESCRIBED A THIOPURINE?

Although determining TPMT activity in thiopurine-naïve patients will assist clinicians in selecting a thiopurine starting dose or in deciding if an alternative agent is warranted, there are instances when a clinician may elect to not perform a TPMT genotype or phenotype test. For example, determining TPMT activity is not recommended for patients who previously tolerated thiopurine therapy at full steady-state doses.

The required starting dose of a thiopurine can influence the decision on whether or not to test for TPMT activity. TPMT genotyping or phenotyping may be of most benefit for patients requiring immediate full doses of a thiopurine.¹¹ Ideally, TPMT activity should be determined before prescribing immediate full doses of a thiopurine. This could be achieved by preemptively ordering a TPMT test in patients likely to require immunosuppression—for example, in patients diagnosed with inflammatory or autoimmune diseases. If therapy cannot be delayed and TPMT activity is unknown, ordering a TPMT test at the time of prescribing a full thiopurine dose is still of benefit. Depending on the clinical laboratory utilized for testing, TPMT phenotype results are usually reported in 3 to 5 days, and TPMT genotype results are usually reported in 5 to 7 days. Because most patients will not reach steady-state concentrations for 2 to 6 weeks, clinicians could initiate immediate full doses of a thiopurine and modify therapy based on TPMT test results before accumulation of thioguanine nucleotide metabolites occurs. Caution should be used with this approach, particularly in situations where the clinical laboratory may not return results in a timely manner.

For patients who are candidates for an initial low dose of a thiopurine, clinicians may choose to slowly titrate doses based on response and tolerability instead of determining TPMT activity.¹¹ Depending on the starting dose and how slowly titration occurs, initiating a thiopurine at a low dose and titrating based on response can be a feasible approach for patients with intermediate TPMT activity. Because drastic thiopurine dose reductions of approximately 10-fold are required for patients with low TPMT activity, which is a much smaller dosage than most clinicians will initially prescribe, the starting dosage will likely not be low enough to prevent myelosuppression in patients with low TPMT activity.^1,10

Determining TPMT activity can help clinicians establish an appropriate titration schedule. Patients with normal TPMT activity will usually reach thiopurine steady-state concentrations in 2 weeks, and the dosage can be titrated based on response.¹ Alterations in TPMT activity influence the pharmacokinetic parameters of thiopurines, and the time to reach steady-state is extended to 4 or 6 weeks for those with intermediate or low TPMT activity.¹ Increasing the thiopurine dosage before reaching steady state can lead to the prescribing of doses that will not be tolerated, resulting in myelosuppression.

Factors to consider when deciding if TPMT activity should be assessed include the disease state being treated and corresponding starting dose, the need for immediate full doses, and previous documented tolerance of thiopurines at steady-state doses. As with many aspects of medicine that have multiple options, coupled with an increase in patient access to healthcare information, the decision to test for TPMT activity may include shared decision-making between patients and providers. Although TPMT genotyping or phenotyping can help identify those at greatest risk of severe myelosuppression, such assays do not replace routine monitoring for myelosuppression, hepatotoxicity, or pancreatitis that may be caused by thiopurines.

WHAT TESTS ARE AVAILABLE TO DETERMINE TPMT ACTIVITY?

Patients with intermediate or low TPMT activity can be identified by either genotyping or phenotyping. There are considerations, though, that clinicians should be aware of before selecting a particular test.

TPMT genotyping

Four TPMT alleles, TPMT*2, *3A, *3B, and *3C, account for over 90% of inactivating polymorphisms.¹² Therefore, most reference laboratories only analyze for those genetic variants. Based on the reported test result, a predicted phenotype (eg, normal, intermediate, or low TPMT activity) can be assigned. Table 1 lists the predicted phenotypes for select genotyping results.

TPMT phenotyping

Phenotyping quantitates TPMT enzyme activity in erythrocytes, and based on the result, patients are classified as having normal, intermediate, or low TPMT activity. Because internal standards and other testing conditions may differ between reference laboratories, test results must be interpreted in the context of the laboratory that performed the assay.

Which test is right for my patient?

In most cases, either the genotype or the phenotype test provides sufficient information to guide thiopurine therapy. There are certain circumstances, though, in which the genotype or phenotype test is less informative.

TPMT genotyping, when performed using a blood specimen, is not recommended in those with a history of allogeneic bone marrow transplantation, as the result would reflect the donor’s genotype, not the patient’s. In such instances, monitoring of white blood cell counts and thiopurine metabolites may be more beneficial.

TPMT phenotyping may be inaccurate if performed within 30 to 90 days of an erythrocyte transfusion, as the test result may be influenced by donor erythrocytes. If a patient is receiving erythrocyte transfusions, TPMT genotyping is preferable to phenotyping.

Test cost may also be a consideration when determining if the genotype or phenotype test is best for your patient. Costs vary by laboratory, but phenotyping is generally less expensive than genotyping. The cost of genotyping, though, continues to decrease.¹³ The approximate commercial cost is $200 for phenotyping and $450 for genotyping, but laboratory fees may be substantially higher. Several insurance plans, including Medicare, cover TPMT testing, but reimbursement and copayments vary, depending on the patient’s specific plan.

There are conflicting data as to whether determining TPMT status is^11,14–18 or is not¹⁹ cost-effective. Multiple studies suggest that the cost of genotyping a sufficient number of patients to identify a single individual at high risk of myelosuppression is cheaper than the costs associated with treating an adverse event. Additional cost-benefit studies are needed, particularly studies that consider how bundled payments and outcomes-based reimbursement influence cost-effectiveness.

MODIFYING THIOPURINE THERAPY BASED ON TPMT ACTIVITY

There is a strong correlation between TPMT activity and tolerated thiopurine doses, with those having intermediate or low TPMT activity requiring lower doses.^10,20–23 Adjusting mercaptopurine doses based on TPMT activity to prevent hematopoietic toxicity has been successfully demonstrated in pediatric patients with acute lymphoblastic leukemia.²⁴ Furthermore, reducing initial thiopurine doses to avoid myelosuppression and titrating based on response has been shown to not compromise outcomes.^1,25,26 The Clinical Pharmacogenetic Implementation Consortium (CPIC) has developed an evidence-based guideline on how to adjust thiopurine doses based on TPMT activity,¹ summarized in Table 2. These dosing recommendations are classified as “strong.”

Patients with normal TPMT activity should be prescribed the usual thiopurine starting dose as indicated by disease-specific guidelines.

For those with intermediate TPMT activity, the CPIC guideline recommends reducing the initial targeted full dose of azathioprine and mercaptopurine by 30% to 70% and reducing the targeted full dose of thioguanine by 30% to 50%. The percentage of dose reduction depends on the targeted full dose. Siegel and Sands²⁷ suggested that for those who are diagnosed with inflammatory bowel disease and have intermediate TPMT activity, azathioprine should be initiated at a low dose and titrated to 1.25 mg/kg and mercaptopurine should be initiated at a low dose and titrated to 0.75 mg/kg. Based on these titration goals, if the targeted full dose for mercaptopurine is 1 mg/kg, then a dose reduction of approximately 30% would be more appropriate. If the targeted full dose is 1.5 mg/kg, a dose reduction of approximately 50% would be more appropriate. Thiopurine doses should be titrated based on response and disease-specific guidelines, allowing 2 to 4 weeks to reach steady state before dose titration.

For those with low TPMT activity, alternative therapy should be considered for nonmalignant conditions because of the risk of severe myelosuppression. For malignancy, or if a thiopurine is warranted for a nonmalignant condition, consider a 90% dose reduction and give the drug three times per week instead of daily. For example, acute lymphoblastic leukemia patients with low TPMT activity can be started on mercaptopurine 10 mg/m² three times per week instead of the usual starting dose.¹⁰ Thiopurine doses should be titrated based on response and disease-specific guidelines, allowing 4 to 6 weeks to reach steady state before dose titration.

RECOMMENDATIONS

Individuals with intermediate or low TPMT activity have an increased risk of myelosuppression. Because of the elevated risk for morbidity and death, especially for patients with low TPMT activity, multiple guidelines and regulatory agencies recommend TPMT genotyping or phenotyping if a thiopurine is prescribed.^25,28–32 Although additional cost-benefit analysis studies are needed, evidence suggests testing for TPMT activity may be cheaper than the costs associated with treating myelosuppression.

In view of treatment guidelines, the recommendations of regulatory agencies, cost-benefit analyses, and the availability of gene-based dosing recommendations, we consider the benefits of testing for TPMT activity to greatly outweigh any associated risks. Therefore, we recommend that TPMT testing be strongly considered before initiating therapy with a thiopurine.

The thiopurines azathioprine, mercaptopurine, and thioguanine are prodrugs that are converted to active thioguanine nucleotide metabolites or methylated by thiopurine methyltransferase (TPMT) to compounds with less pharmacologic activity. In the absence of TPMT activity, patients are likely to have higher concentrations of thioguanine nucleotides, which can pose an increased risk of severe life-threatening myelosuppression. Determining TPMT activity, either directly by phenotyping or indirectly by determining the specific genetic allele (different alleles have different enzymatic activity), can help identify patients at greater risk of severe myelosuppression. Therefore, we recommend that TPMT testing be strongly considered before initiating therapy with a thiopurine.

THIOPURINES AND TPMT

Azathioprine, mercaptopurine, and thioguanine are used for treating autoimmune and inflammatory diseases^1–3 and certain types of cancer such as leukemias and lymphomas.^1,4–6 Typically, azathioprine is used to treat nonmalignant conditions, thioguanine is used to treat malignancies, and mercaptopurine can be used to treat both malignant and nonmalignant conditions.

Although the exact mechanism of action of these drugs has not been completely elucidated, the active thioguanine nucleotide metabolites are thought to be incorporated into the DNA of leukocytes, resulting in DNA damage that subsequently leads to cell death and myelosuppression.^7–9

Variants of the TPMT gene may alter the activity of the TPMT enzyme, resulting in individual variability in thiopurine metabolism. Compared with people with normal (high) TPMT activity, those with intermediate or low TPMT activity metabolize the drugs more slowly, and are likely to have higher thioguanine nucleotide concentrations and therefore an increased risk of myelosuppression.

One of the earliest correlations between TPMT activity and thiopurine-induced myelosuppression was described in a pediatric patient with acute lymphocytic leukemia.¹⁰ After being prescribed a conventional mercaptopurine dosage (75 mg/m² daily), the patient developed severe myelosuppression and was observed to have a thioguanine nucleotide metabolite concentration seven times the observed population median. TPMT phenotyping demonstrated that the patient had low TPMT activity. Reducing the mercaptopurine dose by approximately 90% resulted in normalization of thioguanine nucleotide metabolite concentrations, and the myelosuppression subsequently resolved.

Approximately 10% of the population has intermediate TPMT activity and 0.3% has low or absent TPMT activity, though these percentages vary depending on ancestry.¹ Research has demonstrated that approximately 30% to 60% of those with intermediate TPMT activity cannot tolerate a full thiopurine dose (eg, azathioprine 2–3 mg/kg/day or mercaptopurine 1.5 mg/kg/day).¹ Almost all patients with low TPMT activity will develop life-threating myelosuppression if prescribed a full thiopurine dose.¹

SHOULD TPMT ACTIVITY BE DETERMINED FOR EVERY PATIENT PRESCRIBED A THIOPURINE?

Although determining TPMT activity in thiopurine-naïve patients will assist clinicians in selecting a thiopurine starting dose or in deciding if an alternative agent is warranted, there are instances when a clinician may elect to not perform a TPMT genotype or phenotype test. For example, determining TPMT activity is not recommended for patients who previously tolerated thiopurine therapy at full steady-state doses.

The required starting dose of a thiopurine can influence the decision on whether or not to test for TPMT activity. TPMT genotyping or phenotyping may be of most benefit for patients requiring immediate full doses of a thiopurine.¹¹ Ideally, TPMT activity should be determined before prescribing immediate full doses of a thiopurine. This could be achieved by preemptively ordering a TPMT test in patients likely to require immunosuppression—for example, in patients diagnosed with inflammatory or autoimmune diseases. If therapy cannot be delayed and TPMT activity is unknown, ordering a TPMT test at the time of prescribing a full thiopurine dose is still of benefit. Depending on the clinical laboratory utilized for testing, TPMT phenotype results are usually reported in 3 to 5 days, and TPMT genotype results are usually reported in 5 to 7 days. Because most patients will not reach steady-state concentrations for 2 to 6 weeks, clinicians could initiate immediate full doses of a thiopurine and modify therapy based on TPMT test results before accumulation of thioguanine nucleotide metabolites occurs. Caution should be used with this approach, particularly in situations where the clinical laboratory may not return results in a timely manner.

For patients who are candidates for an initial low dose of a thiopurine, clinicians may choose to slowly titrate doses based on response and tolerability instead of determining TPMT activity.¹¹ Depending on the starting dose and how slowly titration occurs, initiating a thiopurine at a low dose and titrating based on response can be a feasible approach for patients with intermediate TPMT activity. Because drastic thiopurine dose reductions of approximately 10-fold are required for patients with low TPMT activity, which is a much smaller dosage than most clinicians will initially prescribe, the starting dosage will likely not be low enough to prevent myelosuppression in patients with low TPMT activity.^1,10

Determining TPMT activity can help clinicians establish an appropriate titration schedule. Patients with normal TPMT activity will usually reach thiopurine steady-state concentrations in 2 weeks, and the dosage can be titrated based on response.¹ Alterations in TPMT activity influence the pharmacokinetic parameters of thiopurines, and the time to reach steady-state is extended to 4 or 6 weeks for those with intermediate or low TPMT activity.¹ Increasing the thiopurine dosage before reaching steady state can lead to the prescribing of doses that will not be tolerated, resulting in myelosuppression.

Factors to consider when deciding if TPMT activity should be assessed include the disease state being treated and corresponding starting dose, the need for immediate full doses, and previous documented tolerance of thiopurines at steady-state doses. As with many aspects of medicine that have multiple options, coupled with an increase in patient access to healthcare information, the decision to test for TPMT activity may include shared decision-making between patients and providers. Although TPMT genotyping or phenotyping can help identify those at greatest risk of severe myelosuppression, such assays do not replace routine monitoring for myelosuppression, hepatotoxicity, or pancreatitis that may be caused by thiopurines.

WHAT TESTS ARE AVAILABLE TO DETERMINE TPMT ACTIVITY?

Patients with intermediate or low TPMT activity can be identified by either genotyping or phenotyping. There are considerations, though, that clinicians should be aware of before selecting a particular test.

TPMT genotyping

Four TPMT alleles, TPMT*2, *3A, *3B, and *3C, account for over 90% of inactivating polymorphisms.¹² Therefore, most reference laboratories only analyze for those genetic variants. Based on the reported test result, a predicted phenotype (eg, normal, intermediate, or low TPMT activity) can be assigned. Table 1 lists the predicted phenotypes for select genotyping results.

TPMT phenotyping

Phenotyping quantitates TPMT enzyme activity in erythrocytes, and based on the result, patients are classified as having normal, intermediate, or low TPMT activity. Because internal standards and other testing conditions may differ between reference laboratories, test results must be interpreted in the context of the laboratory that performed the assay.

Which test is right for my patient?

In most cases, either the genotype or the phenotype test provides sufficient information to guide thiopurine therapy. There are certain circumstances, though, in which the genotype or phenotype test is less informative.

TPMT genotyping, when performed using a blood specimen, is not recommended in those with a history of allogeneic bone marrow transplantation, as the result would reflect the donor’s genotype, not the patient’s. In such instances, monitoring of white blood cell counts and thiopurine metabolites may be more beneficial.

TPMT phenotyping may be inaccurate if performed within 30 to 90 days of an erythrocyte transfusion, as the test result may be influenced by donor erythrocytes. If a patient is receiving erythrocyte transfusions, TPMT genotyping is preferable to phenotyping.

Test cost may also be a consideration when determining if the genotype or phenotype test is best for your patient. Costs vary by laboratory, but phenotyping is generally less expensive than genotyping. The cost of genotyping, though, continues to decrease.¹³ The approximate commercial cost is $200 for phenotyping and $450 for genotyping, but laboratory fees may be substantially higher. Several insurance plans, including Medicare, cover TPMT testing, but reimbursement and copayments vary, depending on the patient’s specific plan.

There are conflicting data as to whether determining TPMT status is^11,14–18 or is not¹⁹ cost-effective. Multiple studies suggest that the cost of genotyping a sufficient number of patients to identify a single individual at high risk of myelosuppression is cheaper than the costs associated with treating an adverse event. Additional cost-benefit studies are needed, particularly studies that consider how bundled payments and outcomes-based reimbursement influence cost-effectiveness.

MODIFYING THIOPURINE THERAPY BASED ON TPMT ACTIVITY

There is a strong correlation between TPMT activity and tolerated thiopurine doses, with those having intermediate or low TPMT activity requiring lower doses.^10,20–23 Adjusting mercaptopurine doses based on TPMT activity to prevent hematopoietic toxicity has been successfully demonstrated in pediatric patients with acute lymphoblastic leukemia.²⁴ Furthermore, reducing initial thiopurine doses to avoid myelosuppression and titrating based on response has been shown to not compromise outcomes.^1,25,26 The Clinical Pharmacogenetic Implementation Consortium (CPIC) has developed an evidence-based guideline on how to adjust thiopurine doses based on TPMT activity,¹ summarized in Table 2. These dosing recommendations are classified as “strong.”

Patients with normal TPMT activity should be prescribed the usual thiopurine starting dose as indicated by disease-specific guidelines.

For those with intermediate TPMT activity, the CPIC guideline recommends reducing the initial targeted full dose of azathioprine and mercaptopurine by 30% to 70% and reducing the targeted full dose of thioguanine by 30% to 50%. The percentage of dose reduction depends on the targeted full dose. Siegel and Sands²⁷ suggested that for those who are diagnosed with inflammatory bowel disease and have intermediate TPMT activity, azathioprine should be initiated at a low dose and titrated to 1.25 mg/kg and mercaptopurine should be initiated at a low dose and titrated to 0.75 mg/kg. Based on these titration goals, if the targeted full dose for mercaptopurine is 1 mg/kg, then a dose reduction of approximately 30% would be more appropriate. If the targeted full dose is 1.5 mg/kg, a dose reduction of approximately 50% would be more appropriate. Thiopurine doses should be titrated based on response and disease-specific guidelines, allowing 2 to 4 weeks to reach steady state before dose titration.

For those with low TPMT activity, alternative therapy should be considered for nonmalignant conditions because of the risk of severe myelosuppression. For malignancy, or if a thiopurine is warranted for a nonmalignant condition, consider a 90% dose reduction and give the drug three times per week instead of daily. For example, acute lymphoblastic leukemia patients with low TPMT activity can be started on mercaptopurine 10 mg/m² three times per week instead of the usual starting dose.¹⁰ Thiopurine doses should be titrated based on response and disease-specific guidelines, allowing 4 to 6 weeks to reach steady state before dose titration.

RECOMMENDATIONS

Individuals with intermediate or low TPMT activity have an increased risk of myelosuppression. Because of the elevated risk for morbidity and death, especially for patients with low TPMT activity, multiple guidelines and regulatory agencies recommend TPMT genotyping or phenotyping if a thiopurine is prescribed.^25,28–32 Although additional cost-benefit analysis studies are needed, evidence suggests testing for TPMT activity may be cheaper than the costs associated with treating myelosuppression.

In view of treatment guidelines, the recommendations of regulatory agencies, cost-benefit analyses, and the availability of gene-based dosing recommendations, we consider the benefits of testing for TPMT activity to greatly outweigh any associated risks. Therefore, we recommend that TPMT testing be strongly considered before initiating therapy with a thiopurine.

Any time patients enter or leave the hospital, they risk being harmed by errors in their medications.¹ Adverse events from medication errors during transitions of care are common but often preventable. One key approach is to systematically review every patient’s medication list on admission and discharge and resolve any discrepancies. These transitions are also an opportunity to address other medication-related problems, such as adherence, drug interactions, and clinical appropriateness.

This article summarizes the types and prevalence of medication problems that occur during hospital-based transitions of care, and suggests strategies to decrease the risk of medication errors, focusing on medication reconciliation and related interventions that clinicians can use at the bedside to improve medication safety.

DEFINING TERMS

A medication discrepancy is any variance noted in a patient’s documented medication regimen across different medication lists or sites of care. While some differences reflect intentional and clinically appropriate changes to the regimen, others are unintentional and reflect inaccurate or incomplete information. These unintentional discrepancies are medication errors.

Depending on the clinical circumstances and medications involved, such errors may lead to an adverse drug event (ADE), defined as actual harm or injury resulting from a medication. Sometimes a medication error does not cause harm immediately but could if left uncorrected; this is called a potential ADE.

An important goal during transitions of care is to reduce unintentional medication discrepancies, thereby reducing potential and actual ADEs.

ERRORS ARISE AT DISCHARGE—AND EVEN MORE AT ADMISSION

Hospital discharge is a widely recognized transition in which patient harm occurs. As many as 70% of patients may have an unintentional medication discrepancy at hospital discharge, with many of those discrepancies having potential for harm.² Indeed, during the first few weeks after discharge, 50% of patients have a clinically important medication error,³ and 20% experience an adverse event, most commonly an ADE.⁴ ADEs are associated with excess health care utilization,^5–7 and many are preventable through strategies such as medication reconciliation.^5,8

Importantly, more errors arise at hospital admission than at other times.^9,10

Errors in medication histories are the most common source of discrepancies, affecting up to two-thirds of admitted patients.^11,12 More than one-quarter of hospital prescribing errors can be attributed to incomplete medication histories at the time of admission,¹³ and nearly three times as many clinically important medication discrepancies are related to history-taking errors on admission rather than reconciliation errors at discharge.⁹

Most discrepancies occurring at the time of admission have the potential to cause harm, particularly if the errors persist beyond discharge.¹⁴ Therefore, taking a complete and accurate medication history on hospital admission is critical to ensuring safe care transitions.

MEDICATION RECONCILIATION: BARRIERS AND FACILITATORS

Medication reconciliation is a strategy for reducing medication discrepancies in patients moving across care settings. Simply put, it is the process by which a patient’s medication list is obtained, compared, and clarified across different sites of care.¹⁵ It has consistently been shown to decrease medication errors compared with usual care,¹⁶ and it is strongly supported by national and international organizations.^17–21

In clinical practice, many physicians and institutions have found medication reconciliation difficult to implement, owing to barriers at the level of the patient, provider, and system (Table  1). In response to these challenges, two initiatives have synthesized best practices and offer toolkits that hospitals and clinicians can use: the Medications at Transitions and Clinical Handoffs (MATCH) program²² and the Multi-Center Medication Reconciliation Quality Improvement Study (MARQUIS).²³

Lack of resources is a widely acknowledged challenge. Thus, the MARQUIS investigators²³ suggested focusing on the admission history, where most errors occur, and applying the most resource-intensive interventions in patients at highest risk of ADEs, ie, those who are elderly, have multiple comorbid conditions, or take numerous medications.¹⁶

Although the risk of an ADE increases with the number of medications a patient takes,⁴ the exact number of drugs that defines high risk has not been well established. Targeting patients who take 10 or more maintenance medications is a reasonable initial approach,²⁴ but institutions should tailor risk stratification to their patient populations and available resources. Patients taking high-risk medications such as anticoagulants and insulin could also be prioritized for review, since these medications are more likely to cause serious patient harm when used without appropriate clinical oversight.⁷

Using pharmacy staff to perform medication history-taking, reconciliation, and patient counseling has been shown to produce favorable patient outcomes, particularly for higher-risk patients.^16,23

The MARQUIS investigators found they could boost the chances of success by sharing stories of patient harm to foster “buy-in” among frontline staff, providing formal training to clinicians on how to take a medication history, and obtaining the support of nursing leaders to champion improvement efforts.²³

Additionally, patients should be empowered to maintain an accurate medication list. We address strategies for improving patient engagement and adherence in a later section.

BEST PRACTICES FOR IMPROVING MEDICATION SAFETY

Medication reconciliation is one of several measures necessary to optimize medication safety during transitions of care. It typically includes the following actions:

• Interview the patient or caregiver to determine the list of medications the patient is currently taking (or supposed to be taking); consult other sources if needed.
• List medications that are being ordered during the clinical encounter.
• Compare these two lists, making note of medications that are stopped, changed, or newly prescribed.
• Resolve any discrepancies.
• Communicate the reconciled list to the patient, appropriate caregivers, and providers of follow-up care.

At a rudimentary level, medication reconciliation encompasses medication list management along the continuum of care. However, we recommend leveraging medication reconciliation as an opportunity to further enhance medication safety by reviewing the appropriateness of each medication, seizing opportunities to streamline or simplify the regimen, assessing patient and caregiver understanding of medication instructions and potential ADEs, and delivering appropriate counseling to enhance medication use. Table 2 outlines our framework for medication management during hospital-based transitions.

STEP 1: OBTAIN A COMPLETE PREADMISSION MEDICATION LIST

The “best-possible medication history” is obtained in a systematic process of interviewing the patient or caregiver plus reviewing at least one other reliable source.²³ The resulting list should include all medications the patient is taking (prescription and nonprescription), doses, directions for use, formulations if applicable, indications, start and stop dates, and medication allergies and reactions.

Review existing information. Before eliciting a history from the patient, review his or her recorded medical history and existing medication lists (eg, prior discharge summaries, records from other facilities, records from outpatient visits, pharmacy fill data). This will provide context about the regimen and help identify issues and questions that can be addressed during the history-taking.

Ask open-ended questions. Instead of just asking the patient to confirm the accuracy of the existing medication list, we recommend actively obtaining the full medication list from the patient or caregiver. The conversation should begin with an open-ended question such as, “What medications do you take at home?” This approach will also allow the clinician to gauge the patient’s level of understanding of each medication’s indication and dosing instructions. Using a series of prompts such as those recommended in Table 3 will elicit a best-possible medical history, while verifying all of the medications on the existing list.

Clarify discrepancies. Resolve differences between the existing medication lists and the patient’s or caregiver’s report during the preadmission interview. Examples include errors of omission (a medication is missing), errors of commission (an additional medication is present), and discrepancies in the strength, formulation, dosing instructions, and indications for the drugs. If necessary, other sources of information should be consulted, such as the patient’s medication bottles, pharmacy or pharmacies, primary care physician, and a family member or caregiver.

Assess adherence. The extent to which patients take their medications as directed is an important component of the history, but is often left out. Medication nonadherence rates in the United States are 40% to 70%,²⁵ contributing to poor patient outcomes and imposing extraordinary costs on the health care system.²⁶

Asking open-ended, nonjudgmental questions at the time of hospital admission will help to uncover medication-taking behaviors as well as barriers to adherence (Table 3). The patient’s responses should be taken into account when determining the treatment plan.

Document your findings. After completing the medication history and clarifying discrepancies, document the preadmission list in the medical record. All members of the health care team should have access to view and update the same list, as new information about the preadmission medications may be uncovered after the initial history.

Make clinical decisions. Complete the admission medication reconciliation by deciding whether each medication on the list should be continued, changed, held, or discontinued on the basis of the patient’s clinical condition. Well-designed information technology applications enable the provider to document each action and the rationale for it, as well as carry that information into the order-entry system. Medications marked as held or discontinued on admission should be revisited as the patient’s clinical condition changes and at discharge.

STEP 2: AVOID RECONCILIATION ERRORS

Reconciliation errors reflect discrepancies between the medication history and the medications that are ordered after admission.

Reconciliation errors are less common than medication history errors, accounting for approximately one-third of potentially harmful medication errors in hospitalized medical patients.⁹ These include errors of omission (a medication is omitted from the orders), errors of commission (a medication is prescribed with no indication for continuation), and therapeutic duplication.

Preventing errors of omission

Medications are often held at transition points for appropriate clinical reasons. Examples include holding anticoagulants and antiplatelet agents in patients who have gastrointestinal bleeding or an upcoming procedure, antihypertensives in patients with hemodynamic instability, and other chronic medications in patients with an acute illness.

Poor documentation and communication of these decisions can lead to a failure to resume the medications—an error of omission—at hospital discharge.

Hospitalized patients are at risk of unintentional discontinuation of their chronic medications, including antiplatelet drugs, anticoagulants, statins, and thyroid replacement, particularly if admitted to the intensive care unit.¹² These errors can be minimized by a standardized medication reconciliation process at each transition and clear documentation of the medication plan.

Communication among providers can be improved if the admitting clinician documents clearly whether each preadmission medication is being continued, changed, or stopped, along with the reason for doing so, and makes this information available throughout the hospital stay. Upon transfer to another unit and at discharge, the physician should review each; preadmission medication that was held and the patient’s current clinical status and, based on that information, decide whether medications that were held should be resumed. If a medication will be restarted later, specific instructions should be documented and communicated to the patient and the physicians who are taking over his or her care.

Preventing errors of commission

Failure to perform a complete reconciliation at each transition of care and match each medication with an appropriate indication can lead to errors of commission.

One study showed that 44% of patients were prescribed at least one unnecessary drug at hospital discharge, one-fourth of which were started during the hospitalization.²⁷ Commonly prescribed unnecessarily were gastrointestinal agents, central nervous system drugs, nutrients, and supplements.

It is critical to assess each medication’s ongoing need, appropriateness, and risk-benefit ratio at every transition. Medications no longer indicated should be discontinued in order to simplify the regimen, avoid unnecessary drug exposure, and prevent ADEs.

For example, proton pump inhibitors or histamine 2 receptor blockers are often started in the hospital for stress ulcer prophylaxis. One-third of patients are then discharged home on the medication, and 6 months later half of those patients are still taking the unnecessary drug.²⁸ This situation can be avoided by limiting use of these medications to appropriate circumstances, clearly marking the indication as stress ulcer prophylaxis (as opposed to an ongoing condition that will require continuing it after discharge), and discontinuing the agent when appropriate.

All drugs, even common and seemingly benign ones, carry some risk and should be discontinued when no longer needed. Thus, medications added during the hospitalization to control acute symptoms should also be reviewed at each transition to prevent inappropriate continuation when symptoms have resolved.

One study, for example, found that many patients were discharged with inappropriate prescriptions for atypical antipsychotics after receiving them in the intensive care unit, likely for delirium.²⁹ Documenting that an acute issue such as delirium has resolved should prompt the discontinuation of therapy.

Preventing therapeutic duplication

Therapeutic duplication occurs in about 8% of discharges.¹ These errors often result from formulary substitutions or altering the dosage form in the acute setting. For example, patients who receive a prescription for the substituted agent at discharge and also resume their prehospitalization medications end up with duplicate therapy.

Therapeutic substitution is common at the time of admission to the hospital as a result of formulary restrictions. Drug classes that are frequently substituted include statins, antihypertensives, urinary antispasmodics, and proton pump inhibitors. Physicians should be familiar with the preferred agents on the hospital formulary and make careful note when a substitution occurs. Furthermore, hospital systems should be developed to remind the physician to switch back to the outpatient medication at discharge.

Similar problems occur when home medications are replaced with different dosage forms with different pharmacokinetic properties. For example, a long-acting medication may be temporarily replaced with an intravenous solution or immediate-release tablet for several reasons, including nothing-by-mouth status, unstable clinical condition, need for titration, and need to crush the tablet to give the drug per tube. The differing formulations must be reconciled throughout the patient’s hospital course and at discharge to avoid therapeutic duplication and serious medication errors. Deliberate changes to the dosage form should be clearly communicated in the discharge medication list so that patients and other clinicians are aware.

Hospital systems should also have the capability to identify duplications in the medication list and to warn prescribers of these errors. The ability to group medications by drug class or sort the medication list alphabetically by generic name can help uncover duplication errors.

STEP 3: REVIEW THE LIST IN VIEW OF THE CLINICAL PICTURE

Transitions of care should prompt providers to review the medication list for possible drug-disease interactions, confirm compliance with evidence-based guidelines, and evaluate the risks and benefits of each medication in the context of the patient’s age and acute and chronic medical issues. This is also an opportunity to screen the full list for potentially inappropriate medications and high-alert drugs such as insulin or anticoagulants, which are more likely than other drugs to cause severe harm when used in error.

Acute kidney injury. New drug-disease interactions can arise during a hospitalization and can affect dosing and the choice of drug. The onset of acute kidney injury, for example, often necessitates adjusting or discontinuing nephrotoxic and renally excreted medications. ADEs or potential ADEs have been reported in 43% of hospitalized patients with acute kidney injury.³⁰

Because acute kidney injury is often transient, medications may need to be held or adjusted several times until renal function stabilizes. This can be challenging across the continuum of care and requires close monitoring of the serum creatinine level and associated drug doses and levels, if applicable. Well-designed clinical decision support tools can integrate laboratory data and alert the prescriber to a clinically important increase or decrease in serum creatinine that may warrant a change in therapy. Modifications to the regimen and a plan for timely follow-up of the serum creatinine level should be clearly documented in the discharge plan.

Liver disease. Similar attention should be given to drugs that are hepatically metabolized if a patient has acute or chronic liver impairment.

Geriatric patients, particularly those who present with altered mental status, falls, or urinary retention, should have their medication list reviewed for potentially inappropriate medications, which are drugs that pose increased risk of poor outcomes in older adults.^31,32 Patients and providers may have been willing to accept the risk of medications such as anticholinergics or sedative-hypnotics when the drugs were initiated, but circumstances can change over time, especially in this patient population. Hospitalization is a prime opportunity to screen for medications that meet the Beers criteria³¹ for agents to avoid or use with caution in older adults.

As-needed medications. Medications prescribed on an as-needed basis in the hospital should be reviewed for continuation or discontinuation at discharge. How often the medication was given can inform this decision.

For example, if as-needed opioids were used frequently, failure to develop a plan of care for pain can lead to persistent symptoms and, possibly, to readmission.^33,34 Similar scenarios occur with use of as-needed blood pressure medications, laxatives, and correction-dose insulin.

If an as-needed medication was used consistently during hospitalization, the physician should consider whether a regularly scheduled medication is needed. Conversely, if the medication was not used during the inpatient admission, it can likely be discontinued.

STEP 4: PREPARE THE PATIENT AND FOLLOW-UP PROVIDER

Once a clinician has performed medication reconciliation, including obtaining a best-possible medical history and carefully reviewing the medication list and orders for errors and clinical appropriateness, the next steps are to ensure the patient understands what he or she needs to do and to confirm that suitable follow-up plans are in place. These measures should be taken at all transitions of care but are critically important at hospital discharge.

Preparing the patient and caregiver

An accurate, reconciled medication list should be given to the patient, caregiver, or both, and should be reviewed before discharge.¹⁷

Approximately one-third of Americans have low health literacy skills, so medication lists and associated materials should be easy to understand.³⁵ Medication lists should be written in plain language and formatted for optimal readability (Table 4), clearly stating which medications to continue, change, hold temporarily, and stop.

Patients recall and comprehend about half of the information provided during a medical encounter.³⁶ Thus, medication teaching should focus on key points including changes or additions to the regimen, specific instructions for follow-up and monitoring, and how to handle common and serious side effects.

To confirm patient understanding, clinicians should use “teach-back,” ie, provide the patient with information and then ask him or her to repeat back key points.^37,38 The patient and family should also be encouraged to ask questions before discharge.

If not already addressed during the hospital stay, barriers to medication adherence and ability to obtain the medications should be attended to at this time (Table 5). Also, the plan to pick up the medications should be verified with the patient and caregiver. Verify that there is transportation to a particular pharmacy that is open at the time of discharge, and that the patient can afford the medications.

Ensuring appropriate follow-up

Studies have shown that timely in-home or telephone follow-up after discharge can decrease adverse events and postdischarge health care utilization.^39,40 Telephone follow-up that includes thorough medication reconciliation can help detect and resolve medication issues early after discharge and can close gaps related to monitoring and follow-up.

Medication reconciliation by telephone can be time-consuming. Depending on the number of medications that need to be reviewed, calls can take between 10 and 60 minutes. Postdischarge phone calls should be performed by clinical personnel who are able to identify medication-related problems. A pharmacist should be an available resource to assist with complex regimens, to help resolve medication discrepancies, and to address patient concerns. Table 6 provides tips for conducting follow-up phone calls.

Resolving discrepancies identified during follow-up calls can be difficult, as changes to the medication regimen are often not communicated effectively to other members of the care team. Physicians should document the complete medication list and plan in the discharge summary, and there should be a method for the caller to record updates to the medication list in the medical record so that they are apparent at the outpatient follow-up visit.

An additional challenge is that it is frequently unclear which physician “owns” which medications. Therefore, designating a contact person for each medication until follow-up can be very valuable. At a minimum, a “physician owner” for high-alert medications such as insulin, anticoagulants, and diuretics should be identified to provide close follow-up, titration, and monitoring.

There should also be a plan for the patient to obtain refills of essential long-term medications, such as antiplatelet agents following stent placement.

SUMMARY AND RECOMMENDATIONS

Medication-related problems during hospital admission and discharge are common and range from minor discrepancies in the medication list to errors in history-taking, prescribing, and reconciliation that can lead to potential or actual patient harm. Putting systems in place to facilitate medication reconciliation can decrease the occurrence of medication discrepancies and ADEs, thereby improving patient safety during these critical transitions between care settings and providers. Institutional medication reconciliation programs should focus resources on the admission history-taking step, target the highest-risk patients for the most intensive interventions, and involve pharmacy personnel when possible.

On an individual level, clinicians can incorporate additional interventions into their workflows to optimize medication safety for hospitalized patients. Using a structured approach to obtain a complete and accurate medication list at the time of hospital admission will help providers identify medication-related problems and prevent the propagation of errors throughout the hospital stay and at discharge. Focusing additional time and effort on a comprehensive review of the medication list for errors of omission and commission, patient-specific needs, and high-alert drugs will further decrease the risk of medication errors. Finally, providing discharge counseling targeting patient barriers to adherence and ensuring a proper handover of medication information and rationale for medication changes to outpatient providers will improve the chances of a safe transition.

Any time patients enter or leave the hospital, they risk being harmed by errors in their medications.¹ Adverse events from medication errors during transitions of care are common but often preventable. One key approach is to systematically review every patient’s medication list on admission and discharge and resolve any discrepancies. These transitions are also an opportunity to address other medication-related problems, such as adherence, drug interactions, and clinical appropriateness.

This article summarizes the types and prevalence of medication problems that occur during hospital-based transitions of care, and suggests strategies to decrease the risk of medication errors, focusing on medication reconciliation and related interventions that clinicians can use at the bedside to improve medication safety.

DEFINING TERMS

A medication discrepancy is any variance noted in a patient’s documented medication regimen across different medication lists or sites of care. While some differences reflect intentional and clinically appropriate changes to the regimen, others are unintentional and reflect inaccurate or incomplete information. These unintentional discrepancies are medication errors.

Depending on the clinical circumstances and medications involved, such errors may lead to an adverse drug event (ADE), defined as actual harm or injury resulting from a medication. Sometimes a medication error does not cause harm immediately but could if left uncorrected; this is called a potential ADE.

An important goal during transitions of care is to reduce unintentional medication discrepancies, thereby reducing potential and actual ADEs.

ERRORS ARISE AT DISCHARGE—AND EVEN MORE AT ADMISSION

Hospital discharge is a widely recognized transition in which patient harm occurs. As many as 70% of patients may have an unintentional medication discrepancy at hospital discharge, with many of those discrepancies having potential for harm.² Indeed, during the first few weeks after discharge, 50% of patients have a clinically important medication error,³ and 20% experience an adverse event, most commonly an ADE.⁴ ADEs are associated with excess health care utilization,^5–7 and many are preventable through strategies such as medication reconciliation.^5,8

Importantly, more errors arise at hospital admission than at other times.^9,10

Errors in medication histories are the most common source of discrepancies, affecting up to two-thirds of admitted patients.^11,12 More than one-quarter of hospital prescribing errors can be attributed to incomplete medication histories at the time of admission,¹³ and nearly three times as many clinically important medication discrepancies are related to history-taking errors on admission rather than reconciliation errors at discharge.⁹

Most discrepancies occurring at the time of admission have the potential to cause harm, particularly if the errors persist beyond discharge.¹⁴ Therefore, taking a complete and accurate medication history on hospital admission is critical to ensuring safe care transitions.

MEDICATION RECONCILIATION: BARRIERS AND FACILITATORS

Medication reconciliation is a strategy for reducing medication discrepancies in patients moving across care settings. Simply put, it is the process by which a patient’s medication list is obtained, compared, and clarified across different sites of care.¹⁵ It has consistently been shown to decrease medication errors compared with usual care,¹⁶ and it is strongly supported by national and international organizations.^17–21

In clinical practice, many physicians and institutions have found medication reconciliation difficult to implement, owing to barriers at the level of the patient, provider, and system (Table  1). In response to these challenges, two initiatives have synthesized best practices and offer toolkits that hospitals and clinicians can use: the Medications at Transitions and Clinical Handoffs (MATCH) program²² and the Multi-Center Medication Reconciliation Quality Improvement Study (MARQUIS).²³

Lack of resources is a widely acknowledged challenge. Thus, the MARQUIS investigators²³ suggested focusing on the admission history, where most errors occur, and applying the most resource-intensive interventions in patients at highest risk of ADEs, ie, those who are elderly, have multiple comorbid conditions, or take numerous medications.¹⁶

Although the risk of an ADE increases with the number of medications a patient takes,⁴ the exact number of drugs that defines high risk has not been well established. Targeting patients who take 10 or more maintenance medications is a reasonable initial approach,²⁴ but institutions should tailor risk stratification to their patient populations and available resources. Patients taking high-risk medications such as anticoagulants and insulin could also be prioritized for review, since these medications are more likely to cause serious patient harm when used without appropriate clinical oversight.⁷

Using pharmacy staff to perform medication history-taking, reconciliation, and patient counseling has been shown to produce favorable patient outcomes, particularly for higher-risk patients.^16,23

The MARQUIS investigators found they could boost the chances of success by sharing stories of patient harm to foster “buy-in” among frontline staff, providing formal training to clinicians on how to take a medication history, and obtaining the support of nursing leaders to champion improvement efforts.²³

Additionally, patients should be empowered to maintain an accurate medication list. We address strategies for improving patient engagement and adherence in a later section.

BEST PRACTICES FOR IMPROVING MEDICATION SAFETY

Medication reconciliation is one of several measures necessary to optimize medication safety during transitions of care. It typically includes the following actions:

• Interview the patient or caregiver to determine the list of medications the patient is currently taking (or supposed to be taking); consult other sources if needed.
• List medications that are being ordered during the clinical encounter.
• Compare these two lists, making note of medications that are stopped, changed, or newly prescribed.
• Resolve any discrepancies.
• Communicate the reconciled list to the patient, appropriate caregivers, and providers of follow-up care.

At a rudimentary level, medication reconciliation encompasses medication list management along the continuum of care. However, we recommend leveraging medication reconciliation as an opportunity to further enhance medication safety by reviewing the appropriateness of each medication, seizing opportunities to streamline or simplify the regimen, assessing patient and caregiver understanding of medication instructions and potential ADEs, and delivering appropriate counseling to enhance medication use. Table 2 outlines our framework for medication management during hospital-based transitions.

STEP 1: OBTAIN A COMPLETE PREADMISSION MEDICATION LIST

The “best-possible medication history” is obtained in a systematic process of interviewing the patient or caregiver plus reviewing at least one other reliable source.²³ The resulting list should include all medications the patient is taking (prescription and nonprescription), doses, directions for use, formulations if applicable, indications, start and stop dates, and medication allergies and reactions.

Review existing information. Before eliciting a history from the patient, review his or her recorded medical history and existing medication lists (eg, prior discharge summaries, records from other facilities, records from outpatient visits, pharmacy fill data). This will provide context about the regimen and help identify issues and questions that can be addressed during the history-taking.

Ask open-ended questions. Instead of just asking the patient to confirm the accuracy of the existing medication list, we recommend actively obtaining the full medication list from the patient or caregiver. The conversation should begin with an open-ended question such as, “What medications do you take at home?” This approach will also allow the clinician to gauge the patient’s level of understanding of each medication’s indication and dosing instructions. Using a series of prompts such as those recommended in Table 3 will elicit a best-possible medical history, while verifying all of the medications on the existing list.

Clarify discrepancies. Resolve differences between the existing medication lists and the patient’s or caregiver’s report during the preadmission interview. Examples include errors of omission (a medication is missing), errors of commission (an additional medication is present), and discrepancies in the strength, formulation, dosing instructions, and indications for the drugs. If necessary, other sources of information should be consulted, such as the patient’s medication bottles, pharmacy or pharmacies, primary care physician, and a family member or caregiver.

Assess adherence. The extent to which patients take their medications as directed is an important component of the history, but is often left out. Medication nonadherence rates in the United States are 40% to 70%,²⁵ contributing to poor patient outcomes and imposing extraordinary costs on the health care system.²⁶

Asking open-ended, nonjudgmental questions at the time of hospital admission will help to uncover medication-taking behaviors as well as barriers to adherence (Table 3). The patient’s responses should be taken into account when determining the treatment plan.

Document your findings. After completing the medication history and clarifying discrepancies, document the preadmission list in the medical record. All members of the health care team should have access to view and update the same list, as new information about the preadmission medications may be uncovered after the initial history.

Make clinical decisions. Complete the admission medication reconciliation by deciding whether each medication on the list should be continued, changed, held, or discontinued on the basis of the patient’s clinical condition. Well-designed information technology applications enable the provider to document each action and the rationale for it, as well as carry that information into the order-entry system. Medications marked as held or discontinued on admission should be revisited as the patient’s clinical condition changes and at discharge.

STEP 2: AVOID RECONCILIATION ERRORS

Reconciliation errors reflect discrepancies between the medication history and the medications that are ordered after admission.

Reconciliation errors are less common than medication history errors, accounting for approximately one-third of potentially harmful medication errors in hospitalized medical patients.⁹ These include errors of omission (a medication is omitted from the orders), errors of commission (a medication is prescribed with no indication for continuation), and therapeutic duplication.

Preventing errors of omission

Medications are often held at transition points for appropriate clinical reasons. Examples include holding anticoagulants and antiplatelet agents in patients who have gastrointestinal bleeding or an upcoming procedure, antihypertensives in patients with hemodynamic instability, and other chronic medications in patients with an acute illness.

Poor documentation and communication of these decisions can lead to a failure to resume the medications—an error of omission—at hospital discharge.

Hospitalized patients are at risk of unintentional discontinuation of their chronic medications, including antiplatelet drugs, anticoagulants, statins, and thyroid replacement, particularly if admitted to the intensive care unit.¹² These errors can be minimized by a standardized medication reconciliation process at each transition and clear documentation of the medication plan.

Communication among providers can be improved if the admitting clinician documents clearly whether each preadmission medication is being continued, changed, or stopped, along with the reason for doing so, and makes this information available throughout the hospital stay. Upon transfer to another unit and at discharge, the physician should review each; preadmission medication that was held and the patient’s current clinical status and, based on that information, decide whether medications that were held should be resumed. If a medication will be restarted later, specific instructions should be documented and communicated to the patient and the physicians who are taking over his or her care.

Preventing errors of commission

Failure to perform a complete reconciliation at each transition of care and match each medication with an appropriate indication can lead to errors of commission.

One study showed that 44% of patients were prescribed at least one unnecessary drug at hospital discharge, one-fourth of which were started during the hospitalization.²⁷ Commonly prescribed unnecessarily were gastrointestinal agents, central nervous system drugs, nutrients, and supplements.

It is critical to assess each medication’s ongoing need, appropriateness, and risk-benefit ratio at every transition. Medications no longer indicated should be discontinued in order to simplify the regimen, avoid unnecessary drug exposure, and prevent ADEs.

For example, proton pump inhibitors or histamine 2 receptor blockers are often started in the hospital for stress ulcer prophylaxis. One-third of patients are then discharged home on the medication, and 6 months later half of those patients are still taking the unnecessary drug.²⁸ This situation can be avoided by limiting use of these medications to appropriate circumstances, clearly marking the indication as stress ulcer prophylaxis (as opposed to an ongoing condition that will require continuing it after discharge), and discontinuing the agent when appropriate.

All drugs, even common and seemingly benign ones, carry some risk and should be discontinued when no longer needed. Thus, medications added during the hospitalization to control acute symptoms should also be reviewed at each transition to prevent inappropriate continuation when symptoms have resolved.

One study, for example, found that many patients were discharged with inappropriate prescriptions for atypical antipsychotics after receiving them in the intensive care unit, likely for delirium.²⁹ Documenting that an acute issue such as delirium has resolved should prompt the discontinuation of therapy.

Preventing therapeutic duplication

Therapeutic duplication occurs in about 8% of discharges.¹ These errors often result from formulary substitutions or altering the dosage form in the acute setting. For example, patients who receive a prescription for the substituted agent at discharge and also resume their prehospitalization medications end up with duplicate therapy.

Therapeutic substitution is common at the time of admission to the hospital as a result of formulary restrictions. Drug classes that are frequently substituted include statins, antihypertensives, urinary antispasmodics, and proton pump inhibitors. Physicians should be familiar with the preferred agents on the hospital formulary and make careful note when a substitution occurs. Furthermore, hospital systems should be developed to remind the physician to switch back to the outpatient medication at discharge.

Similar problems occur when home medications are replaced with different dosage forms with different pharmacokinetic properties. For example, a long-acting medication may be temporarily replaced with an intravenous solution or immediate-release tablet for several reasons, including nothing-by-mouth status, unstable clinical condition, need for titration, and need to crush the tablet to give the drug per tube. The differing formulations must be reconciled throughout the patient’s hospital course and at discharge to avoid therapeutic duplication and serious medication errors. Deliberate changes to the dosage form should be clearly communicated in the discharge medication list so that patients and other clinicians are aware.

Hospital systems should also have the capability to identify duplications in the medication list and to warn prescribers of these errors. The ability to group medications by drug class or sort the medication list alphabetically by generic name can help uncover duplication errors.

STEP 3: REVIEW THE LIST IN VIEW OF THE CLINICAL PICTURE

Transitions of care should prompt providers to review the medication list for possible drug-disease interactions, confirm compliance with evidence-based guidelines, and evaluate the risks and benefits of each medication in the context of the patient’s age and acute and chronic medical issues. This is also an opportunity to screen the full list for potentially inappropriate medications and high-alert drugs such as insulin or anticoagulants, which are more likely than other drugs to cause severe harm when used in error.

Acute kidney injury. New drug-disease interactions can arise during a hospitalization and can affect dosing and the choice of drug. The onset of acute kidney injury, for example, often necessitates adjusting or discontinuing nephrotoxic and renally excreted medications. ADEs or potential ADEs have been reported in 43% of hospitalized patients with acute kidney injury.³⁰

Because acute kidney injury is often transient, medications may need to be held or adjusted several times until renal function stabilizes. This can be challenging across the continuum of care and requires close monitoring of the serum creatinine level and associated drug doses and levels, if applicable. Well-designed clinical decision support tools can integrate laboratory data and alert the prescriber to a clinically important increase or decrease in serum creatinine that may warrant a change in therapy. Modifications to the regimen and a plan for timely follow-up of the serum creatinine level should be clearly documented in the discharge plan.

Liver disease. Similar attention should be given to drugs that are hepatically metabolized if a patient has acute or chronic liver impairment.

Geriatric patients, particularly those who present with altered mental status, falls, or urinary retention, should have their medication list reviewed for potentially inappropriate medications, which are drugs that pose increased risk of poor outcomes in older adults.^31,32 Patients and providers may have been willing to accept the risk of medications such as anticholinergics or sedative-hypnotics when the drugs were initiated, but circumstances can change over time, especially in this patient population. Hospitalization is a prime opportunity to screen for medications that meet the Beers criteria³¹ for agents to avoid or use with caution in older adults.

As-needed medications. Medications prescribed on an as-needed basis in the hospital should be reviewed for continuation or discontinuation at discharge. How often the medication was given can inform this decision.

For example, if as-needed opioids were used frequently, failure to develop a plan of care for pain can lead to persistent symptoms and, possibly, to readmission.^33,34 Similar scenarios occur with use of as-needed blood pressure medications, laxatives, and correction-dose insulin.

If an as-needed medication was used consistently during hospitalization, the physician should consider whether a regularly scheduled medication is needed. Conversely, if the medication was not used during the inpatient admission, it can likely be discontinued.

STEP 4: PREPARE THE PATIENT AND FOLLOW-UP PROVIDER

Once a clinician has performed medication reconciliation, including obtaining a best-possible medical history and carefully reviewing the medication list and orders for errors and clinical appropriateness, the next steps are to ensure the patient understands what he or she needs to do and to confirm that suitable follow-up plans are in place. These measures should be taken at all transitions of care but are critically important at hospital discharge.

Preparing the patient and caregiver

An accurate, reconciled medication list should be given to the patient, caregiver, or both, and should be reviewed before discharge.¹⁷

Approximately one-third of Americans have low health literacy skills, so medication lists and associated materials should be easy to understand.³⁵ Medication lists should be written in plain language and formatted for optimal readability (Table 4), clearly stating which medications to continue, change, hold temporarily, and stop.

Patients recall and comprehend about half of the information provided during a medical encounter.³⁶ Thus, medication teaching should focus on key points including changes or additions to the regimen, specific instructions for follow-up and monitoring, and how to handle common and serious side effects.

To confirm patient understanding, clinicians should use “teach-back,” ie, provide the patient with information and then ask him or her to repeat back key points.^37,38 The patient and family should also be encouraged to ask questions before discharge.

If not already addressed during the hospital stay, barriers to medication adherence and ability to obtain the medications should be attended to at this time (Table 5). Also, the plan to pick up the medications should be verified with the patient and caregiver. Verify that there is transportation to a particular pharmacy that is open at the time of discharge, and that the patient can afford the medications.

Ensuring appropriate follow-up

Studies have shown that timely in-home or telephone follow-up after discharge can decrease adverse events and postdischarge health care utilization.^39,40 Telephone follow-up that includes thorough medication reconciliation can help detect and resolve medication issues early after discharge and can close gaps related to monitoring and follow-up.

Medication reconciliation by telephone can be time-consuming. Depending on the number of medications that need to be reviewed, calls can take between 10 and 60 minutes. Postdischarge phone calls should be performed by clinical personnel who are able to identify medication-related problems. A pharmacist should be an available resource to assist with complex regimens, to help resolve medication discrepancies, and to address patient concerns. Table 6 provides tips for conducting follow-up phone calls.

Resolving discrepancies identified during follow-up calls can be difficult, as changes to the medication regimen are often not communicated effectively to other members of the care team. Physicians should document the complete medication list and plan in the discharge summary, and there should be a method for the caller to record updates to the medication list in the medical record so that they are apparent at the outpatient follow-up visit.

An additional challenge is that it is frequently unclear which physician “owns” which medications. Therefore, designating a contact person for each medication until follow-up can be very valuable. At a minimum, a “physician owner” for high-alert medications such as insulin, anticoagulants, and diuretics should be identified to provide close follow-up, titration, and monitoring.

There should also be a plan for the patient to obtain refills of essential long-term medications, such as antiplatelet agents following stent placement.

SUMMARY AND RECOMMENDATIONS

Medication-related problems during hospital admission and discharge are common and range from minor discrepancies in the medication list to errors in history-taking, prescribing, and reconciliation that can lead to potential or actual patient harm. Putting systems in place to facilitate medication reconciliation can decrease the occurrence of medication discrepancies and ADEs, thereby improving patient safety during these critical transitions between care settings and providers. Institutional medication reconciliation programs should focus resources on the admission history-taking step, target the highest-risk patients for the most intensive interventions, and involve pharmacy personnel when possible.

On an individual level, clinicians can incorporate additional interventions into their workflows to optimize medication safety for hospitalized patients. Using a structured approach to obtain a complete and accurate medication list at the time of hospital admission will help providers identify medication-related problems and prevent the propagation of errors throughout the hospital stay and at discharge. Focusing additional time and effort on a comprehensive review of the medication list for errors of omission and commission, patient-specific needs, and high-alert drugs will further decrease the risk of medication errors. Finally, providing discharge counseling targeting patient barriers to adherence and ensuring a proper handover of medication information and rationale for medication changes to outpatient providers will improve the chances of a safe transition.

Any time patients enter or leave the hospital, they risk being harmed by errors in their medications.¹ Adverse events from medication errors during transitions of care are common but often preventable. One key approach is to systematically review every patient’s medication list on admission and discharge and resolve any discrepancies. These transitions are also an opportunity to address other medication-related problems, such as adherence, drug interactions, and clinical appropriateness.

This article summarizes the types and prevalence of medication problems that occur during hospital-based transitions of care, and suggests strategies to decrease the risk of medication errors, focusing on medication reconciliation and related interventions that clinicians can use at the bedside to improve medication safety.

DEFINING TERMS

A medication discrepancy is any variance noted in a patient’s documented medication regimen across different medication lists or sites of care. While some differences reflect intentional and clinically appropriate changes to the regimen, others are unintentional and reflect inaccurate or incomplete information. These unintentional discrepancies are medication errors.

Depending on the clinical circumstances and medications involved, such errors may lead to an adverse drug event (ADE), defined as actual harm or injury resulting from a medication. Sometimes a medication error does not cause harm immediately but could if left uncorrected; this is called a potential ADE.

An important goal during transitions of care is to reduce unintentional medication discrepancies, thereby reducing potential and actual ADEs.

ERRORS ARISE AT DISCHARGE—AND EVEN MORE AT ADMISSION

Hospital discharge is a widely recognized transition in which patient harm occurs. As many as 70% of patients may have an unintentional medication discrepancy at hospital discharge, with many of those discrepancies having potential for harm.² Indeed, during the first few weeks after discharge, 50% of patients have a clinically important medication error,³ and 20% experience an adverse event, most commonly an ADE.⁴ ADEs are associated with excess health care utilization,^5–7 and many are preventable through strategies such as medication reconciliation.^5,8

Importantly, more errors arise at hospital admission than at other times.^9,10

Errors in medication histories are the most common source of discrepancies, affecting up to two-thirds of admitted patients.^11,12 More than one-quarter of hospital prescribing errors can be attributed to incomplete medication histories at the time of admission,¹³ and nearly three times as many clinically important medication discrepancies are related to history-taking errors on admission rather than reconciliation errors at discharge.⁹

Most discrepancies occurring at the time of admission have the potential to cause harm, particularly if the errors persist beyond discharge.¹⁴ Therefore, taking a complete and accurate medication history on hospital admission is critical to ensuring safe care transitions.

MEDICATION RECONCILIATION: BARRIERS AND FACILITATORS

Medication reconciliation is a strategy for reducing medication discrepancies in patients moving across care settings. Simply put, it is the process by which a patient’s medication list is obtained, compared, and clarified across different sites of care.¹⁵ It has consistently been shown to decrease medication errors compared with usual care,¹⁶ and it is strongly supported by national and international organizations.^17–21

In clinical practice, many physicians and institutions have found medication reconciliation difficult to implement, owing to barriers at the level of the patient, provider, and system (Table  1). In response to these challenges, two initiatives have synthesized best practices and offer toolkits that hospitals and clinicians can use: the Medications at Transitions and Clinical Handoffs (MATCH) program²² and the Multi-Center Medication Reconciliation Quality Improvement Study (MARQUIS).²³

Lack of resources is a widely acknowledged challenge. Thus, the MARQUIS investigators²³ suggested focusing on the admission history, where most errors occur, and applying the most resource-intensive interventions in patients at highest risk of ADEs, ie, those who are elderly, have multiple comorbid conditions, or take numerous medications.¹⁶

Although the risk of an ADE increases with the number of medications a patient takes,⁴ the exact number of drugs that defines high risk has not been well established. Targeting patients who take 10 or more maintenance medications is a reasonable initial approach,²⁴ but institutions should tailor risk stratification to their patient populations and available resources. Patients taking high-risk medications such as anticoagulants and insulin could also be prioritized for review, since these medications are more likely to cause serious patient harm when used without appropriate clinical oversight.⁷

Using pharmacy staff to perform medication history-taking, reconciliation, and patient counseling has been shown to produce favorable patient outcomes, particularly for higher-risk patients.^16,23

The MARQUIS investigators found they could boost the chances of success by sharing stories of patient harm to foster “buy-in” among frontline staff, providing formal training to clinicians on how to take a medication history, and obtaining the support of nursing leaders to champion improvement efforts.²³

Additionally, patients should be empowered to maintain an accurate medication list. We address strategies for improving patient engagement and adherence in a later section.

BEST PRACTICES FOR IMPROVING MEDICATION SAFETY

Medication reconciliation is one of several measures necessary to optimize medication safety during transitions of care. It typically includes the following actions:

• Interview the patient or caregiver to determine the list of medications the patient is currently taking (or supposed to be taking); consult other sources if needed.
• List medications that are being ordered during the clinical encounter.
• Compare these two lists, making note of medications that are stopped, changed, or newly prescribed.
• Resolve any discrepancies.
• Communicate the reconciled list to the patient, appropriate caregivers, and providers of follow-up care.

At a rudimentary level, medication reconciliation encompasses medication list management along the continuum of care. However, we recommend leveraging medication reconciliation as an opportunity to further enhance medication safety by reviewing the appropriateness of each medication, seizing opportunities to streamline or simplify the regimen, assessing patient and caregiver understanding of medication instructions and potential ADEs, and delivering appropriate counseling to enhance medication use. Table 2 outlines our framework for medication management during hospital-based transitions.

STEP 1: OBTAIN A COMPLETE PREADMISSION MEDICATION LIST

The “best-possible medication history” is obtained in a systematic process of interviewing the patient or caregiver plus reviewing at least one other reliable source.²³ The resulting list should include all medications the patient is taking (prescription and nonprescription), doses, directions for use, formulations if applicable, indications, start and stop dates, and medication allergies and reactions.

Review existing information. Before eliciting a history from the patient, review his or her recorded medical history and existing medication lists (eg, prior discharge summaries, records from other facilities, records from outpatient visits, pharmacy fill data). This will provide context about the regimen and help identify issues and questions that can be addressed during the history-taking.

Ask open-ended questions. Instead of just asking the patient to confirm the accuracy of the existing medication list, we recommend actively obtaining the full medication list from the patient or caregiver. The conversation should begin with an open-ended question such as, “What medications do you take at home?” This approach will also allow the clinician to gauge the patient’s level of understanding of each medication’s indication and dosing instructions. Using a series of prompts such as those recommended in Table 3 will elicit a best-possible medical history, while verifying all of the medications on the existing list.

Clarify discrepancies. Resolve differences between the existing medication lists and the patient’s or caregiver’s report during the preadmission interview. Examples include errors of omission (a medication is missing), errors of commission (an additional medication is present), and discrepancies in the strength, formulation, dosing instructions, and indications for the drugs. If necessary, other sources of information should be consulted, such as the patient’s medication bottles, pharmacy or pharmacies, primary care physician, and a family member or caregiver.

Assess adherence. The extent to which patients take their medications as directed is an important component of the history, but is often left out. Medication nonadherence rates in the United States are 40% to 70%,²⁵ contributing to poor patient outcomes and imposing extraordinary costs on the health care system.²⁶

Asking open-ended, nonjudgmental questions at the time of hospital admission will help to uncover medication-taking behaviors as well as barriers to adherence (Table 3). The patient’s responses should be taken into account when determining the treatment plan.

Document your findings. After completing the medication history and clarifying discrepancies, document the preadmission list in the medical record. All members of the health care team should have access to view and update the same list, as new information about the preadmission medications may be uncovered after the initial history.

Make clinical decisions. Complete the admission medication reconciliation by deciding whether each medication on the list should be continued, changed, held, or discontinued on the basis of the patient’s clinical condition. Well-designed information technology applications enable the provider to document each action and the rationale for it, as well as carry that information into the order-entry system. Medications marked as held or discontinued on admission should be revisited as the patient’s clinical condition changes and at discharge.

STEP 2: AVOID RECONCILIATION ERRORS

Reconciliation errors reflect discrepancies between the medication history and the medications that are ordered after admission.

Reconciliation errors are less common than medication history errors, accounting for approximately one-third of potentially harmful medication errors in hospitalized medical patients.⁹ These include errors of omission (a medication is omitted from the orders), errors of commission (a medication is prescribed with no indication for continuation), and therapeutic duplication.

Preventing errors of omission

Medications are often held at transition points for appropriate clinical reasons. Examples include holding anticoagulants and antiplatelet agents in patients who have gastrointestinal bleeding or an upcoming procedure, antihypertensives in patients with hemodynamic instability, and other chronic medications in patients with an acute illness.

Poor documentation and communication of these decisions can lead to a failure to resume the medications—an error of omission—at hospital discharge.

Hospitalized patients are at risk of unintentional discontinuation of their chronic medications, including antiplatelet drugs, anticoagulants, statins, and thyroid replacement, particularly if admitted to the intensive care unit.¹² These errors can be minimized by a standardized medication reconciliation process at each transition and clear documentation of the medication plan.

Communication among providers can be improved if the admitting clinician documents clearly whether each preadmission medication is being continued, changed, or stopped, along with the reason for doing so, and makes this information available throughout the hospital stay. Upon transfer to another unit and at discharge, the physician should review each; preadmission medication that was held and the patient’s current clinical status and, based on that information, decide whether medications that were held should be resumed. If a medication will be restarted later, specific instructions should be documented and communicated to the patient and the physicians who are taking over his or her care.

Preventing errors of commission

Failure to perform a complete reconciliation at each transition of care and match each medication with an appropriate indication can lead to errors of commission.

One study showed that 44% of patients were prescribed at least one unnecessary drug at hospital discharge, one-fourth of which were started during the hospitalization.²⁷ Commonly prescribed unnecessarily were gastrointestinal agents, central nervous system drugs, nutrients, and supplements.

It is critical to assess each medication’s ongoing need, appropriateness, and risk-benefit ratio at every transition. Medications no longer indicated should be discontinued in order to simplify the regimen, avoid unnecessary drug exposure, and prevent ADEs.

For example, proton pump inhibitors or histamine 2 receptor blockers are often started in the hospital for stress ulcer prophylaxis. One-third of patients are then discharged home on the medication, and 6 months later half of those patients are still taking the unnecessary drug.²⁸ This situation can be avoided by limiting use of these medications to appropriate circumstances, clearly marking the indication as stress ulcer prophylaxis (as opposed to an ongoing condition that will require continuing it after discharge), and discontinuing the agent when appropriate.

All drugs, even common and seemingly benign ones, carry some risk and should be discontinued when no longer needed. Thus, medications added during the hospitalization to control acute symptoms should also be reviewed at each transition to prevent inappropriate continuation when symptoms have resolved.

One study, for example, found that many patients were discharged with inappropriate prescriptions for atypical antipsychotics after receiving them in the intensive care unit, likely for delirium.²⁹ Documenting that an acute issue such as delirium has resolved should prompt the discontinuation of therapy.

Preventing therapeutic duplication

Therapeutic duplication occurs in about 8% of discharges.¹ These errors often result from formulary substitutions or altering the dosage form in the acute setting. For example, patients who receive a prescription for the substituted agent at discharge and also resume their prehospitalization medications end up with duplicate therapy.

Therapeutic substitution is common at the time of admission to the hospital as a result of formulary restrictions. Drug classes that are frequently substituted include statins, antihypertensives, urinary antispasmodics, and proton pump inhibitors. Physicians should be familiar with the preferred agents on the hospital formulary and make careful note when a substitution occurs. Furthermore, hospital systems should be developed to remind the physician to switch back to the outpatient medication at discharge.

Similar problems occur when home medications are replaced with different dosage forms with different pharmacokinetic properties. For example, a long-acting medication may be temporarily replaced with an intravenous solution or immediate-release tablet for several reasons, including nothing-by-mouth status, unstable clinical condition, need for titration, and need to crush the tablet to give the drug per tube. The differing formulations must be reconciled throughout the patient’s hospital course and at discharge to avoid therapeutic duplication and serious medication errors. Deliberate changes to the dosage form should be clearly communicated in the discharge medication list so that patients and other clinicians are aware.

Hospital systems should also have the capability to identify duplications in the medication list and to warn prescribers of these errors. The ability to group medications by drug class or sort the medication list alphabetically by generic name can help uncover duplication errors.

STEP 3: REVIEW THE LIST IN VIEW OF THE CLINICAL PICTURE

Transitions of care should prompt providers to review the medication list for possible drug-disease interactions, confirm compliance with evidence-based guidelines, and evaluate the risks and benefits of each medication in the context of the patient’s age and acute and chronic medical issues. This is also an opportunity to screen the full list for potentially inappropriate medications and high-alert drugs such as insulin or anticoagulants, which are more likely than other drugs to cause severe harm when used in error.

Acute kidney injury. New drug-disease interactions can arise during a hospitalization and can affect dosing and the choice of drug. The onset of acute kidney injury, for example, often necessitates adjusting or discontinuing nephrotoxic and renally excreted medications. ADEs or potential ADEs have been reported in 43% of hospitalized patients with acute kidney injury.³⁰

Because acute kidney injury is often transient, medications may need to be held or adjusted several times until renal function stabilizes. This can be challenging across the continuum of care and requires close monitoring of the serum creatinine level and associated drug doses and levels, if applicable. Well-designed clinical decision support tools can integrate laboratory data and alert the prescriber to a clinically important increase or decrease in serum creatinine that may warrant a change in therapy. Modifications to the regimen and a plan for timely follow-up of the serum creatinine level should be clearly documented in the discharge plan.

Liver disease. Similar attention should be given to drugs that are hepatically metabolized if a patient has acute or chronic liver impairment.

Geriatric patients, particularly those who present with altered mental status, falls, or urinary retention, should have their medication list reviewed for potentially inappropriate medications, which are drugs that pose increased risk of poor outcomes in older adults.^31,32 Patients and providers may have been willing to accept the risk of medications such as anticholinergics or sedative-hypnotics when the drugs were initiated, but circumstances can change over time, especially in this patient population. Hospitalization is a prime opportunity to screen for medications that meet the Beers criteria³¹ for agents to avoid or use with caution in older adults.

As-needed medications. Medications prescribed on an as-needed basis in the hospital should be reviewed for continuation or discontinuation at discharge. How often the medication was given can inform this decision.

For example, if as-needed opioids were used frequently, failure to develop a plan of care for pain can lead to persistent symptoms and, possibly, to readmission.^33,34 Similar scenarios occur with use of as-needed blood pressure medications, laxatives, and correction-dose insulin.

If an as-needed medication was used consistently during hospitalization, the physician should consider whether a regularly scheduled medication is needed. Conversely, if the medication was not used during the inpatient admission, it can likely be discontinued.

STEP 4: PREPARE THE PATIENT AND FOLLOW-UP PROVIDER

Once a clinician has performed medication reconciliation, including obtaining a best-possible medical history and carefully reviewing the medication list and orders for errors and clinical appropriateness, the next steps are to ensure the patient understands what he or she needs to do and to confirm that suitable follow-up plans are in place. These measures should be taken at all transitions of care but are critically important at hospital discharge.

Preparing the patient and caregiver

An accurate, reconciled medication list should be given to the patient, caregiver, or both, and should be reviewed before discharge.¹⁷

Approximately one-third of Americans have low health literacy skills, so medication lists and associated materials should be easy to understand.³⁵ Medication lists should be written in plain language and formatted for optimal readability (Table 4), clearly stating which medications to continue, change, hold temporarily, and stop.

Patients recall and comprehend about half of the information provided during a medical encounter.³⁶ Thus, medication teaching should focus on key points including changes or additions to the regimen, specific instructions for follow-up and monitoring, and how to handle common and serious side effects.

To confirm patient understanding, clinicians should use “teach-back,” ie, provide the patient with information and then ask him or her to repeat back key points.^37,38 The patient and family should also be encouraged to ask questions before discharge.

If not already addressed during the hospital stay, barriers to medication adherence and ability to obtain the medications should be attended to at this time (Table 5). Also, the plan to pick up the medications should be verified with the patient and caregiver. Verify that there is transportation to a particular pharmacy that is open at the time of discharge, and that the patient can afford the medications.

Ensuring appropriate follow-up

Studies have shown that timely in-home or telephone follow-up after discharge can decrease adverse events and postdischarge health care utilization.^39,40 Telephone follow-up that includes thorough medication reconciliation can help detect and resolve medication issues early after discharge and can close gaps related to monitoring and follow-up.

Medication reconciliation by telephone can be time-consuming. Depending on the number of medications that need to be reviewed, calls can take between 10 and 60 minutes. Postdischarge phone calls should be performed by clinical personnel who are able to identify medication-related problems. A pharmacist should be an available resource to assist with complex regimens, to help resolve medication discrepancies, and to address patient concerns. Table 6 provides tips for conducting follow-up phone calls.

Resolving discrepancies identified during follow-up calls can be difficult, as changes to the medication regimen are often not communicated effectively to other members of the care team. Physicians should document the complete medication list and plan in the discharge summary, and there should be a method for the caller to record updates to the medication list in the medical record so that they are apparent at the outpatient follow-up visit.

An additional challenge is that it is frequently unclear which physician “owns” which medications. Therefore, designating a contact person for each medication until follow-up can be very valuable. At a minimum, a “physician owner” for high-alert medications such as insulin, anticoagulants, and diuretics should be identified to provide close follow-up, titration, and monitoring.

There should also be a plan for the patient to obtain refills of essential long-term medications, such as antiplatelet agents following stent placement.

SUMMARY AND RECOMMENDATIONS

Medication-related problems during hospital admission and discharge are common and range from minor discrepancies in the medication list to errors in history-taking, prescribing, and reconciliation that can lead to potential or actual patient harm. Putting systems in place to facilitate medication reconciliation can decrease the occurrence of medication discrepancies and ADEs, thereby improving patient safety during these critical transitions between care settings and providers. Institutional medication reconciliation programs should focus resources on the admission history-taking step, target the highest-risk patients for the most intensive interventions, and involve pharmacy personnel when possible.

On an individual level, clinicians can incorporate additional interventions into their workflows to optimize medication safety for hospitalized patients. Using a structured approach to obtain a complete and accurate medication list at the time of hospital admission will help providers identify medication-related problems and prevent the propagation of errors throughout the hospital stay and at discharge. Focusing additional time and effort on a comprehensive review of the medication list for errors of omission and commission, patient-specific needs, and high-alert drugs will further decrease the risk of medication errors. Finally, providing discharge counseling targeting patient barriers to adherence and ensuring a proper handover of medication information and rationale for medication changes to outpatient providers will improve the chances of a safe transition.

New targeted therapies are changing the way patients with advanced dermatologic diseases are treated. Innovative molecular biology techniques developed as far back as the 1970s have engendered tremendous insight into the cellular and molecular pathogenesis of numerous diseases. Novel medications based on these insights are now bearing fruit, as directed biologic therapies that are revolutionizing clinical practice are increasingly becoming available.

This article reviews advances in targeted therapies for advanced basal cell carcinoma, psoriasis, and metastatic melanoma.

TARGETED THERAPY FOR BASAL CELL CARCINOMA

Case 1. A 56-year-old man presents with a progressively enlarging leg ulcer. Although it has been treated empirically for years as a venous stasis ulcer, biopsy reveals that it is basal cell carcinoma. Imaging shows muscle and tendon invasion, making surgical intervention short of amputation challenging (Figure 1). What are his options?

Courtesy of Allison Vidimos, MD. Magnetic resonance image courtesy of Todd Stultz, MD, and Claus Simpfendorfer, MD

Basal cell carcinoma is the most common cancer in humans, accounting for 25% of all cancers and more than 2 million cases in the United States every year. In most cases, surgical excision is curative, but a subset of patients have inoperable, locally advanced, or metastatic disease that drastically limits treatment options. The median survival in metastatic basal cell carcinoma is 24 months, and conventional chemotherapy has not been shown to improve the prognosis.^1,2

In addition to the burden of sporadic basal cell carcinoma, patients with the rare autosomal-dominant genetic disorder basal cell nevus syndrome (Gorlin syndrome) develop multiple basal cell lesions over their lifetime. The syndrome may also involve abnormalities of the skeletal system, genitourinary tract, and central nervous system, including development of medulloblastoma.

In Gorlin syndrome, basal cell carcinomas occur often and early; about half of white patients with the syndrome develop their first lesions by age 21, and 90% by age 35. The lesions occur in multiple numbers and can develop anywhere on the body, including on non–sun-exposed areas. Patients who have Gorlin syndrome need meticulous monitoring every 2 to 3 months so that basal cell lesions can be recognized early and treated before they become locally advanced. Keeping up with the numerous medical appointments and invasive treatments can be physically and mentally taxing for patients.

Specific pathway and mutations identified

In 1996, Gorlin syndrome was found to be caused by mutations of the human homolog of the PATCHED gene, which codes for a receptor in the “hedgehog” pathway.³ Two years later, the same mutations were found to be involved in many sporadic basal cell carcinomas, and we now believe that at least 85% of basal cell carcinomas involve abnormal activation of hedgehog pathway signaling.^4,5 

Vismodegib developed as targeted therapy

In 2009, Robarge et al⁶ described a potent inhibitor of the hedgehog pathway that was later optimized for potency and desirable pharmacologic traits, resulting in the drug vismodegib.^7,8

Two phase 2 multicenter clinical trials^9,10 of vismodegib were published in 2012. In the first, which was not randomized,⁹ 33 patients with metastatic basal cell carcinoma and 63 patients with locally advanced disease were treated with vismodegib. Of those with metastatic disease, 30% achieved an objective response. Of those with locally advanced disease, 43% achieved an objective response and 21% achieved a complete response.

In the second trial,¹⁰ patients with Gorlin syndrome were randomized to either vismodegib (26 patients) or placebo (16 patients). After 8 months, the vismodegib group had developed significantly fewer new surgically eligible tumors (2 vs 29 per year), their tumors were smaller (change from baseline of the sum of the longest diameters –65% vs –11%), and they needed fewer surgeries (mean 0.31 vs 4.4 per patient). No tumors progressed in the treatment group. Results in some patients were dramatic, with complete healing of large ulcerative tumors. The trial was ended early in view of significant efficacy in the treatment group.

Based on these trials, the US Food and Drug Administration (FDA) approved vismodegib for treating metastatic and locally advanced basal cell carcinoma.

Resistance and adverse effects common

Unfortunately, vismodegib has significant drawbacks. About 20% of patients develop resistance, with tumors recurring after several months of therapy.¹¹ Adverse effects most commonly reported were muscle spasms (68%), alopecia (63%), taste distortion (51%), weight loss (46%), and fatigue (36%). Although these effects were considered mild or moderate, they tended to persist, and almost every patient developed at least one. In the nonrandomized trial,⁹ more than 25% of patients discontinued treatment because of adverse effects, and more than half of patients did the same in the basal cell nevus syndrome trial.¹⁰

New uses may reduce shortcomings

Studies are under way to determine how best to use vismodegib.

One possibility is to use the drug for a few months to shrink tumors to the point that they become eligible for surgery. This is especially important for high-risk tumors, such as those near the eye or other vital structures. In 11 patients, Ally et al¹² found that the surgical defect area was reduced by 27% from baseline after 4 months of treatment with vismodegib, allowing for curative surgery in some.

Another option is to combine vismodegib with other agents—either new ones on the horizon or existing nonspecific medications. For example, the antifungal itraconazole has been shown to inhibit hedgehog signaling and perhaps could be combined with vismodegib to increase response and reduce resistance.

Finally, a topical or intralesional form of vismodegib would be useful not only to reduce systemic toxicity, but also to increase efficacy when combined with other topical or systemic medications.

TARGETED THERAPY FOR PSORIASIS VULGARIS

Case 2. A 28-year-old woman presents with worsening psoriasis. About 35% of her body surface is involved, including the palms and soles, making it difficult for her to perform activities of daily living (Figure 2). What are her options?

Psoriasis is a chronic immune-mediated disease that affects up to 3% of people worldwide. In its moderate to severe forms, we recognize psoriasis as a systemic inflammatory disease that may adversely affect organ systems other than the skin. Commonly associated comorbid diseases include inflammatory (psoriatic) arthritis, cardiovascular disease, malignancies (eg, lymphoma), and inflammatory bowel disease. In addition, patients are well known to have significantly impaired quality of life because of low self-esteem, stigmatization affecting their social and work relationships, and, in up to 60%, clinical depression.^13,14 The onset of psoriatic arthritis, particularly of erosive disease, is an important decision point for starting aggressive treatment, as joint destruction is irreversible.

Early targeted therapy aimed at TNF alpha, IL-12, and IL-23

Histologically, psoriasis involves thickening of the epidermis caused by hyperproliferation of keratinocytes. Based on this, prior to the 1980s, the dominant hypothesis concerning its pathogenesis was that it was caused by an inherent defect of keratinocytes. In the 1980s and 1990s, however, molecular research revealed that psoriasis was an immune-mediated disease caused by immunologic dysregulation predominantly involving T-helper 1  (Th-1) cells, with the inflammatory cytokines tumor necrosis factor (TNF) alpha, interferon gamma, interleukin (IL) 12, and IL-23 playing prominent roles.¹⁵ These findings led to the development and FDA approval of the first effective, targeted, psoriasis treatments, TNF-alpha inhibitors and the IL-12/23 inhibitor ustekinumab.

Etanercept, the first TNF-alpha inhibitor to become available, was approved in 2004 for moderate to severe psoriasis. In 2008, the IL-12/23 inhibitor ustekinumab was approved for the same indication. These drugs are efficacious, are generally safe, and have revolutionized the treatment of psoriasis and psoriatic arthritis, and they are now prescribed on a daily basis.^16,17

In the clinical trials that led to approval of these drugs, the main outcome measure was the Psoriasis Area and Severity Index (PASI), a clinical scoring tool that assesses clinical aspects of psoriatic disease including body surface area involvement, degree of thickness, erythema, and scaling of psoriatic plaques. PASI scores range from 0 (no psoriasis) to 72 (most severe psoriasis). Achieving “PASI 75” indicates at least 75% improvement from the baseline score and represents the most common primary outcome measure in clinical trials assessing efficacy of new treatments. Up to 80% of patients who received currently available TNF-alpha inhibitors and ustekinumab in pivotal clinical trials achieved PASI 75 when assessed at 12 to 16 weeks after starting treatment. A moderate percentage of patients (19%–57%, depending on the trial) achieved 90% improvement (PASI 90), and a minority (up to 18%) achieved PASI 100, indicating complete clearing of their psoriasis.^18–22

Newly developed therapies target IL-17A

In the mid-2000s, Th-17 cells were discovered, a new lineage of T cells distinct from Th-1 and Th-2 cells. Th-17 cells are characterized by their production of IL-17, a pro-inflammatory cytokine with six family members (IL-17A through IL-17F). Over the next few years, experiments revealed that Th-17 cells and IL-17A play key roles in psoriasis immunologic dysregulation.¹⁵ These findings led to a paradigm shift in hypotheses concerning psoriasis pathogenesis, with Th-17 cells and IL-17 replacing Th-1 cells and associated cytokines as dominant mediators of tissue damage.

Additionally, these findings led to new ideas for treatment. Three monoclonal antibodies that target IL-17 inhibition are currently under investigation. Secukinumab and ixekizumab bind to IL-17A and inhibit it from downstream signaling, whereas brodalumab binds to the IL-17A receptor, blocking all six IL-17 cytokines (IL-17A to IL-17F).²³

Clinical trials of IL-17 inhibitors show excellent skin improvement

Secukinumab. In 2014, the results of two phase 3 trials of secukinumab were published.²⁴

In the Efficacy and Safety of Subcutaneous Secukinumab for Moderate to Severe Chronic Plaque-type Psoriasis for up to 1 Year trial,²⁴ patients were given either secukinumab 300 mg or 150 mg subcutaneously at defined time points; 82% and 72%, respectively, attained PASI 75 at 12 weeks.

Similar results were seen in the Safety and Efficacy of Secukinumab Compared to Etanercept in Subjects With Moderate to Severe, Chronic Plaque-Type Psoriasis study,²⁴ in which PASI 75 was achieved by 77% of patients receiving secukinumab 300 mg, 67% of those receiving secukinumab 150 mg, and only 44% of those receiving etanercept 50 mg twice weekly at 12 weeks. Rates of infection with secukinumab and etanercept were similar.

The most striking results of these trials were that more than half of patients receiving the 300-mg dose achieved at least 90% improvement in their PASI score (PASI 90) by week 12, and in more than a quarter of patients the psoriasis completely cleared (PASI 100). These results were dramatically better than for etanercept (PASI 90 21%; PASI 100 4%).

Additionally, secukinumab worked fast. The median time to PASI 50 with secukinumab 300 mg was less than half that seen with etanercept (3 weeks vs 7 weeks).

Ixekizumab. In 2012, a phase 2 trial evaluated subcutaneous injections of ixekizumab in dosages ranging from 10 to 150 mg at defined intervals for 16 weeks.²⁵ Of those receiving the highest dosage, 82% attained PASI 75 at 12 weeks, on par with what is noted in patients receiving TNF-alpha inhibitors and IL-12/23 inhibitors. Remarkably, however, almost three-quarters of patients (71%) achieved PASI 90, and 39% achieved PASI 100. Improvement in psoriasis was apparent as early as 1 week after injection.

Brodalumab. A 2012 phase 2 trial of various dosages of the IL-17 receptor inhibitor brodalumab²⁶ also showed excellent PASI 75 achievement with the highest dosage (82%). Astonishingly, though, PASI 90 was achieved by 75% of patients, and PASI 100 by 62%.

Overall, although the percentages of patients achieving PASI 75 with the new IL-17 inhibitor drugs are comparable to those seen with TNF-alpha inhibitors and IL-12/23 inhibitors, the extraordinarily high percentages of patients who achieved PASI 90 and PASI 100 are unprecedented.^18–22

Arthritis improvement not shown

Where the IL-17 inhibitors eventually settle within algorithms of psoriasis treatment largely depends on their efficacy in treating psoriatic arthritis compared with TNF-alpha inhibitors and IL-12/23 inhibitors. Joint inflammation is typically evaluated with the American College of Rheumatology (ACR) scoring tool, which in simple terms can be thought of as analogous to the PASI scoring tool for the skin. Although the ACR scoring tool was developed to assess joint inflammation in clinical trials for patients with rheumatoid arthritis, it is commonly used to assess improvement of psoriatic arthritis in clinical trials. The ACR tool involves assessing and scoring the number of swollen and tender joints, but also incorporates serologic assessment of acute-phase reactants (erythrocyte sedimentation rate or C-reactive protein level), patient and physician global assessment, pain, and function. ACR 20 implies roughly a 20% improvement in these criteria, whereas ACR 50 indicates 50% improvement, and so on.

Two phase 2 trials of IL-17 inhibitors for psoriatic arthritis have been published, one with secukinumab²⁷ and one with brodalumab.²⁸ Neither had impressive improvement in the ACR score vs TNF inhibitors—39% for ACR 20 at week 12 and less than 10% for ACR 70. Clinical trial design may have played a role, and phase 3 trials are under way for all three IL-17 inhibitors.

Adverse effects of IL-17 inhibitors

For the most part, adverse effects reported with the IL-17 inhibitors have been mild  and similar to those reported with available biologic treatments for psoriasis. Adverse effects most commonly reported have been nasopharyngitis, upper respiratory infection, arthralgia, and mild injection-site reactions. In the future, attention will be paid to the rate of infections known to be associated with IL-17, mainly localized infections with Staphylococcus aureus and Candida species. Some patients have developed Candida esophagitis, but this appears to resolve with discontinuation of the drugs. Neutropenia has occurred, but very few patients have developed grade 3 (500–1,000 cells/mm³) or worse. All adverse effects were reversible with discontinuation of treatment.

Approval of secukinumab, and current studies of IL-17 inhibitors

On January 21, 2015, secukinumab was approved by the FDA for treatment of moderate to severe psoriasis vulgaris in adult patients and is now available by prescription.
More trials of IL-17 inhibitors for the treatment of psoriasis and psoriatic arthritis are under way and are at various phases at the time of this writing.²³

TARGETED THERAPY FOR ADVANCED MELANOMA

Case 3. A 58-year-old man presents with an irregular pigmented lesion on his back. Biopsy shows malignant melanoma with an intense, chronic inflammatory infiltrate surrounding the tumor (Figure 3). The tumor was surgically excised with standard margins. Two years later, the patient developed multiple pigmented lesions on the face and complained of headache. Magnetic resonance imaging of the brain revealed multiple enhancing lesions consistent with metastatic melanoma (Figure 3). What are this patient’s options?

Melanoma is the fifth most common cancer in humans, with about 132,000 new cases diagnosed worldwide each year and 48,000 deaths from advanced disease. Its incidence has risen rapidly over the last few decades. Advanced disease has a poor prognosis, with the median overall survival less than 1 year and 5-year survival less than 10%.

Despite decades of research, a paucity of FDA-approved medications were available to treat advanced melanoma until recently. The alkylating agent dacarbazine was approved in 1975, interferon alpha in 1995, and high-dose IL-2 in 1998. Although some patients respond, studies have not shown significant improvement in survival with any of these medications.^29–31

In 2002, Davies et al³² found that 50% to 65% of metastatic cutaneous melanomas have a mutation in the BRAF gene. Interestingly, 80% of these patients share a single specific mutation: substitution of glutamic acid for valine in codon 600 (BRAF V600E). The second most common mutation is a single substitution of a lysine for that same valine (BRAF V600K). Additionally, NRAS is mutated in about 20% of melanomas. These discoveries implicated a mitogen-activated protein kinase (MAPK) pathway (Figure 4) as playing a critical role in metastatic melanoma for a large percentage of patients.²⁹

Medical Illustrator: Ross Papalardo

Based on this knowledge, several targeted therapies for melanoma have been developed, and some have been approved.

BRAF inhibitors—first success against melanoma

Vemurafenib. In 2010, Flaherty et al³³ reported on a phase 1 and phase 2 clinical trial of vemurafenib (960 mg orally twice daily), a potent inhibitor of BRAF with the V600E mutation. They demonstrated a clinical benefit in 80% of patients with stage IV BRAF-mutant melanoma, an unprecedented response that opened the door to changes in the treatment of metastatic melanoma.

The phase 3 BRAF Inhibitor in Melanoma (BRIM)-3 clinical trial,³⁴ published in 2011, randomized 675 previously untreated patients with advanced melanoma to either vemurafenib 960 mg orally twice daily or dacarbazine, the standard of care. The trial was terminated early when an interim analysis showed a significant overall advantage for vemurafenib (median progression-free survival 5.3 months vs 1.6 months for dacarbazine). Based on these results, vemurafenib was FDA-approved in August 2011 for use in patients with BRAF-mutant melanoma.

Dabrafenib. In a phase 3 clinical trial in 2012, Hauschild et al³⁵ randomized 250 patients with BRAF (V600E)-mutated melanoma in a 3:1 ratio to receive either dabrafenib, a more potent second-generation BRAF inhibitor, or dacarbazine. Half of patients responded to dabrafenib, with a significantly improved progression-free survival rate (5.1 vs 2.7 months respectively), leading to FDA approval for its use in BRAF-mutant melanoma in May 2013.

Adverse effects common to vemurafenib and dabrafenib include rash, fatigue, fever, and joint pain. In addition, up to 25% of patients develop multiple secondary cutaneous squamous cell carcinomas and keratoacanthomas, usually within the first few months of therapy, which are believed to be caused by paradoxical activation of the MAPK pathway.

A more important problem with these medications is the development of resistance. Tumors typically progress again after a median progression-free survival of 6 to 7 months.

MEK inhibitors—another line of defense

Inhibitors of MEK—a serine-threonine kinase that is part of the same MAPK pathway involving BRAF—have been developed as well.

Trametinib. In 2012, trametinib, an allosteric MEK inhibitor, was used in an open-label phase 3 trial in 322 patients with advanced melanoma. Progression-free survival was 4.8 months for trametinib-treated patients compared with 1.5 months for the standard chemotherapy group (dacarbazine or paclitaxel).³⁶ These results led to FDA approval of trametinib in May 2013 for treating BRAF-mutant melanoma.²⁹

Cobimetinib is a second MEK inhibitor being evaluated alone and in combination with other targeted treatments for advanced melanoma.

Both MEK inhibitors have adverse effects similar to those seen with the BRAF inhibitors, including diarrhea, rash, fatigue, and edema. They also tend to cause asymptomatic elevated creatine kinase and transient retinopathy, reduced ejection fraction, and ventricular dysfunction. Unlike BRAF inhibitors, they are not associated with development of secondary cutaneous squamous cell carcinomas or keratoacanthomas. However, as with BRAF inhibitors, resistance is a problem with MEK inhibitors, with most patients relapsing less than a year after starting therapy.

Combination therapy improves outcomes

Possible mechanisms underlying resistance to these medications are being studied. A number of important factors appear to drive resistance, including expression of truncated BRAF proteins that do not bind the BRAF inhibitors and still activate downstream signaling, and amplification of BRAF to such a degree that it overwhelms the medications. This has led to the idea of combining BRAF inhibitors and MEK inhibitors to block the MAPK pathway at two points, potentially increasing the response and decreasing resistance.

Two trials have evaluated combinations of BRAF and MEK inhibitors in patients with advanced melanoma. Larkin et al³⁷ conducted a phase 3 study evaluating combined vemurafenib (a BRAF inhibitor) and cobimetinib (a MEK inhibitor) vs combined vemurafenib and placebo. Survival with the combination therapy was 9.9 months vs 6.2 months with the single treatment.

The incidence of serious adverse effects was not significantly increased with the combination therapy, and keratoacanthomas, cutaneous squamous cell carcinomas, alopecia, and arthralgias were reduced compared with the vemurafenib and placebo group.

Another trial³⁸ evaluating combined dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) vs combined dabrafenib and placebo had similar findings: increased survival in the combined therapy group (9.3 months vs 8.8 months) and lower rates of squamous cell carcinoma (2% vs 9%).

In January 2014, the FDA approved the combination of BRAF and MEK inhibitors for the treatment of BRAF-mutant metastatic melanoma based on improved survival and generally reduced adverse effects.

IMMUNOTHERAPIES FOR NON-BRAF MELANOMA

Although BRAF and MEK inhibitors represent tremendous advances, their use is limited to the approximately 50% to 65% of patients with advanced melanoma who have BRAF V600 mutations. For others, only the traditional standard medications have been available until recently.

Two of those standard FDA-approved medications, interferon alpha-2b and IL-2, represent immunotherapies. Interferon alpha-2b up-regulates antigen presentation and increases antigen recognition by T cells. Overall, about 20% of patients in clinical trials have achieved responses.

IL-2 is a cytokine that increases T-cell proliferation and maturation into effector T cells. High-dose IL-2 has produced responses in 15% of patients, with a durable complete response in a small proportion.

Though success with these medications was modest, the fact that some patients responded to them indicates that immunotherapy could be a viable strategy for treating metastatic melanoma.³⁰ This is underscored by the fact that some patients can mount an adaptive immune response specifically directed against antigenic proteins expressed in their tumors, resulting in expansion of cytotoxic T cells and control or even elimination of the malignancy.³⁰

Tumors manipulate host immune checkpoints

Molecular biology has provided tremendous insight into tumor immunology over the past several decades, and we now recognize that a hallmark of cancer is escape from immune control.

Cancer cells contain a multitude of mutations that produce proteins that should be recognized by the immune system as foreign but in most individuals are not. This is because T-cell activity is down-regulated in cancer due to cancer cells’ ability to manipulate the host’s normal immunologic inhibitory pathways critical for maintaining self-tolerance.

In general, T-cell activation is initiated when an antigen-presenting cell presents an antigen to a T cell in a major histocompatibility complex-restricted manner. To prevent T cells from being activated by self-antigens and initiating autoimmunity, the interaction between antigen-presenting cells and T cells is regulated by checkpoints (Figure 5). First, for an antigen-presenting cell/T-cell interaction to result in T-cell activation, the T-cell receptor CD28 must bind CD80 on the antigen-presenting cell to drive a “positive” signal. Early in the interaction, the T-cell receptor CTLA-4 is up-regulated and competes with CD28 for binding of CD80. If CTLA-4, and not CD28, binds CD80, a “negative” signal is sent to the T cell and down-regulates it, making the interaction unproductive. Importantly, it is the CTLA-4:CD80 interaction that appears to be crucial for the ability of tumors to dampen T-cell responses to cancer cells.

Medical Illustrator: Ross Papalardo

Ipilimumab is a fully humanized monoclonal antibody that binds to CTLA-4, blocking its ability to bind to CD80 and thereby enhancing T-cell activation. In a phase 3 trial, Hodi et al³⁹ evaluated its use in treating advanced melanoma, with some enrolled patients having failed IL-2 treatment. Patients receiving ipilimumab with or without a glycoprotein-100 peptide vaccine (gp100) had an overall survival benefit of 10.1 months compared with 6.4 months for patients treated with gp100 alone. At 24 months, the survival rate with ipilimumab alone was 23.5%, almost double that of patients receiving gp100 alone.

Ipilimumab received FDA approval for treatment of metastatic melanoma in March 2011. This, and the BRAF inhibitors, were the first drugs approved by the FDA for the treatment of advanced melanoma in more than a decade.

Common adverse effects of ipilimumab include fatigue, diarrhea, rash, and pruritus. As expected, given its mechanism of action, up to about 25% of patients experience severe autoimmune-related events that may variably manifest as colitis, rash, hepatitis, neuritis, hypothyroidism, hypopituitarism, and hypophysitis. Another problem with this medication is that a subset of patients do not respond.

Cancer cells disguised as normal cells

Cancer cells can also manipulate another immunologic checkpoint to evade attack by the host immune system (Figure 5). Cytotoxic T cells may recognize antigens on tumor cells and become activated and primed to directly destroy them. However, tumor cells, like normal cells express the programmed death ligands RTK-L1 and PD-L2. These ligands function to bind to the PD-1 receptor on activated T cells to indicate they are “self” and inhibit the cytotoxic T cells from destroying them.

Evasion of immune system attack by manipulating checkpoints involving CTLA-4 and PD-1 helps explain why malignancies can seemingly be associated with brisk inflammatory responses, such as the tumor in Case 3, yet progress and eventually metastasize (Figure 3).

Two medications—nivolumab and pembrolizumab—have been developed in an attempt to disrupt the ability of tumor cells to trick the immune system into accepting them as “self” by manipulating the PD-L1/PD-L2: PD-1 interaction. Both drugs are monoclonal antibodies that bind to PD-1 and, thus, effectively block the ability of PD-L1 or PD-L2 on tumor cells to bind these ligands and signal to activated T cells that they are “self.” This blocking allows T cells to then carry out their killing of tumor cells they initially recognize as foreign.

Nivolumab. In 2014, a phase 3 trial⁴⁰ compared nivolumab and dacarbazine in patients with untreated advanced melanoma without a BRAF mutation. Objective response rates were 40.0% in the nivolumab group vs 13.9% in the dacarbazine group. This trial was stopped early because of significantly better survival rates in patients taking nivolumab compared with standard chemotherapy.

Interestingly, only 35% of patients who responded to nivolumab had evidence of PD-L1 expression on the surface of their tumor cells as assessed by immunohistochemical assay. Regardless of PD-L1 status, nivolumab-treated patients had improved overall survival compared with those treated with dacarbazine. The response rate with nivolumab was only slightly better in the subgroup of patients whose tumors expressed PD-L1 than in the subgroup without PD-L1.

On December 22, 2014, the FDA granted accelerated approval to nivolumab for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab treatment and, if BRAF V600 mutation-positive, a BRAF inhibitor.

Pembrolizumab. Also in 2014, an open-label, randomized, phase 1b trial of pembrolizumab treatment at two different dosage schedules was conducted in patients with advanced melanoma that had become refractory either to ipilimumab or a BRAF inhibitor.⁴¹ Treatment with pembrolizumab had an objective response rate of 26% at both doses.

In September 2014, the FDA granted accelerated approval for the use of pembrolizumab to treat patients with unresectable or metastatic melanoma and disease progression following treatment with ipilimumab or a BRAF inhibitor.

Adverse effects of PD-1 inhibitors are similar to those seen with ipilimumab, the most common (occurring in at least 20%) being fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, muscle pain, and diarrhea. Serious effects from pembrolizumab (occurring in at least 2%) were kidney failure, dyspnea, pneumonia, and cellulitis. As seen with ipilimumab, clinically significant autoimmune adverse reactions occur with PD-1 inhibitors, including pneumonitis, colitis, hypophysitis, nephritis, and hepatitis.

Combination therapy under investigation

A phase 1 trial using combination therapy with both immune checkpoint inhibitors—nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4)—in patients with treatment-resistant metastatic melanoma was published in 2013.⁴² More than half of patients achieved objective responses, with tumor regression of at least 80% in those who had a response. Tumor response was evident in all subgroups of patients studied—those with pretreatment elevated lactate dehydrogenase levels (one of the strongest prognostic factors in metastatic melanoma), metastases to distant sites, and bulky, multifocal tumor burden. Based on these results, a phase 3 trial is now under way looking at the combination of these two medications vs either one alone.

In summary, targeted treatments are changing the paradigm of how common dermatologic conditions associated with significant morbidity and mortality are treated. Although implementation of the above treatments into everyday clinical practice is exciting, future studies surrounding each are needed to address unanswered issues, such as the optimal dosing and treatment schedules in terms of both disease response and inhibition of resistance, optimal patient/disease characteristics for use, and optimal drug treatment combinations. In the meantime, basic research still utilizing classic molecular biology techniques to uncover pathogenic disease mechanisms in even more detail is ongoing and hopefully will lead to development of even better targeted treatments or even cures for these diseases.

New targeted therapies are changing the way patients with advanced dermatologic diseases are treated. Innovative molecular biology techniques developed as far back as the 1970s have engendered tremendous insight into the cellular and molecular pathogenesis of numerous diseases. Novel medications based on these insights are now bearing fruit, as directed biologic therapies that are revolutionizing clinical practice are increasingly becoming available.

This article reviews advances in targeted therapies for advanced basal cell carcinoma, psoriasis, and metastatic melanoma.

TARGETED THERAPY FOR BASAL CELL CARCINOMA

Case 1. A 56-year-old man presents with a progressively enlarging leg ulcer. Although it has been treated empirically for years as a venous stasis ulcer, biopsy reveals that it is basal cell carcinoma. Imaging shows muscle and tendon invasion, making surgical intervention short of amputation challenging (Figure 1). What are his options?

Courtesy of Allison Vidimos, MD. Magnetic resonance image courtesy of Todd Stultz, MD, and Claus Simpfendorfer, MD

Basal cell carcinoma is the most common cancer in humans, accounting for 25% of all cancers and more than 2 million cases in the United States every year. In most cases, surgical excision is curative, but a subset of patients have inoperable, locally advanced, or metastatic disease that drastically limits treatment options. The median survival in metastatic basal cell carcinoma is 24 months, and conventional chemotherapy has not been shown to improve the prognosis.^1,2

In addition to the burden of sporadic basal cell carcinoma, patients with the rare autosomal-dominant genetic disorder basal cell nevus syndrome (Gorlin syndrome) develop multiple basal cell lesions over their lifetime. The syndrome may also involve abnormalities of the skeletal system, genitourinary tract, and central nervous system, including development of medulloblastoma.

In Gorlin syndrome, basal cell carcinomas occur often and early; about half of white patients with the syndrome develop their first lesions by age 21, and 90% by age 35. The lesions occur in multiple numbers and can develop anywhere on the body, including on non–sun-exposed areas. Patients who have Gorlin syndrome need meticulous monitoring every 2 to 3 months so that basal cell lesions can be recognized early and treated before they become locally advanced. Keeping up with the numerous medical appointments and invasive treatments can be physically and mentally taxing for patients.

Specific pathway and mutations identified

In 1996, Gorlin syndrome was found to be caused by mutations of the human homolog of the PATCHED gene, which codes for a receptor in the “hedgehog” pathway.³ Two years later, the same mutations were found to be involved in many sporadic basal cell carcinomas, and we now believe that at least 85% of basal cell carcinomas involve abnormal activation of hedgehog pathway signaling.^4,5 

Vismodegib developed as targeted therapy

In 2009, Robarge et al⁶ described a potent inhibitor of the hedgehog pathway that was later optimized for potency and desirable pharmacologic traits, resulting in the drug vismodegib.^7,8

Two phase 2 multicenter clinical trials^9,10 of vismodegib were published in 2012. In the first, which was not randomized,⁹ 33 patients with metastatic basal cell carcinoma and 63 patients with locally advanced disease were treated with vismodegib. Of those with metastatic disease, 30% achieved an objective response. Of those with locally advanced disease, 43% achieved an objective response and 21% achieved a complete response.

In the second trial,¹⁰ patients with Gorlin syndrome were randomized to either vismodegib (26 patients) or placebo (16 patients). After 8 months, the vismodegib group had developed significantly fewer new surgically eligible tumors (2 vs 29 per year), their tumors were smaller (change from baseline of the sum of the longest diameters –65% vs –11%), and they needed fewer surgeries (mean 0.31 vs 4.4 per patient). No tumors progressed in the treatment group. Results in some patients were dramatic, with complete healing of large ulcerative tumors. The trial was ended early in view of significant efficacy in the treatment group.

Based on these trials, the US Food and Drug Administration (FDA) approved vismodegib for treating metastatic and locally advanced basal cell carcinoma.

Resistance and adverse effects common

Unfortunately, vismodegib has significant drawbacks. About 20% of patients develop resistance, with tumors recurring after several months of therapy.¹¹ Adverse effects most commonly reported were muscle spasms (68%), alopecia (63%), taste distortion (51%), weight loss (46%), and fatigue (36%). Although these effects were considered mild or moderate, they tended to persist, and almost every patient developed at least one. In the nonrandomized trial,⁹ more than 25% of patients discontinued treatment because of adverse effects, and more than half of patients did the same in the basal cell nevus syndrome trial.¹⁰

New uses may reduce shortcomings

Studies are under way to determine how best to use vismodegib.

One possibility is to use the drug for a few months to shrink tumors to the point that they become eligible for surgery. This is especially important for high-risk tumors, such as those near the eye or other vital structures. In 11 patients, Ally et al¹² found that the surgical defect area was reduced by 27% from baseline after 4 months of treatment with vismodegib, allowing for curative surgery in some.

Another option is to combine vismodegib with other agents—either new ones on the horizon or existing nonspecific medications. For example, the antifungal itraconazole has been shown to inhibit hedgehog signaling and perhaps could be combined with vismodegib to increase response and reduce resistance.

Finally, a topical or intralesional form of vismodegib would be useful not only to reduce systemic toxicity, but also to increase efficacy when combined with other topical or systemic medications.

TARGETED THERAPY FOR PSORIASIS VULGARIS

Case 2. A 28-year-old woman presents with worsening psoriasis. About 35% of her body surface is involved, including the palms and soles, making it difficult for her to perform activities of daily living (Figure 2). What are her options?

Psoriasis is a chronic immune-mediated disease that affects up to 3% of people worldwide. In its moderate to severe forms, we recognize psoriasis as a systemic inflammatory disease that may adversely affect organ systems other than the skin. Commonly associated comorbid diseases include inflammatory (psoriatic) arthritis, cardiovascular disease, malignancies (eg, lymphoma), and inflammatory bowel disease. In addition, patients are well known to have significantly impaired quality of life because of low self-esteem, stigmatization affecting their social and work relationships, and, in up to 60%, clinical depression.^13,14 The onset of psoriatic arthritis, particularly of erosive disease, is an important decision point for starting aggressive treatment, as joint destruction is irreversible.

Early targeted therapy aimed at TNF alpha, IL-12, and IL-23

Histologically, psoriasis involves thickening of the epidermis caused by hyperproliferation of keratinocytes. Based on this, prior to the 1980s, the dominant hypothesis concerning its pathogenesis was that it was caused by an inherent defect of keratinocytes. In the 1980s and 1990s, however, molecular research revealed that psoriasis was an immune-mediated disease caused by immunologic dysregulation predominantly involving T-helper 1  (Th-1) cells, with the inflammatory cytokines tumor necrosis factor (TNF) alpha, interferon gamma, interleukin (IL) 12, and IL-23 playing prominent roles.¹⁵ These findings led to the development and FDA approval of the first effective, targeted, psoriasis treatments, TNF-alpha inhibitors and the IL-12/23 inhibitor ustekinumab.

Etanercept, the first TNF-alpha inhibitor to become available, was approved in 2004 for moderate to severe psoriasis. In 2008, the IL-12/23 inhibitor ustekinumab was approved for the same indication. These drugs are efficacious, are generally safe, and have revolutionized the treatment of psoriasis and psoriatic arthritis, and they are now prescribed on a daily basis.^16,17

In the clinical trials that led to approval of these drugs, the main outcome measure was the Psoriasis Area and Severity Index (PASI), a clinical scoring tool that assesses clinical aspects of psoriatic disease including body surface area involvement, degree of thickness, erythema, and scaling of psoriatic plaques. PASI scores range from 0 (no psoriasis) to 72 (most severe psoriasis). Achieving “PASI 75” indicates at least 75% improvement from the baseline score and represents the most common primary outcome measure in clinical trials assessing efficacy of new treatments. Up to 80% of patients who received currently available TNF-alpha inhibitors and ustekinumab in pivotal clinical trials achieved PASI 75 when assessed at 12 to 16 weeks after starting treatment. A moderate percentage of patients (19%–57%, depending on the trial) achieved 90% improvement (PASI 90), and a minority (up to 18%) achieved PASI 100, indicating complete clearing of their psoriasis.^18–22

Newly developed therapies target IL-17A

In the mid-2000s, Th-17 cells were discovered, a new lineage of T cells distinct from Th-1 and Th-2 cells. Th-17 cells are characterized by their production of IL-17, a pro-inflammatory cytokine with six family members (IL-17A through IL-17F). Over the next few years, experiments revealed that Th-17 cells and IL-17A play key roles in psoriasis immunologic dysregulation.¹⁵ These findings led to a paradigm shift in hypotheses concerning psoriasis pathogenesis, with Th-17 cells and IL-17 replacing Th-1 cells and associated cytokines as dominant mediators of tissue damage.

Additionally, these findings led to new ideas for treatment. Three monoclonal antibodies that target IL-17 inhibition are currently under investigation. Secukinumab and ixekizumab bind to IL-17A and inhibit it from downstream signaling, whereas brodalumab binds to the IL-17A receptor, blocking all six IL-17 cytokines (IL-17A to IL-17F).²³

Clinical trials of IL-17 inhibitors show excellent skin improvement

Secukinumab. In 2014, the results of two phase 3 trials of secukinumab were published.²⁴

In the Efficacy and Safety of Subcutaneous Secukinumab for Moderate to Severe Chronic Plaque-type Psoriasis for up to 1 Year trial,²⁴ patients were given either secukinumab 300 mg or 150 mg subcutaneously at defined time points; 82% and 72%, respectively, attained PASI 75 at 12 weeks.

Similar results were seen in the Safety and Efficacy of Secukinumab Compared to Etanercept in Subjects With Moderate to Severe, Chronic Plaque-Type Psoriasis study,²⁴ in which PASI 75 was achieved by 77% of patients receiving secukinumab 300 mg, 67% of those receiving secukinumab 150 mg, and only 44% of those receiving etanercept 50 mg twice weekly at 12 weeks. Rates of infection with secukinumab and etanercept were similar.

The most striking results of these trials were that more than half of patients receiving the 300-mg dose achieved at least 90% improvement in their PASI score (PASI 90) by week 12, and in more than a quarter of patients the psoriasis completely cleared (PASI 100). These results were dramatically better than for etanercept (PASI 90 21%; PASI 100 4%).

Additionally, secukinumab worked fast. The median time to PASI 50 with secukinumab 300 mg was less than half that seen with etanercept (3 weeks vs 7 weeks).

Ixekizumab. In 2012, a phase 2 trial evaluated subcutaneous injections of ixekizumab in dosages ranging from 10 to 150 mg at defined intervals for 16 weeks.²⁵ Of those receiving the highest dosage, 82% attained PASI 75 at 12 weeks, on par with what is noted in patients receiving TNF-alpha inhibitors and IL-12/23 inhibitors. Remarkably, however, almost three-quarters of patients (71%) achieved PASI 90, and 39% achieved PASI 100. Improvement in psoriasis was apparent as early as 1 week after injection.

Brodalumab. A 2012 phase 2 trial of various dosages of the IL-17 receptor inhibitor brodalumab²⁶ also showed excellent PASI 75 achievement with the highest dosage (82%). Astonishingly, though, PASI 90 was achieved by 75% of patients, and PASI 100 by 62%.

Overall, although the percentages of patients achieving PASI 75 with the new IL-17 inhibitor drugs are comparable to those seen with TNF-alpha inhibitors and IL-12/23 inhibitors, the extraordinarily high percentages of patients who achieved PASI 90 and PASI 100 are unprecedented.^18–22

Arthritis improvement not shown

Where the IL-17 inhibitors eventually settle within algorithms of psoriasis treatment largely depends on their efficacy in treating psoriatic arthritis compared with TNF-alpha inhibitors and IL-12/23 inhibitors. Joint inflammation is typically evaluated with the American College of Rheumatology (ACR) scoring tool, which in simple terms can be thought of as analogous to the PASI scoring tool for the skin. Although the ACR scoring tool was developed to assess joint inflammation in clinical trials for patients with rheumatoid arthritis, it is commonly used to assess improvement of psoriatic arthritis in clinical trials. The ACR tool involves assessing and scoring the number of swollen and tender joints, but also incorporates serologic assessment of acute-phase reactants (erythrocyte sedimentation rate or C-reactive protein level), patient and physician global assessment, pain, and function. ACR 20 implies roughly a 20% improvement in these criteria, whereas ACR 50 indicates 50% improvement, and so on.

Two phase 2 trials of IL-17 inhibitors for psoriatic arthritis have been published, one with secukinumab²⁷ and one with brodalumab.²⁸ Neither had impressive improvement in the ACR score vs TNF inhibitors—39% for ACR 20 at week 12 and less than 10% for ACR 70. Clinical trial design may have played a role, and phase 3 trials are under way for all three IL-17 inhibitors.

Adverse effects of IL-17 inhibitors

For the most part, adverse effects reported with the IL-17 inhibitors have been mild  and similar to those reported with available biologic treatments for psoriasis. Adverse effects most commonly reported have been nasopharyngitis, upper respiratory infection, arthralgia, and mild injection-site reactions. In the future, attention will be paid to the rate of infections known to be associated with IL-17, mainly localized infections with Staphylococcus aureus and Candida species. Some patients have developed Candida esophagitis, but this appears to resolve with discontinuation of the drugs. Neutropenia has occurred, but very few patients have developed grade 3 (500–1,000 cells/mm³) or worse. All adverse effects were reversible with discontinuation of treatment.

Approval of secukinumab, and current studies of IL-17 inhibitors

On January 21, 2015, secukinumab was approved by the FDA for treatment of moderate to severe psoriasis vulgaris in adult patients and is now available by prescription.
More trials of IL-17 inhibitors for the treatment of psoriasis and psoriatic arthritis are under way and are at various phases at the time of this writing.²³

TARGETED THERAPY FOR ADVANCED MELANOMA

Case 3. A 58-year-old man presents with an irregular pigmented lesion on his back. Biopsy shows malignant melanoma with an intense, chronic inflammatory infiltrate surrounding the tumor (Figure 3). The tumor was surgically excised with standard margins. Two years later, the patient developed multiple pigmented lesions on the face and complained of headache. Magnetic resonance imaging of the brain revealed multiple enhancing lesions consistent with metastatic melanoma (Figure 3). What are this patient’s options?

Melanoma is the fifth most common cancer in humans, with about 132,000 new cases diagnosed worldwide each year and 48,000 deaths from advanced disease. Its incidence has risen rapidly over the last few decades. Advanced disease has a poor prognosis, with the median overall survival less than 1 year and 5-year survival less than 10%.

Despite decades of research, a paucity of FDA-approved medications were available to treat advanced melanoma until recently. The alkylating agent dacarbazine was approved in 1975, interferon alpha in 1995, and high-dose IL-2 in 1998. Although some patients respond, studies have not shown significant improvement in survival with any of these medications.^29–31

In 2002, Davies et al³² found that 50% to 65% of metastatic cutaneous melanomas have a mutation in the BRAF gene. Interestingly, 80% of these patients share a single specific mutation: substitution of glutamic acid for valine in codon 600 (BRAF V600E). The second most common mutation is a single substitution of a lysine for that same valine (BRAF V600K). Additionally, NRAS is mutated in about 20% of melanomas. These discoveries implicated a mitogen-activated protein kinase (MAPK) pathway (Figure 4) as playing a critical role in metastatic melanoma for a large percentage of patients.²⁹

Medical Illustrator: Ross Papalardo

Based on this knowledge, several targeted therapies for melanoma have been developed, and some have been approved.

BRAF inhibitors—first success against melanoma

Vemurafenib. In 2010, Flaherty et al³³ reported on a phase 1 and phase 2 clinical trial of vemurafenib (960 mg orally twice daily), a potent inhibitor of BRAF with the V600E mutation. They demonstrated a clinical benefit in 80% of patients with stage IV BRAF-mutant melanoma, an unprecedented response that opened the door to changes in the treatment of metastatic melanoma.

The phase 3 BRAF Inhibitor in Melanoma (BRIM)-3 clinical trial,³⁴ published in 2011, randomized 675 previously untreated patients with advanced melanoma to either vemurafenib 960 mg orally twice daily or dacarbazine, the standard of care. The trial was terminated early when an interim analysis showed a significant overall advantage for vemurafenib (median progression-free survival 5.3 months vs 1.6 months for dacarbazine). Based on these results, vemurafenib was FDA-approved in August 2011 for use in patients with BRAF-mutant melanoma.

Dabrafenib. In a phase 3 clinical trial in 2012, Hauschild et al³⁵ randomized 250 patients with BRAF (V600E)-mutated melanoma in a 3:1 ratio to receive either dabrafenib, a more potent second-generation BRAF inhibitor, or dacarbazine. Half of patients responded to dabrafenib, with a significantly improved progression-free survival rate (5.1 vs 2.7 months respectively), leading to FDA approval for its use in BRAF-mutant melanoma in May 2013.

Adverse effects common to vemurafenib and dabrafenib include rash, fatigue, fever, and joint pain. In addition, up to 25% of patients develop multiple secondary cutaneous squamous cell carcinomas and keratoacanthomas, usually within the first few months of therapy, which are believed to be caused by paradoxical activation of the MAPK pathway.

A more important problem with these medications is the development of resistance. Tumors typically progress again after a median progression-free survival of 6 to 7 months.

MEK inhibitors—another line of defense

Inhibitors of MEK—a serine-threonine kinase that is part of the same MAPK pathway involving BRAF—have been developed as well.

Trametinib. In 2012, trametinib, an allosteric MEK inhibitor, was used in an open-label phase 3 trial in 322 patients with advanced melanoma. Progression-free survival was 4.8 months for trametinib-treated patients compared with 1.5 months for the standard chemotherapy group (dacarbazine or paclitaxel).³⁶ These results led to FDA approval of trametinib in May 2013 for treating BRAF-mutant melanoma.²⁹

Cobimetinib is a second MEK inhibitor being evaluated alone and in combination with other targeted treatments for advanced melanoma.

Both MEK inhibitors have adverse effects similar to those seen with the BRAF inhibitors, including diarrhea, rash, fatigue, and edema. They also tend to cause asymptomatic elevated creatine kinase and transient retinopathy, reduced ejection fraction, and ventricular dysfunction. Unlike BRAF inhibitors, they are not associated with development of secondary cutaneous squamous cell carcinomas or keratoacanthomas. However, as with BRAF inhibitors, resistance is a problem with MEK inhibitors, with most patients relapsing less than a year after starting therapy.

Combination therapy improves outcomes

Possible mechanisms underlying resistance to these medications are being studied. A number of important factors appear to drive resistance, including expression of truncated BRAF proteins that do not bind the BRAF inhibitors and still activate downstream signaling, and amplification of BRAF to such a degree that it overwhelms the medications. This has led to the idea of combining BRAF inhibitors and MEK inhibitors to block the MAPK pathway at two points, potentially increasing the response and decreasing resistance.

Two trials have evaluated combinations of BRAF and MEK inhibitors in patients with advanced melanoma. Larkin et al³⁷ conducted a phase 3 study evaluating combined vemurafenib (a BRAF inhibitor) and cobimetinib (a MEK inhibitor) vs combined vemurafenib and placebo. Survival with the combination therapy was 9.9 months vs 6.2 months with the single treatment.

The incidence of serious adverse effects was not significantly increased with the combination therapy, and keratoacanthomas, cutaneous squamous cell carcinomas, alopecia, and arthralgias were reduced compared with the vemurafenib and placebo group.

Another trial³⁸ evaluating combined dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) vs combined dabrafenib and placebo had similar findings: increased survival in the combined therapy group (9.3 months vs 8.8 months) and lower rates of squamous cell carcinoma (2% vs 9%).

In January 2014, the FDA approved the combination of BRAF and MEK inhibitors for the treatment of BRAF-mutant metastatic melanoma based on improved survival and generally reduced adverse effects.

IMMUNOTHERAPIES FOR NON-BRAF MELANOMA

Although BRAF and MEK inhibitors represent tremendous advances, their use is limited to the approximately 50% to 65% of patients with advanced melanoma who have BRAF V600 mutations. For others, only the traditional standard medications have been available until recently.

Two of those standard FDA-approved medications, interferon alpha-2b and IL-2, represent immunotherapies. Interferon alpha-2b up-regulates antigen presentation and increases antigen recognition by T cells. Overall, about 20% of patients in clinical trials have achieved responses.

IL-2 is a cytokine that increases T-cell proliferation and maturation into effector T cells. High-dose IL-2 has produced responses in 15% of patients, with a durable complete response in a small proportion.

Though success with these medications was modest, the fact that some patients responded to them indicates that immunotherapy could be a viable strategy for treating metastatic melanoma.³⁰ This is underscored by the fact that some patients can mount an adaptive immune response specifically directed against antigenic proteins expressed in their tumors, resulting in expansion of cytotoxic T cells and control or even elimination of the malignancy.³⁰

Tumors manipulate host immune checkpoints

Molecular biology has provided tremendous insight into tumor immunology over the past several decades, and we now recognize that a hallmark of cancer is escape from immune control.

Cancer cells contain a multitude of mutations that produce proteins that should be recognized by the immune system as foreign but in most individuals are not. This is because T-cell activity is down-regulated in cancer due to cancer cells’ ability to manipulate the host’s normal immunologic inhibitory pathways critical for maintaining self-tolerance.

In general, T-cell activation is initiated when an antigen-presenting cell presents an antigen to a T cell in a major histocompatibility complex-restricted manner. To prevent T cells from being activated by self-antigens and initiating autoimmunity, the interaction between antigen-presenting cells and T cells is regulated by checkpoints (Figure 5). First, for an antigen-presenting cell/T-cell interaction to result in T-cell activation, the T-cell receptor CD28 must bind CD80 on the antigen-presenting cell to drive a “positive” signal. Early in the interaction, the T-cell receptor CTLA-4 is up-regulated and competes with CD28 for binding of CD80. If CTLA-4, and not CD28, binds CD80, a “negative” signal is sent to the T cell and down-regulates it, making the interaction unproductive. Importantly, it is the CTLA-4:CD80 interaction that appears to be crucial for the ability of tumors to dampen T-cell responses to cancer cells.

Medical Illustrator: Ross Papalardo

Ipilimumab is a fully humanized monoclonal antibody that binds to CTLA-4, blocking its ability to bind to CD80 and thereby enhancing T-cell activation. In a phase 3 trial, Hodi et al³⁹ evaluated its use in treating advanced melanoma, with some enrolled patients having failed IL-2 treatment. Patients receiving ipilimumab with or without a glycoprotein-100 peptide vaccine (gp100) had an overall survival benefit of 10.1 months compared with 6.4 months for patients treated with gp100 alone. At 24 months, the survival rate with ipilimumab alone was 23.5%, almost double that of patients receiving gp100 alone.

Ipilimumab received FDA approval for treatment of metastatic melanoma in March 2011. This, and the BRAF inhibitors, were the first drugs approved by the FDA for the treatment of advanced melanoma in more than a decade.

Common adverse effects of ipilimumab include fatigue, diarrhea, rash, and pruritus. As expected, given its mechanism of action, up to about 25% of patients experience severe autoimmune-related events that may variably manifest as colitis, rash, hepatitis, neuritis, hypothyroidism, hypopituitarism, and hypophysitis. Another problem with this medication is that a subset of patients do not respond.

Cancer cells disguised as normal cells

Cancer cells can also manipulate another immunologic checkpoint to evade attack by the host immune system (Figure 5). Cytotoxic T cells may recognize antigens on tumor cells and become activated and primed to directly destroy them. However, tumor cells, like normal cells express the programmed death ligands RTK-L1 and PD-L2. These ligands function to bind to the PD-1 receptor on activated T cells to indicate they are “self” and inhibit the cytotoxic T cells from destroying them.

Evasion of immune system attack by manipulating checkpoints involving CTLA-4 and PD-1 helps explain why malignancies can seemingly be associated with brisk inflammatory responses, such as the tumor in Case 3, yet progress and eventually metastasize (Figure 3).

Two medications—nivolumab and pembrolizumab—have been developed in an attempt to disrupt the ability of tumor cells to trick the immune system into accepting them as “self” by manipulating the PD-L1/PD-L2: PD-1 interaction. Both drugs are monoclonal antibodies that bind to PD-1 and, thus, effectively block the ability of PD-L1 or PD-L2 on tumor cells to bind these ligands and signal to activated T cells that they are “self.” This blocking allows T cells to then carry out their killing of tumor cells they initially recognize as foreign.

Nivolumab. In 2014, a phase 3 trial⁴⁰ compared nivolumab and dacarbazine in patients with untreated advanced melanoma without a BRAF mutation. Objective response rates were 40.0% in the nivolumab group vs 13.9% in the dacarbazine group. This trial was stopped early because of significantly better survival rates in patients taking nivolumab compared with standard chemotherapy.

Interestingly, only 35% of patients who responded to nivolumab had evidence of PD-L1 expression on the surface of their tumor cells as assessed by immunohistochemical assay. Regardless of PD-L1 status, nivolumab-treated patients had improved overall survival compared with those treated with dacarbazine. The response rate with nivolumab was only slightly better in the subgroup of patients whose tumors expressed PD-L1 than in the subgroup without PD-L1.

On December 22, 2014, the FDA granted accelerated approval to nivolumab for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab treatment and, if BRAF V600 mutation-positive, a BRAF inhibitor.

Pembrolizumab. Also in 2014, an open-label, randomized, phase 1b trial of pembrolizumab treatment at two different dosage schedules was conducted in patients with advanced melanoma that had become refractory either to ipilimumab or a BRAF inhibitor.⁴¹ Treatment with pembrolizumab had an objective response rate of 26% at both doses.

In September 2014, the FDA granted accelerated approval for the use of pembrolizumab to treat patients with unresectable or metastatic melanoma and disease progression following treatment with ipilimumab or a BRAF inhibitor.

Adverse effects of PD-1 inhibitors are similar to those seen with ipilimumab, the most common (occurring in at least 20%) being fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, muscle pain, and diarrhea. Serious effects from pembrolizumab (occurring in at least 2%) were kidney failure, dyspnea, pneumonia, and cellulitis. As seen with ipilimumab, clinically significant autoimmune adverse reactions occur with PD-1 inhibitors, including pneumonitis, colitis, hypophysitis, nephritis, and hepatitis.

Combination therapy under investigation

A phase 1 trial using combination therapy with both immune checkpoint inhibitors—nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4)—in patients with treatment-resistant metastatic melanoma was published in 2013.⁴² More than half of patients achieved objective responses, with tumor regression of at least 80% in those who had a response. Tumor response was evident in all subgroups of patients studied—those with pretreatment elevated lactate dehydrogenase levels (one of the strongest prognostic factors in metastatic melanoma), metastases to distant sites, and bulky, multifocal tumor burden. Based on these results, a phase 3 trial is now under way looking at the combination of these two medications vs either one alone.

In summary, targeted treatments are changing the paradigm of how common dermatologic conditions associated with significant morbidity and mortality are treated. Although implementation of the above treatments into everyday clinical practice is exciting, future studies surrounding each are needed to address unanswered issues, such as the optimal dosing and treatment schedules in terms of both disease response and inhibition of resistance, optimal patient/disease characteristics for use, and optimal drug treatment combinations. In the meantime, basic research still utilizing classic molecular biology techniques to uncover pathogenic disease mechanisms in even more detail is ongoing and hopefully will lead to development of even better targeted treatments or even cures for these diseases.

New targeted therapies are changing the way patients with advanced dermatologic diseases are treated. Innovative molecular biology techniques developed as far back as the 1970s have engendered tremendous insight into the cellular and molecular pathogenesis of numerous diseases. Novel medications based on these insights are now bearing fruit, as directed biologic therapies that are revolutionizing clinical practice are increasingly becoming available.

This article reviews advances in targeted therapies for advanced basal cell carcinoma, psoriasis, and metastatic melanoma.

TARGETED THERAPY FOR BASAL CELL CARCINOMA

Case 1. A 56-year-old man presents with a progressively enlarging leg ulcer. Although it has been treated empirically for years as a venous stasis ulcer, biopsy reveals that it is basal cell carcinoma. Imaging shows muscle and tendon invasion, making surgical intervention short of amputation challenging (Figure 1). What are his options?

Courtesy of Allison Vidimos, MD. Magnetic resonance image courtesy of Todd Stultz, MD, and Claus Simpfendorfer, MD

Basal cell carcinoma is the most common cancer in humans, accounting for 25% of all cancers and more than 2 million cases in the United States every year. In most cases, surgical excision is curative, but a subset of patients have inoperable, locally advanced, or metastatic disease that drastically limits treatment options. The median survival in metastatic basal cell carcinoma is 24 months, and conventional chemotherapy has not been shown to improve the prognosis.^1,2

In addition to the burden of sporadic basal cell carcinoma, patients with the rare autosomal-dominant genetic disorder basal cell nevus syndrome (Gorlin syndrome) develop multiple basal cell lesions over their lifetime. The syndrome may also involve abnormalities of the skeletal system, genitourinary tract, and central nervous system, including development of medulloblastoma.

In Gorlin syndrome, basal cell carcinomas occur often and early; about half of white patients with the syndrome develop their first lesions by age 21, and 90% by age 35. The lesions occur in multiple numbers and can develop anywhere on the body, including on non–sun-exposed areas. Patients who have Gorlin syndrome need meticulous monitoring every 2 to 3 months so that basal cell lesions can be recognized early and treated before they become locally advanced. Keeping up with the numerous medical appointments and invasive treatments can be physically and mentally taxing for patients.

Specific pathway and mutations identified

In 1996, Gorlin syndrome was found to be caused by mutations of the human homolog of the PATCHED gene, which codes for a receptor in the “hedgehog” pathway.³ Two years later, the same mutations were found to be involved in many sporadic basal cell carcinomas, and we now believe that at least 85% of basal cell carcinomas involve abnormal activation of hedgehog pathway signaling.^4,5 

Vismodegib developed as targeted therapy

In 2009, Robarge et al⁶ described a potent inhibitor of the hedgehog pathway that was later optimized for potency and desirable pharmacologic traits, resulting in the drug vismodegib.^7,8

Two phase 2 multicenter clinical trials^9,10 of vismodegib were published in 2012. In the first, which was not randomized,⁹ 33 patients with metastatic basal cell carcinoma and 63 patients with locally advanced disease were treated with vismodegib. Of those with metastatic disease, 30% achieved an objective response. Of those with locally advanced disease, 43% achieved an objective response and 21% achieved a complete response.

In the second trial,¹⁰ patients with Gorlin syndrome were randomized to either vismodegib (26 patients) or placebo (16 patients). After 8 months, the vismodegib group had developed significantly fewer new surgically eligible tumors (2 vs 29 per year), their tumors were smaller (change from baseline of the sum of the longest diameters –65% vs –11%), and they needed fewer surgeries (mean 0.31 vs 4.4 per patient). No tumors progressed in the treatment group. Results in some patients were dramatic, with complete healing of large ulcerative tumors. The trial was ended early in view of significant efficacy in the treatment group.

Based on these trials, the US Food and Drug Administration (FDA) approved vismodegib for treating metastatic and locally advanced basal cell carcinoma.

Resistance and adverse effects common

Unfortunately, vismodegib has significant drawbacks. About 20% of patients develop resistance, with tumors recurring after several months of therapy.¹¹ Adverse effects most commonly reported were muscle spasms (68%), alopecia (63%), taste distortion (51%), weight loss (46%), and fatigue (36%). Although these effects were considered mild or moderate, they tended to persist, and almost every patient developed at least one. In the nonrandomized trial,⁹ more than 25% of patients discontinued treatment because of adverse effects, and more than half of patients did the same in the basal cell nevus syndrome trial.¹⁰

New uses may reduce shortcomings

Studies are under way to determine how best to use vismodegib.

One possibility is to use the drug for a few months to shrink tumors to the point that they become eligible for surgery. This is especially important for high-risk tumors, such as those near the eye or other vital structures. In 11 patients, Ally et al¹² found that the surgical defect area was reduced by 27% from baseline after 4 months of treatment with vismodegib, allowing for curative surgery in some.

Another option is to combine vismodegib with other agents—either new ones on the horizon or existing nonspecific medications. For example, the antifungal itraconazole has been shown to inhibit hedgehog signaling and perhaps could be combined with vismodegib to increase response and reduce resistance.

Finally, a topical or intralesional form of vismodegib would be useful not only to reduce systemic toxicity, but also to increase efficacy when combined with other topical or systemic medications.

TARGETED THERAPY FOR PSORIASIS VULGARIS

Case 2. A 28-year-old woman presents with worsening psoriasis. About 35% of her body surface is involved, including the palms and soles, making it difficult for her to perform activities of daily living (Figure 2). What are her options?

Psoriasis is a chronic immune-mediated disease that affects up to 3% of people worldwide. In its moderate to severe forms, we recognize psoriasis as a systemic inflammatory disease that may adversely affect organ systems other than the skin. Commonly associated comorbid diseases include inflammatory (psoriatic) arthritis, cardiovascular disease, malignancies (eg, lymphoma), and inflammatory bowel disease. In addition, patients are well known to have significantly impaired quality of life because of low self-esteem, stigmatization affecting their social and work relationships, and, in up to 60%, clinical depression.^13,14 The onset of psoriatic arthritis, particularly of erosive disease, is an important decision point for starting aggressive treatment, as joint destruction is irreversible.

Early targeted therapy aimed at TNF alpha, IL-12, and IL-23

Histologically, psoriasis involves thickening of the epidermis caused by hyperproliferation of keratinocytes. Based on this, prior to the 1980s, the dominant hypothesis concerning its pathogenesis was that it was caused by an inherent defect of keratinocytes. In the 1980s and 1990s, however, molecular research revealed that psoriasis was an immune-mediated disease caused by immunologic dysregulation predominantly involving T-helper 1  (Th-1) cells, with the inflammatory cytokines tumor necrosis factor (TNF) alpha, interferon gamma, interleukin (IL) 12, and IL-23 playing prominent roles.¹⁵ These findings led to the development and FDA approval of the first effective, targeted, psoriasis treatments, TNF-alpha inhibitors and the IL-12/23 inhibitor ustekinumab.

Etanercept, the first TNF-alpha inhibitor to become available, was approved in 2004 for moderate to severe psoriasis. In 2008, the IL-12/23 inhibitor ustekinumab was approved for the same indication. These drugs are efficacious, are generally safe, and have revolutionized the treatment of psoriasis and psoriatic arthritis, and they are now prescribed on a daily basis.^16,17

In the clinical trials that led to approval of these drugs, the main outcome measure was the Psoriasis Area and Severity Index (PASI), a clinical scoring tool that assesses clinical aspects of psoriatic disease including body surface area involvement, degree of thickness, erythema, and scaling of psoriatic plaques. PASI scores range from 0 (no psoriasis) to 72 (most severe psoriasis). Achieving “PASI 75” indicates at least 75% improvement from the baseline score and represents the most common primary outcome measure in clinical trials assessing efficacy of new treatments. Up to 80% of patients who received currently available TNF-alpha inhibitors and ustekinumab in pivotal clinical trials achieved PASI 75 when assessed at 12 to 16 weeks after starting treatment. A moderate percentage of patients (19%–57%, depending on the trial) achieved 90% improvement (PASI 90), and a minority (up to 18%) achieved PASI 100, indicating complete clearing of their psoriasis.^18–22

Newly developed therapies target IL-17A

In the mid-2000s, Th-17 cells were discovered, a new lineage of T cells distinct from Th-1 and Th-2 cells. Th-17 cells are characterized by their production of IL-17, a pro-inflammatory cytokine with six family members (IL-17A through IL-17F). Over the next few years, experiments revealed that Th-17 cells and IL-17A play key roles in psoriasis immunologic dysregulation.¹⁵ These findings led to a paradigm shift in hypotheses concerning psoriasis pathogenesis, with Th-17 cells and IL-17 replacing Th-1 cells and associated cytokines as dominant mediators of tissue damage.

Additionally, these findings led to new ideas for treatment. Three monoclonal antibodies that target IL-17 inhibition are currently under investigation. Secukinumab and ixekizumab bind to IL-17A and inhibit it from downstream signaling, whereas brodalumab binds to the IL-17A receptor, blocking all six IL-17 cytokines (IL-17A to IL-17F).²³

Clinical trials of IL-17 inhibitors show excellent skin improvement

Secukinumab. In 2014, the results of two phase 3 trials of secukinumab were published.²⁴

In the Efficacy and Safety of Subcutaneous Secukinumab for Moderate to Severe Chronic Plaque-type Psoriasis for up to 1 Year trial,²⁴ patients were given either secukinumab 300 mg or 150 mg subcutaneously at defined time points; 82% and 72%, respectively, attained PASI 75 at 12 weeks.

Similar results were seen in the Safety and Efficacy of Secukinumab Compared to Etanercept in Subjects With Moderate to Severe, Chronic Plaque-Type Psoriasis study,²⁴ in which PASI 75 was achieved by 77% of patients receiving secukinumab 300 mg, 67% of those receiving secukinumab 150 mg, and only 44% of those receiving etanercept 50 mg twice weekly at 12 weeks. Rates of infection with secukinumab and etanercept were similar.

The most striking results of these trials were that more than half of patients receiving the 300-mg dose achieved at least 90% improvement in their PASI score (PASI 90) by week 12, and in more than a quarter of patients the psoriasis completely cleared (PASI 100). These results were dramatically better than for etanercept (PASI 90 21%; PASI 100 4%).

Additionally, secukinumab worked fast. The median time to PASI 50 with secukinumab 300 mg was less than half that seen with etanercept (3 weeks vs 7 weeks).

Ixekizumab. In 2012, a phase 2 trial evaluated subcutaneous injections of ixekizumab in dosages ranging from 10 to 150 mg at defined intervals for 16 weeks.²⁵ Of those receiving the highest dosage, 82% attained PASI 75 at 12 weeks, on par with what is noted in patients receiving TNF-alpha inhibitors and IL-12/23 inhibitors. Remarkably, however, almost three-quarters of patients (71%) achieved PASI 90, and 39% achieved PASI 100. Improvement in psoriasis was apparent as early as 1 week after injection.

Brodalumab. A 2012 phase 2 trial of various dosages of the IL-17 receptor inhibitor brodalumab²⁶ also showed excellent PASI 75 achievement with the highest dosage (82%). Astonishingly, though, PASI 90 was achieved by 75% of patients, and PASI 100 by 62%.

Overall, although the percentages of patients achieving PASI 75 with the new IL-17 inhibitor drugs are comparable to those seen with TNF-alpha inhibitors and IL-12/23 inhibitors, the extraordinarily high percentages of patients who achieved PASI 90 and PASI 100 are unprecedented.^18–22

Arthritis improvement not shown

Where the IL-17 inhibitors eventually settle within algorithms of psoriasis treatment largely depends on their efficacy in treating psoriatic arthritis compared with TNF-alpha inhibitors and IL-12/23 inhibitors. Joint inflammation is typically evaluated with the American College of Rheumatology (ACR) scoring tool, which in simple terms can be thought of as analogous to the PASI scoring tool for the skin. Although the ACR scoring tool was developed to assess joint inflammation in clinical trials for patients with rheumatoid arthritis, it is commonly used to assess improvement of psoriatic arthritis in clinical trials. The ACR tool involves assessing and scoring the number of swollen and tender joints, but also incorporates serologic assessment of acute-phase reactants (erythrocyte sedimentation rate or C-reactive protein level), patient and physician global assessment, pain, and function. ACR 20 implies roughly a 20% improvement in these criteria, whereas ACR 50 indicates 50% improvement, and so on.

Two phase 2 trials of IL-17 inhibitors for psoriatic arthritis have been published, one with secukinumab²⁷ and one with brodalumab.²⁸ Neither had impressive improvement in the ACR score vs TNF inhibitors—39% for ACR 20 at week 12 and less than 10% for ACR 70. Clinical trial design may have played a role, and phase 3 trials are under way for all three IL-17 inhibitors.

Adverse effects of IL-17 inhibitors

For the most part, adverse effects reported with the IL-17 inhibitors have been mild  and similar to those reported with available biologic treatments for psoriasis. Adverse effects most commonly reported have been nasopharyngitis, upper respiratory infection, arthralgia, and mild injection-site reactions. In the future, attention will be paid to the rate of infections known to be associated with IL-17, mainly localized infections with Staphylococcus aureus and Candida species. Some patients have developed Candida esophagitis, but this appears to resolve with discontinuation of the drugs. Neutropenia has occurred, but very few patients have developed grade 3 (500–1,000 cells/mm³) or worse. All adverse effects were reversible with discontinuation of treatment.

Approval of secukinumab, and current studies of IL-17 inhibitors

On January 21, 2015, secukinumab was approved by the FDA for treatment of moderate to severe psoriasis vulgaris in adult patients and is now available by prescription.
More trials of IL-17 inhibitors for the treatment of psoriasis and psoriatic arthritis are under way and are at various phases at the time of this writing.²³

TARGETED THERAPY FOR ADVANCED MELANOMA

Case 3. A 58-year-old man presents with an irregular pigmented lesion on his back. Biopsy shows malignant melanoma with an intense, chronic inflammatory infiltrate surrounding the tumor (Figure 3). The tumor was surgically excised with standard margins. Two years later, the patient developed multiple pigmented lesions on the face and complained of headache. Magnetic resonance imaging of the brain revealed multiple enhancing lesions consistent with metastatic melanoma (Figure 3). What are this patient’s options?

Melanoma is the fifth most common cancer in humans, with about 132,000 new cases diagnosed worldwide each year and 48,000 deaths from advanced disease. Its incidence has risen rapidly over the last few decades. Advanced disease has a poor prognosis, with the median overall survival less than 1 year and 5-year survival less than 10%.

Despite decades of research, a paucity of FDA-approved medications were available to treat advanced melanoma until recently. The alkylating agent dacarbazine was approved in 1975, interferon alpha in 1995, and high-dose IL-2 in 1998. Although some patients respond, studies have not shown significant improvement in survival with any of these medications.^29–31

In 2002, Davies et al³² found that 50% to 65% of metastatic cutaneous melanomas have a mutation in the BRAF gene. Interestingly, 80% of these patients share a single specific mutation: substitution of glutamic acid for valine in codon 600 (BRAF V600E). The second most common mutation is a single substitution of a lysine for that same valine (BRAF V600K). Additionally, NRAS is mutated in about 20% of melanomas. These discoveries implicated a mitogen-activated protein kinase (MAPK) pathway (Figure 4) as playing a critical role in metastatic melanoma for a large percentage of patients.²⁹

Medical Illustrator: Ross Papalardo

Based on this knowledge, several targeted therapies for melanoma have been developed, and some have been approved.

BRAF inhibitors—first success against melanoma

Vemurafenib. In 2010, Flaherty et al³³ reported on a phase 1 and phase 2 clinical trial of vemurafenib (960 mg orally twice daily), a potent inhibitor of BRAF with the V600E mutation. They demonstrated a clinical benefit in 80% of patients with stage IV BRAF-mutant melanoma, an unprecedented response that opened the door to changes in the treatment of metastatic melanoma.

The phase 3 BRAF Inhibitor in Melanoma (BRIM)-3 clinical trial,³⁴ published in 2011, randomized 675 previously untreated patients with advanced melanoma to either vemurafenib 960 mg orally twice daily or dacarbazine, the standard of care. The trial was terminated early when an interim analysis showed a significant overall advantage for vemurafenib (median progression-free survival 5.3 months vs 1.6 months for dacarbazine). Based on these results, vemurafenib was FDA-approved in August 2011 for use in patients with BRAF-mutant melanoma.

Dabrafenib. In a phase 3 clinical trial in 2012, Hauschild et al³⁵ randomized 250 patients with BRAF (V600E)-mutated melanoma in a 3:1 ratio to receive either dabrafenib, a more potent second-generation BRAF inhibitor, or dacarbazine. Half of patients responded to dabrafenib, with a significantly improved progression-free survival rate (5.1 vs 2.7 months respectively), leading to FDA approval for its use in BRAF-mutant melanoma in May 2013.

Adverse effects common to vemurafenib and dabrafenib include rash, fatigue, fever, and joint pain. In addition, up to 25% of patients develop multiple secondary cutaneous squamous cell carcinomas and keratoacanthomas, usually within the first few months of therapy, which are believed to be caused by paradoxical activation of the MAPK pathway.

A more important problem with these medications is the development of resistance. Tumors typically progress again after a median progression-free survival of 6 to 7 months.

MEK inhibitors—another line of defense

Inhibitors of MEK—a serine-threonine kinase that is part of the same MAPK pathway involving BRAF—have been developed as well.

Trametinib. In 2012, trametinib, an allosteric MEK inhibitor, was used in an open-label phase 3 trial in 322 patients with advanced melanoma. Progression-free survival was 4.8 months for trametinib-treated patients compared with 1.5 months for the standard chemotherapy group (dacarbazine or paclitaxel).³⁶ These results led to FDA approval of trametinib in May 2013 for treating BRAF-mutant melanoma.²⁹

Cobimetinib is a second MEK inhibitor being evaluated alone and in combination with other targeted treatments for advanced melanoma.

Both MEK inhibitors have adverse effects similar to those seen with the BRAF inhibitors, including diarrhea, rash, fatigue, and edema. They also tend to cause asymptomatic elevated creatine kinase and transient retinopathy, reduced ejection fraction, and ventricular dysfunction. Unlike BRAF inhibitors, they are not associated with development of secondary cutaneous squamous cell carcinomas or keratoacanthomas. However, as with BRAF inhibitors, resistance is a problem with MEK inhibitors, with most patients relapsing less than a year after starting therapy.

Combination therapy improves outcomes

Possible mechanisms underlying resistance to these medications are being studied. A number of important factors appear to drive resistance, including expression of truncated BRAF proteins that do not bind the BRAF inhibitors and still activate downstream signaling, and amplification of BRAF to such a degree that it overwhelms the medications. This has led to the idea of combining BRAF inhibitors and MEK inhibitors to block the MAPK pathway at two points, potentially increasing the response and decreasing resistance.

Two trials have evaluated combinations of BRAF and MEK inhibitors in patients with advanced melanoma. Larkin et al³⁷ conducted a phase 3 study evaluating combined vemurafenib (a BRAF inhibitor) and cobimetinib (a MEK inhibitor) vs combined vemurafenib and placebo. Survival with the combination therapy was 9.9 months vs 6.2 months with the single treatment.

The incidence of serious adverse effects was not significantly increased with the combination therapy, and keratoacanthomas, cutaneous squamous cell carcinomas, alopecia, and arthralgias were reduced compared with the vemurafenib and placebo group.

Another trial³⁸ evaluating combined dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) vs combined dabrafenib and placebo had similar findings: increased survival in the combined therapy group (9.3 months vs 8.8 months) and lower rates of squamous cell carcinoma (2% vs 9%).