A significant milestone in evidence-based practice was reached in November 2013, when the American Heart Association and American College of Cardiology (AHA/ACC) published 4 clinical practice guidelines on the prevention of cardiovascular disease.^1-4 These guidelines—on obesity, lifestyle management, cardiovascular disease (CVD) risk assessment, and cholesterol—were developed under the auspices of the National Heart, Lung, and Blood Institute (NHLBI) to update its prior guidelines on the treatment of hypertension, high cholesterol, and obesity that were published more than a decade ago.^5-7 After the NHLBI had organized the respective guideline panels and progressed through most of the guideline development process (which lasted several years each), it arranged for the AHA/ACC to assume sponsorship and publication of the guidelines. The NHLBI decided its role should be to develop evidence reports, leaving the development of guidelines to professional organizations.

While the prior guidelines on hypertension and hypercholesterolemia were influential and widely cited as the standard of care, they were heavily influenced by expert opinion and were not strictly evidence based. The NHLBI sought to develop the new guidelines using more contemporary and rigorous evidence-based processes to meet standards set by the Institute of Medicine (IOM). The group started with key clinical questions, conducted comprehensive systematic reviews of the evidence, and then rated the quality of the evidence and assigned strength of recommendation ratings.⁸ The guidelines and evidence reports are lengthy, and are summarized below.

Listen to Dr. Campos-Outcalt's audiocast, New hypertension guideline: Two numbers to rememberIn December 2013, the Eighth Joint National Committee (the 5th panel organized by the NHLBI to address CVD prevention) published its updated guideline on the treatment of hypertension, which has also generated controversy. Visit www.jfponline.com to listen to an audiocast summary of these recommendations.⁹

Obesity and overweight

The guideline on managing obesity and overweight adults has 17 recommendations, only 3 of which are based on expert opinion.¹ (TABLE 1 summarizes the strong [A] and moderate [B] recommendations.) The recommendations stress screening, diagnosis, and treatment using diet, exercise, and lifestyle modification. They also address bariatric surgery for those with a body mass index (BMI) ≥40 or a persisting BMI ≥35 despite weight loss interventions. This set of recommendations, like those of the United States Preventive Services Task Force, advises intensive interventions for weight management and additionally offers much more detail on recommended diet and exercise.

Lifestyle management

The 10 recommendations on lifestyle management to reduce cardiovascular risk, all evidence based, are limited to diet and exercise as a means to control hypertension and hypercholesterolemia.² They do not cover other important lifestyle modifications for preventing CVD, such as smoking cessation. The guideline panel acknowledged that the interventions are aimed at those with high blood pressure and elevated cholesterol, but they encourage all adults to follow them. Although these recommendations are not particularly controversial, the 2 recommendations to reduce sodium intake are said to be based on strong or moderate strength evidence, in contrast to a recent IOM report that concluded evidence for the health benefits of salt intake <2.3 g/d is weak.¹⁰ This illustrates how separate authoritative groups can rate the strength of the same evidence differently.

Summary highlights:
• Encourage adults who would benefit from lowering either blood pressure (BP) or low-density lipoprotein cholesterol (LDL-C) to eat a diet that emphasizes vegetables, fruits, whole grains, low-fat dairy products, and other notably healthful foods, and to cut down on products high in sugar content and on red meats.
• Review, as appropriate, such options as the DASH (dietary approaches to stop hypertension) eating plan, US Department of Agriculture Food Patterns, or the American Heart Association’s diet.
• Establish a dietary plan that also incorporates nutritional requirements for an existing comorbidity, such as type 2 diabetes mellitus (T2DM).
• Lower saturated-fat intake to 5% to 6% of total calories, and reduce trans fats.
• Advise patients with high BP to reduce sodium consumption to ≤2400 mg/d; or, at the very least, to reduce daily consumption by 1000 mg.
• Promote aerobic activity to reduce either LDL-C or BP, at moderate or vigorous intensity 3 to 4 times a week with 40-minute sessions.

CVD risk assessment

The CVD risk assessment guideline³ has generated a lot of controversy. It proposes a new tool for assessing an individual’s 10-year risk of developing an atherosclerotic cardiovascular disease (ASCVD) event, defined as a fatal or nonfatal heart attack or stroke. While the tool is new, the risk factor categories it uses have been known for decades: age, gender, race, lipid levels, diabetes, smoking status, and BP. It has not performed better in validation studies than other existing tools (all of which are suboptimal), and it may be worse.^11,12 Moreover, this new tool has been tested only in African Americans and non-Hispanic whites. Using it could classify 33 million adults age 40 to 79 years as having a 10-year risk of 7.5%, and 13 million a risk between 5% and 7.5%.¹² The significance of this is discussed in the next section on the management of high cholesterol levels.

Summary highlights:
• Use race- and sex-specific Pooled Cohort Equations to predict 10-year risk for a first hard ASCVD event (nonfatalmyocardial infarction, coronary death, or nonfatal or fatal stroke) in non-Hispanic African Americans and non-Hispanic Whites, 40 to 79 years of age.
• Consider assessing a patient’s family history, high-sensitivity C-reactive protein, coronary artery calcium, or anklebrachial index to help guide treatment decisions if quantitative risk assessment has led to uncertainty. (This recommendation is based on expert opinion.)
• Consider evaluating ASCVD risk factors every 4 to 6 years in individuals 20 to 79 years of age who do not have ASCVD, and calculating the 10-year risk of an ASCVD event in those 40 to 79 years of age.
• Consider evaluating 30-year or lifetime ASCVD risk using traditional risk factors in individuals 20 to 59 years of age who do not have ASCVD and have no high short-term risk. (This is based on low-level evidence.)

The major departure from the old cholesterol guideline is an abandonment of "treating to target" that attempts to lower LDL-C to a specified level.Cholesterol management

The guideline on lowering blood cholesterol4 is a significant departure from the previous one.⁶ It contains 54 recommendations, 21 based on expert opinion. Using an unusual methodology that considered only randomized controlled trials in the evidence report, the guideline panel stated that the evidence demonstrates that 4 groups will benefit from treatment with statins:
• patients with established ASCVD
• individuals whose LDL-C is ≥190 mg/dL
• patients with diabetes and no established ASCVD who are 40 to 75 years of age and have an LDL-C between 70 and 189 mg/dL
• anyone with an estimated 10-year ASCVD risk of ≥7.5% (based on the new risk-assessment tool) and an LDL-C of 70 to 189 mg/dL.

The major departure from the old guideline is an abandonment of “treating to target” that attempts to lower LDL-C to a specified level. The panel concluded that the evidence does not show any benefit in achieving a specified level of LDL-C and that this approach can lead to either over- or under-treatment. The proposed new approach is to use high-, moderate-, or low-intensity statin treatment based on a patient’s age and reason for treatment, and the dose that they can tolerate (TABLE 2).⁴

Absent any contraindications, high-intensity treatment is indicated for:
• patients ≤75 years old with established ASCVD
• patients with an LDL-C level ≥190mg/dL
• patients 40 to 75 years old with diabetes and a ≥7.5% 10-year risk of ASCVD. z

Moderate-intensity treatment is indicated for those who cannot tolerate a high-intensity regimen, and for those ages 40 to 75 with diabetes and <7.5% 10-year ASCVD risk.

Low-intensity treatment is recommended for those who should receive moderate-intensity treatment but cannot tolerate it.

For those >75 years of age, the guideline makes only 2 recommendations:
• Prescribe a statin at the highest tolerable intensity for an LDL-C ≥190mg/dL.
• Assess those with established ASCVD for potential benefits and risks of moderate to high-intensity statin treatment. (It is reasonable to continue statin therapy for those already on it and tolerating it.)

Value of nonstatin drugs is questionable. In another significant departure from the previous guideline, the panel said that other cholesterol-lowering drugs can be considered when LDL-C remains high after statin treatment, but the benefit of these agents in preventing ASCVD is not proven.

Several objections to the new guideline have been raised in the short time since its release. Criticisms center on the large number of adults who would now qualify for statin treatment based on the new risk-assessment tool. Using the 7.5% 10-year risk cutoff, the number needed to treat to prevent one ASCVD event over 10 years would be 67. Also of concern to many is the fact that 7 out of 16 members of the guideline panel had financial ties to the pharmaceutical industry.¹²

Commentary

The new guidelines reflect a more rigorous evidence-based approach than those of the past. That some of them diverge significantly from previous recommendations that relied heavily on expert opinion reveals the pitfalls of making authoritative recommendations based on weak evidence. Such recommendations, especially those emerging from the National Institutes of Health, are used as national and international standards and serve as the basis of performance measures. When they do not stand the test of time because of a weak evidence base, medicine’s reputation is damaged. Notably, the new set of cholesterol recommendations, while an improvement from an evidentiary perspective, is founded partly on a questionable risk-assessment tool, and it is possible it will suffer the same long-term fate as its predecessor. (For more on these guidelines, see “The new cholesterol guideline: Beyond the headlines,” [J Fam Pract. 2013;62:730.])

A significant milestone in evidence-based practice was reached in November 2013, when the American Heart Association and American College of Cardiology (AHA/ACC) published 4 clinical practice guidelines on the prevention of cardiovascular disease.^1-4 These guidelines—on obesity, lifestyle management, cardiovascular disease (CVD) risk assessment, and cholesterol—were developed under the auspices of the National Heart, Lung, and Blood Institute (NHLBI) to update its prior guidelines on the treatment of hypertension, high cholesterol, and obesity that were published more than a decade ago.^5-7 After the NHLBI had organized the respective guideline panels and progressed through most of the guideline development process (which lasted several years each), it arranged for the AHA/ACC to assume sponsorship and publication of the guidelines. The NHLBI decided its role should be to develop evidence reports, leaving the development of guidelines to professional organizations.

While the prior guidelines on hypertension and hypercholesterolemia were influential and widely cited as the standard of care, they were heavily influenced by expert opinion and were not strictly evidence based. The NHLBI sought to develop the new guidelines using more contemporary and rigorous evidence-based processes to meet standards set by the Institute of Medicine (IOM). The group started with key clinical questions, conducted comprehensive systematic reviews of the evidence, and then rated the quality of the evidence and assigned strength of recommendation ratings.⁸ The guidelines and evidence reports are lengthy, and are summarized below.

Listen to Dr. Campos-Outcalt's audiocast, New hypertension guideline: Two numbers to rememberIn December 2013, the Eighth Joint National Committee (the 5th panel organized by the NHLBI to address CVD prevention) published its updated guideline on the treatment of hypertension, which has also generated controversy. Visit www.jfponline.com to listen to an audiocast summary of these recommendations.⁹

Obesity and overweight

The guideline on managing obesity and overweight adults has 17 recommendations, only 3 of which are based on expert opinion.¹ (TABLE 1 summarizes the strong [A] and moderate [B] recommendations.) The recommendations stress screening, diagnosis, and treatment using diet, exercise, and lifestyle modification. They also address bariatric surgery for those with a body mass index (BMI) ≥40 or a persisting BMI ≥35 despite weight loss interventions. This set of recommendations, like those of the United States Preventive Services Task Force, advises intensive interventions for weight management and additionally offers much more detail on recommended diet and exercise.

Lifestyle management

The 10 recommendations on lifestyle management to reduce cardiovascular risk, all evidence based, are limited to diet and exercise as a means to control hypertension and hypercholesterolemia.² They do not cover other important lifestyle modifications for preventing CVD, such as smoking cessation. The guideline panel acknowledged that the interventions are aimed at those with high blood pressure and elevated cholesterol, but they encourage all adults to follow them. Although these recommendations are not particularly controversial, the 2 recommendations to reduce sodium intake are said to be based on strong or moderate strength evidence, in contrast to a recent IOM report that concluded evidence for the health benefits of salt intake <2.3 g/d is weak.¹⁰ This illustrates how separate authoritative groups can rate the strength of the same evidence differently.

Summary highlights:
• Encourage adults who would benefit from lowering either blood pressure (BP) or low-density lipoprotein cholesterol (LDL-C) to eat a diet that emphasizes vegetables, fruits, whole grains, low-fat dairy products, and other notably healthful foods, and to cut down on products high in sugar content and on red meats.
• Review, as appropriate, such options as the DASH (dietary approaches to stop hypertension) eating plan, US Department of Agriculture Food Patterns, or the American Heart Association’s diet.
• Establish a dietary plan that also incorporates nutritional requirements for an existing comorbidity, such as type 2 diabetes mellitus (T2DM).
• Lower saturated-fat intake to 5% to 6% of total calories, and reduce trans fats.
• Advise patients with high BP to reduce sodium consumption to ≤2400 mg/d; or, at the very least, to reduce daily consumption by 1000 mg.
• Promote aerobic activity to reduce either LDL-C or BP, at moderate or vigorous intensity 3 to 4 times a week with 40-minute sessions.

CVD risk assessment

The CVD risk assessment guideline³ has generated a lot of controversy. It proposes a new tool for assessing an individual’s 10-year risk of developing an atherosclerotic cardiovascular disease (ASCVD) event, defined as a fatal or nonfatal heart attack or stroke. While the tool is new, the risk factor categories it uses have been known for decades: age, gender, race, lipid levels, diabetes, smoking status, and BP. It has not performed better in validation studies than other existing tools (all of which are suboptimal), and it may be worse.^11,12 Moreover, this new tool has been tested only in African Americans and non-Hispanic whites. Using it could classify 33 million adults age 40 to 79 years as having a 10-year risk of 7.5%, and 13 million a risk between 5% and 7.5%.¹² The significance of this is discussed in the next section on the management of high cholesterol levels.

Summary highlights:
• Use race- and sex-specific Pooled Cohort Equations to predict 10-year risk for a first hard ASCVD event (nonfatalmyocardial infarction, coronary death, or nonfatal or fatal stroke) in non-Hispanic African Americans and non-Hispanic Whites, 40 to 79 years of age.
• Consider assessing a patient’s family history, high-sensitivity C-reactive protein, coronary artery calcium, or anklebrachial index to help guide treatment decisions if quantitative risk assessment has led to uncertainty. (This recommendation is based on expert opinion.)
• Consider evaluating ASCVD risk factors every 4 to 6 years in individuals 20 to 79 years of age who do not have ASCVD, and calculating the 10-year risk of an ASCVD event in those 40 to 79 years of age.
• Consider evaluating 30-year or lifetime ASCVD risk using traditional risk factors in individuals 20 to 59 years of age who do not have ASCVD and have no high short-term risk. (This is based on low-level evidence.)

The major departure from the old cholesterol guideline is an abandonment of "treating to target" that attempts to lower LDL-C to a specified level.Cholesterol management

The guideline on lowering blood cholesterol4 is a significant departure from the previous one.⁶ It contains 54 recommendations, 21 based on expert opinion. Using an unusual methodology that considered only randomized controlled trials in the evidence report, the guideline panel stated that the evidence demonstrates that 4 groups will benefit from treatment with statins:
• patients with established ASCVD
• individuals whose LDL-C is ≥190 mg/dL
• patients with diabetes and no established ASCVD who are 40 to 75 years of age and have an LDL-C between 70 and 189 mg/dL
• anyone with an estimated 10-year ASCVD risk of ≥7.5% (based on the new risk-assessment tool) and an LDL-C of 70 to 189 mg/dL.

The major departure from the old guideline is an abandonment of “treating to target” that attempts to lower LDL-C to a specified level. The panel concluded that the evidence does not show any benefit in achieving a specified level of LDL-C and that this approach can lead to either over- or under-treatment. The proposed new approach is to use high-, moderate-, or low-intensity statin treatment based on a patient’s age and reason for treatment, and the dose that they can tolerate (TABLE 2).⁴

Absent any contraindications, high-intensity treatment is indicated for:
• patients ≤75 years old with established ASCVD
• patients with an LDL-C level ≥190mg/dL
• patients 40 to 75 years old with diabetes and a ≥7.5% 10-year risk of ASCVD. z

Moderate-intensity treatment is indicated for those who cannot tolerate a high-intensity regimen, and for those ages 40 to 75 with diabetes and <7.5% 10-year ASCVD risk.

Low-intensity treatment is recommended for those who should receive moderate-intensity treatment but cannot tolerate it.

For those >75 years of age, the guideline makes only 2 recommendations:
• Prescribe a statin at the highest tolerable intensity for an LDL-C ≥190mg/dL.
• Assess those with established ASCVD for potential benefits and risks of moderate to high-intensity statin treatment. (It is reasonable to continue statin therapy for those already on it and tolerating it.)

Value of nonstatin drugs is questionable. In another significant departure from the previous guideline, the panel said that other cholesterol-lowering drugs can be considered when LDL-C remains high after statin treatment, but the benefit of these agents in preventing ASCVD is not proven.

Several objections to the new guideline have been raised in the short time since its release. Criticisms center on the large number of adults who would now qualify for statin treatment based on the new risk-assessment tool. Using the 7.5% 10-year risk cutoff, the number needed to treat to prevent one ASCVD event over 10 years would be 67. Also of concern to many is the fact that 7 out of 16 members of the guideline panel had financial ties to the pharmaceutical industry.¹²

Commentary

The new guidelines reflect a more rigorous evidence-based approach than those of the past. That some of them diverge significantly from previous recommendations that relied heavily on expert opinion reveals the pitfalls of making authoritative recommendations based on weak evidence. Such recommendations, especially those emerging from the National Institutes of Health, are used as national and international standards and serve as the basis of performance measures. When they do not stand the test of time because of a weak evidence base, medicine’s reputation is damaged. Notably, the new set of cholesterol recommendations, while an improvement from an evidentiary perspective, is founded partly on a questionable risk-assessment tool, and it is possible it will suffer the same long-term fate as its predecessor. (For more on these guidelines, see “The new cholesterol guideline: Beyond the headlines,” [J Fam Pract. 2013;62:730.])

A significant milestone in evidence-based practice was reached in November 2013, when the American Heart Association and American College of Cardiology (AHA/ACC) published 4 clinical practice guidelines on the prevention of cardiovascular disease.^1-4 These guidelines—on obesity, lifestyle management, cardiovascular disease (CVD) risk assessment, and cholesterol—were developed under the auspices of the National Heart, Lung, and Blood Institute (NHLBI) to update its prior guidelines on the treatment of hypertension, high cholesterol, and obesity that were published more than a decade ago.^5-7 After the NHLBI had organized the respective guideline panels and progressed through most of the guideline development process (which lasted several years each), it arranged for the AHA/ACC to assume sponsorship and publication of the guidelines. The NHLBI decided its role should be to develop evidence reports, leaving the development of guidelines to professional organizations.

While the prior guidelines on hypertension and hypercholesterolemia were influential and widely cited as the standard of care, they were heavily influenced by expert opinion and were not strictly evidence based. The NHLBI sought to develop the new guidelines using more contemporary and rigorous evidence-based processes to meet standards set by the Institute of Medicine (IOM). The group started with key clinical questions, conducted comprehensive systematic reviews of the evidence, and then rated the quality of the evidence and assigned strength of recommendation ratings.⁸ The guidelines and evidence reports are lengthy, and are summarized below.

Listen to Dr. Campos-Outcalt's audiocast, New hypertension guideline: Two numbers to rememberIn December 2013, the Eighth Joint National Committee (the 5th panel organized by the NHLBI to address CVD prevention) published its updated guideline on the treatment of hypertension, which has also generated controversy. Visit www.jfponline.com to listen to an audiocast summary of these recommendations.⁹

Obesity and overweight

The guideline on managing obesity and overweight adults has 17 recommendations, only 3 of which are based on expert opinion.¹ (TABLE 1 summarizes the strong [A] and moderate [B] recommendations.) The recommendations stress screening, diagnosis, and treatment using diet, exercise, and lifestyle modification. They also address bariatric surgery for those with a body mass index (BMI) ≥40 or a persisting BMI ≥35 despite weight loss interventions. This set of recommendations, like those of the United States Preventive Services Task Force, advises intensive interventions for weight management and additionally offers much more detail on recommended diet and exercise.

Lifestyle management

The 10 recommendations on lifestyle management to reduce cardiovascular risk, all evidence based, are limited to diet and exercise as a means to control hypertension and hypercholesterolemia.² They do not cover other important lifestyle modifications for preventing CVD, such as smoking cessation. The guideline panel acknowledged that the interventions are aimed at those with high blood pressure and elevated cholesterol, but they encourage all adults to follow them. Although these recommendations are not particularly controversial, the 2 recommendations to reduce sodium intake are said to be based on strong or moderate strength evidence, in contrast to a recent IOM report that concluded evidence for the health benefits of salt intake <2.3 g/d is weak.¹⁰ This illustrates how separate authoritative groups can rate the strength of the same evidence differently.

Summary highlights:
• Encourage adults who would benefit from lowering either blood pressure (BP) or low-density lipoprotein cholesterol (LDL-C) to eat a diet that emphasizes vegetables, fruits, whole grains, low-fat dairy products, and other notably healthful foods, and to cut down on products high in sugar content and on red meats.
• Review, as appropriate, such options as the DASH (dietary approaches to stop hypertension) eating plan, US Department of Agriculture Food Patterns, or the American Heart Association’s diet.
• Establish a dietary plan that also incorporates nutritional requirements for an existing comorbidity, such as type 2 diabetes mellitus (T2DM).
• Lower saturated-fat intake to 5% to 6% of total calories, and reduce trans fats.
• Advise patients with high BP to reduce sodium consumption to ≤2400 mg/d; or, at the very least, to reduce daily consumption by 1000 mg.
• Promote aerobic activity to reduce either LDL-C or BP, at moderate or vigorous intensity 3 to 4 times a week with 40-minute sessions.

CVD risk assessment

The CVD risk assessment guideline³ has generated a lot of controversy. It proposes a new tool for assessing an individual’s 10-year risk of developing an atherosclerotic cardiovascular disease (ASCVD) event, defined as a fatal or nonfatal heart attack or stroke. While the tool is new, the risk factor categories it uses have been known for decades: age, gender, race, lipid levels, diabetes, smoking status, and BP. It has not performed better in validation studies than other existing tools (all of which are suboptimal), and it may be worse.^11,12 Moreover, this new tool has been tested only in African Americans and non-Hispanic whites. Using it could classify 33 million adults age 40 to 79 years as having a 10-year risk of 7.5%, and 13 million a risk between 5% and 7.5%.¹² The significance of this is discussed in the next section on the management of high cholesterol levels.

Summary highlights:
• Use race- and sex-specific Pooled Cohort Equations to predict 10-year risk for a first hard ASCVD event (nonfatalmyocardial infarction, coronary death, or nonfatal or fatal stroke) in non-Hispanic African Americans and non-Hispanic Whites, 40 to 79 years of age.
• Consider assessing a patient’s family history, high-sensitivity C-reactive protein, coronary artery calcium, or anklebrachial index to help guide treatment decisions if quantitative risk assessment has led to uncertainty. (This recommendation is based on expert opinion.)
• Consider evaluating ASCVD risk factors every 4 to 6 years in individuals 20 to 79 years of age who do not have ASCVD, and calculating the 10-year risk of an ASCVD event in those 40 to 79 years of age.
• Consider evaluating 30-year or lifetime ASCVD risk using traditional risk factors in individuals 20 to 59 years of age who do not have ASCVD and have no high short-term risk. (This is based on low-level evidence.)

The major departure from the old cholesterol guideline is an abandonment of "treating to target" that attempts to lower LDL-C to a specified level.Cholesterol management

The guideline on lowering blood cholesterol4 is a significant departure from the previous one.⁶ It contains 54 recommendations, 21 based on expert opinion. Using an unusual methodology that considered only randomized controlled trials in the evidence report, the guideline panel stated that the evidence demonstrates that 4 groups will benefit from treatment with statins:
• patients with established ASCVD
• individuals whose LDL-C is ≥190 mg/dL
• patients with diabetes and no established ASCVD who are 40 to 75 years of age and have an LDL-C between 70 and 189 mg/dL
• anyone with an estimated 10-year ASCVD risk of ≥7.5% (based on the new risk-assessment tool) and an LDL-C of 70 to 189 mg/dL.

The major departure from the old guideline is an abandonment of “treating to target” that attempts to lower LDL-C to a specified level. The panel concluded that the evidence does not show any benefit in achieving a specified level of LDL-C and that this approach can lead to either over- or under-treatment. The proposed new approach is to use high-, moderate-, or low-intensity statin treatment based on a patient’s age and reason for treatment, and the dose that they can tolerate (TABLE 2).⁴

Absent any contraindications, high-intensity treatment is indicated for:
• patients ≤75 years old with established ASCVD
• patients with an LDL-C level ≥190mg/dL
• patients 40 to 75 years old with diabetes and a ≥7.5% 10-year risk of ASCVD. z

Moderate-intensity treatment is indicated for those who cannot tolerate a high-intensity regimen, and for those ages 40 to 75 with diabetes and <7.5% 10-year ASCVD risk.

Low-intensity treatment is recommended for those who should receive moderate-intensity treatment but cannot tolerate it.

For those >75 years of age, the guideline makes only 2 recommendations:
• Prescribe a statin at the highest tolerable intensity for an LDL-C ≥190mg/dL.
• Assess those with established ASCVD for potential benefits and risks of moderate to high-intensity statin treatment. (It is reasonable to continue statin therapy for those already on it and tolerating it.)

Value of nonstatin drugs is questionable. In another significant departure from the previous guideline, the panel said that other cholesterol-lowering drugs can be considered when LDL-C remains high after statin treatment, but the benefit of these agents in preventing ASCVD is not proven.

Several objections to the new guideline have been raised in the short time since its release. Criticisms center on the large number of adults who would now qualify for statin treatment based on the new risk-assessment tool. Using the 7.5% 10-year risk cutoff, the number needed to treat to prevent one ASCVD event over 10 years would be 67. Also of concern to many is the fact that 7 out of 16 members of the guideline panel had financial ties to the pharmaceutical industry.¹²

Commentary

The new guidelines reflect a more rigorous evidence-based approach than those of the past. That some of them diverge significantly from previous recommendations that relied heavily on expert opinion reveals the pitfalls of making authoritative recommendations based on weak evidence. Such recommendations, especially those emerging from the National Institutes of Health, are used as national and international standards and serve as the basis of performance measures. When they do not stand the test of time because of a weak evidence base, medicine’s reputation is damaged. Notably, the new set of cholesterol recommendations, while an improvement from an evidentiary perspective, is founded partly on a questionable risk-assessment tool, and it is possible it will suffer the same long-term fate as its predecessor. (For more on these guidelines, see “The new cholesterol guideline: Beyond the headlines,” [J Fam Pract. 2013;62:730.])

EVIDENCE SUMMARY

Troponin I and T proteins are specific to cardiac myocytes and, unlike CK-MB, aren’t elevated by damage to skeletal muscle.

Measuring troponin levels increased the number of patients diagnosed with AMI

A multinational prospective cohort study of patients with suspected ACS (N=10,719) found that measuring troponin levels in addition to CK-MB levels improved the diagnosis of AMI.¹ Investigators used elevation of any biomarker (CK, CK-MB, or troponin I or T) above the upper limit of normal as their diagnostic criterion. They found that measuring troponin increased the number of patients diagnosed with AMI by 10.4% over patients diagnosed using CK and CK-MB levels. Elevated troponin levels were associated with an inpatient mortality rate 1.5 to 3 times higher, regardless of the patient’s CK-MB status.

Troponin levels are more sensitive and specific than CK-MB

A prospective cohort study of 718 patients with suspected AMI calculated the area under curve (AUC) of the receiver operator curve—a measure of diagnostic accuracy in which an AUC value of 1 indicates 100% sensitivity and specificity—for troponin and CK-MB levels at initial presentation.² Two independent cardiologists reviewed all available medical records and made the final diagnosis. The AUCs for troponin levels ranged from 0.94 to 0.96 compared with 0.88 for CK-MB.

A prospective study of 1852 patients with suspected ACS from 3 trial populations evaluated the prognostic value of increased troponin levels vs CK-MB levels at initial presentation, compared with a reference group with normal troponin and CK-MB levels.³ Patients with isolated troponin elevation had an increased odds of MI or death at 24 hours (odds ratio [OR]=5.2; 95% confidence interval [CI], 2.2-11.9) and 30 days (OR=2.1; 95% CI, 1.4-3.0), whereas patients with isolated CK-MB elevations didn't. At 30 days, patients with isolated CK-MB elevations equaled the reference group odds for MI and death (OR=1.0; 95% CI, 0.6-1.6).

Serial troponin assessment boosts diagnostic sensitivity

A prospective cohort study found that serial measurements of troponin increased the diagnostic sensitivity for AMI.⁴ Investigators evaluated 1818 consecutive patients with new onset chest pain in 3 German chest-pain units with troponin levels on admission and at 3 and 6 hours later. The gold standard was diagnosis of AMI by 2 independent cardiologists. Troponin measurement produced an AUC of 0.96 at admission, increasing to 0.98 and 0.99 at 3 and 6 hours after admission, respectively.

RECOMMENDATIONS

The American College of Cardiology and American Heart Association recommend measuring biomarkers of cardiac injury in all patients who present with chest discomfort consistent with ACS.⁵ A cardiac-specific troponin is the preferred marker and should be measured in all patients. If troponin is not available, CK-MB is the best alternative. Cardiac biomarkers should be repeated 6 to 9 hours after presentation and, in patients with a high clinical suspicion of AMI, at 12 to 24 hours.^6,7

EVIDENCE SUMMARY

Troponin I and T proteins are specific to cardiac myocytes and, unlike CK-MB, aren’t elevated by damage to skeletal muscle.

Measuring troponin levels increased the number of patients diagnosed with AMI

A multinational prospective cohort study of patients with suspected ACS (N=10,719) found that measuring troponin levels in addition to CK-MB levels improved the diagnosis of AMI.¹ Investigators used elevation of any biomarker (CK, CK-MB, or troponin I or T) above the upper limit of normal as their diagnostic criterion. They found that measuring troponin increased the number of patients diagnosed with AMI by 10.4% over patients diagnosed using CK and CK-MB levels. Elevated troponin levels were associated with an inpatient mortality rate 1.5 to 3 times higher, regardless of the patient’s CK-MB status.

Troponin levels are more sensitive and specific than CK-MB

A prospective cohort study of 718 patients with suspected AMI calculated the area under curve (AUC) of the receiver operator curve—a measure of diagnostic accuracy in which an AUC value of 1 indicates 100% sensitivity and specificity—for troponin and CK-MB levels at initial presentation.² Two independent cardiologists reviewed all available medical records and made the final diagnosis. The AUCs for troponin levels ranged from 0.94 to 0.96 compared with 0.88 for CK-MB.

A prospective study of 1852 patients with suspected ACS from 3 trial populations evaluated the prognostic value of increased troponin levels vs CK-MB levels at initial presentation, compared with a reference group with normal troponin and CK-MB levels.³ Patients with isolated troponin elevation had an increased odds of MI or death at 24 hours (odds ratio [OR]=5.2; 95% confidence interval [CI], 2.2-11.9) and 30 days (OR=2.1; 95% CI, 1.4-3.0), whereas patients with isolated CK-MB elevations didn't. At 30 days, patients with isolated CK-MB elevations equaled the reference group odds for MI and death (OR=1.0; 95% CI, 0.6-1.6).

Serial troponin assessment boosts diagnostic sensitivity

A prospective cohort study found that serial measurements of troponin increased the diagnostic sensitivity for AMI.⁴ Investigators evaluated 1818 consecutive patients with new onset chest pain in 3 German chest-pain units with troponin levels on admission and at 3 and 6 hours later. The gold standard was diagnosis of AMI by 2 independent cardiologists. Troponin measurement produced an AUC of 0.96 at admission, increasing to 0.98 and 0.99 at 3 and 6 hours after admission, respectively.

RECOMMENDATIONS

The American College of Cardiology and American Heart Association recommend measuring biomarkers of cardiac injury in all patients who present with chest discomfort consistent with ACS.⁵ A cardiac-specific troponin is the preferred marker and should be measured in all patients. If troponin is not available, CK-MB is the best alternative. Cardiac biomarkers should be repeated 6 to 9 hours after presentation and, in patients with a high clinical suspicion of AMI, at 12 to 24 hours.^6,7

EVIDENCE SUMMARY

Troponin I and T proteins are specific to cardiac myocytes and, unlike CK-MB, aren’t elevated by damage to skeletal muscle.

Measuring troponin levels increased the number of patients diagnosed with AMI

A multinational prospective cohort study of patients with suspected ACS (N=10,719) found that measuring troponin levels in addition to CK-MB levels improved the diagnosis of AMI.¹ Investigators used elevation of any biomarker (CK, CK-MB, or troponin I or T) above the upper limit of normal as their diagnostic criterion. They found that measuring troponin increased the number of patients diagnosed with AMI by 10.4% over patients diagnosed using CK and CK-MB levels. Elevated troponin levels were associated with an inpatient mortality rate 1.5 to 3 times higher, regardless of the patient’s CK-MB status.

Troponin levels are more sensitive and specific than CK-MB

A prospective cohort study of 718 patients with suspected AMI calculated the area under curve (AUC) of the receiver operator curve—a measure of diagnostic accuracy in which an AUC value of 1 indicates 100% sensitivity and specificity—for troponin and CK-MB levels at initial presentation.² Two independent cardiologists reviewed all available medical records and made the final diagnosis. The AUCs for troponin levels ranged from 0.94 to 0.96 compared with 0.88 for CK-MB.

A prospective study of 1852 patients with suspected ACS from 3 trial populations evaluated the prognostic value of increased troponin levels vs CK-MB levels at initial presentation, compared with a reference group with normal troponin and CK-MB levels.³ Patients with isolated troponin elevation had an increased odds of MI or death at 24 hours (odds ratio [OR]=5.2; 95% confidence interval [CI], 2.2-11.9) and 30 days (OR=2.1; 95% CI, 1.4-3.0), whereas patients with isolated CK-MB elevations didn't. At 30 days, patients with isolated CK-MB elevations equaled the reference group odds for MI and death (OR=1.0; 95% CI, 0.6-1.6).

Serial troponin assessment boosts diagnostic sensitivity

A prospective cohort study found that serial measurements of troponin increased the diagnostic sensitivity for AMI.⁴ Investigators evaluated 1818 consecutive patients with new onset chest pain in 3 German chest-pain units with troponin levels on admission and at 3 and 6 hours later. The gold standard was diagnosis of AMI by 2 independent cardiologists. Troponin measurement produced an AUC of 0.96 at admission, increasing to 0.98 and 0.99 at 3 and 6 hours after admission, respectively.

RECOMMENDATIONS

The American College of Cardiology and American Heart Association recommend measuring biomarkers of cardiac injury in all patients who present with chest discomfort consistent with ACS.⁵ A cardiac-specific troponin is the preferred marker and should be measured in all patients. If troponin is not available, CK-MB is the best alternative. Cardiac biomarkers should be repeated 6 to 9 hours after presentation and, in patients with a high clinical suspicion of AMI, at 12 to 24 hours.^6,7

EVIDENCE SUMMARY

A systematic review and meta-analysis of the effectiveness of oral and topical nucleoside antiviral agents to prevent recurrent HSL in immunocompetent people found 11 RCTs with a total of 1250 patients that compared an active drug against placebo.¹ The medications were topical 5% acyclovir, topical 1% penciclovir, and oral acyclovir, valacyclovir, or famciclovir in various doses. The primary outcome was recurrence of herpes simplex virus type 1 lesions during the treatment period. The relative risk (RR) of recurrence ranged from 0.22 to 1.22. Pooled results found a benefit favoring antiviral agents (RR of recurrence=0.70; 95% confidence interval [CI], 0.55-0.89).

Seven of the trials looked at acyclovir (5 oral, 2 topical). A subgroup analysis demonstrated that oral acyclovir (800-1000 mg/d) was more effective than placebo (RR=0.51; 95% CI, 0.29-0.88), whereas topical acyclovir wasn’t. Oral valacyclovir (2 studies; 500 mg/d for 4 months) also reduced recurrence (RR=0.65; 95% CI, 0.43-0.91). The authors of the meta-analysis noted that although 9 studies favored the use of an antiviral drug, only 4 showed statistically significant differences when compared with placebo, and none of them had a low risk of bias. They concluded that the review supported using oral acyclovir and valacyclovir to prevent recurrent HSL.¹

Oral antivirals produce variable treatment results

Three RCTs evaluated oral antiviral medications against placebo to treat recurrent HSL, with mixed results. The largest RCT found that valacyclovir (2000 mg twice in 24 hours, with or without an additional 1000 mg twice in another 24 hours) modestly but significantly reduced both healing time and duration of pain (by 0.5-0.8 day).² The second RCT showed that a higher, single dose of famciclovir (1500 mg) reduced healing time (by 1.8 days) and pain duration (by 1.2 days) and that a smaller, repeated dose (750 mg twice in 24 hours) reduced healing time alone (by 2.2 days).³

The third RCT demonstrated that acyclovir (400 mg 5 times a day for 5 days) reduced pain duration (by 0.9 day) but didn’t shorten healing time. If acyclovir was started during the prodrome, it decreased the time to disappearance of the lesion’s hard crust (2.1 days’ less time; P=.03), but the clinical significance of this finding is unclear.⁴

Topical treatment shows modest success

Two trials demonstrated that topical acyclovir (5% cream) modestly improved healing time and duration of pain (by as much as half a day). Patients in the first trial (paired RCTs reported together) began treatment within an hour of prodromal symptoms or signs, applying the medication 5 times daily for 4 days.⁵

Topical acyclovir, penciclovir, and docosanol modestly decrease healing time and pain duration—typically by less than a day—and require multiple doses per day.Patients in the second trial used ME-609 cream (5% acyclovir plus 1% hydrocortisone), 5% acyclovir cream, or placebo, all applied 5 times daily for 5 days.⁶ Although the cream with acyclovir and hydrocortisone showed a slight benefit compared with placebo (lessening healing time by 0.8 day and pain duration by 1 day), it didn’t improve healing more than acyclovir alone. Other topical agents (penciclovir 1%; docosanol 10%) produced results similar to topical acyclovir.^7,8

RECOMMENDATIONS

No national guidelines on this topic exist. An online resource notes that most patients don’t require treatment for mild self-limited HSL.⁹ For patients with prodromal symptoms, the authors recommend episodic oral antiviral therapy. Patients who have no prodome but multiple painful or disfiguring lesions may choose to use chronic suppressive therapy with an oral antiviral drug.

EVIDENCE SUMMARY

A systematic review and meta-analysis of the effectiveness of oral and topical nucleoside antiviral agents to prevent recurrent HSL in immunocompetent people found 11 RCTs with a total of 1250 patients that compared an active drug against placebo.¹ The medications were topical 5% acyclovir, topical 1% penciclovir, and oral acyclovir, valacyclovir, or famciclovir in various doses. The primary outcome was recurrence of herpes simplex virus type 1 lesions during the treatment period. The relative risk (RR) of recurrence ranged from 0.22 to 1.22. Pooled results found a benefit favoring antiviral agents (RR of recurrence=0.70; 95% confidence interval [CI], 0.55-0.89).

Seven of the trials looked at acyclovir (5 oral, 2 topical). A subgroup analysis demonstrated that oral acyclovir (800-1000 mg/d) was more effective than placebo (RR=0.51; 95% CI, 0.29-0.88), whereas topical acyclovir wasn’t. Oral valacyclovir (2 studies; 500 mg/d for 4 months) also reduced recurrence (RR=0.65; 95% CI, 0.43-0.91). The authors of the meta-analysis noted that although 9 studies favored the use of an antiviral drug, only 4 showed statistically significant differences when compared with placebo, and none of them had a low risk of bias. They concluded that the review supported using oral acyclovir and valacyclovir to prevent recurrent HSL.¹

Oral antivirals produce variable treatment results

Three RCTs evaluated oral antiviral medications against placebo to treat recurrent HSL, with mixed results. The largest RCT found that valacyclovir (2000 mg twice in 24 hours, with or without an additional 1000 mg twice in another 24 hours) modestly but significantly reduced both healing time and duration of pain (by 0.5-0.8 day).² The second RCT showed that a higher, single dose of famciclovir (1500 mg) reduced healing time (by 1.8 days) and pain duration (by 1.2 days) and that a smaller, repeated dose (750 mg twice in 24 hours) reduced healing time alone (by 2.2 days).³

The third RCT demonstrated that acyclovir (400 mg 5 times a day for 5 days) reduced pain duration (by 0.9 day) but didn’t shorten healing time. If acyclovir was started during the prodrome, it decreased the time to disappearance of the lesion’s hard crust (2.1 days’ less time; P=.03), but the clinical significance of this finding is unclear.⁴

Topical treatment shows modest success

Two trials demonstrated that topical acyclovir (5% cream) modestly improved healing time and duration of pain (by as much as half a day). Patients in the first trial (paired RCTs reported together) began treatment within an hour of prodromal symptoms or signs, applying the medication 5 times daily for 4 days.⁵

Topical acyclovir, penciclovir, and docosanol modestly decrease healing time and pain duration—typically by less than a day—and require multiple doses per day.Patients in the second trial used ME-609 cream (5% acyclovir plus 1% hydrocortisone), 5% acyclovir cream, or placebo, all applied 5 times daily for 5 days.⁶ Although the cream with acyclovir and hydrocortisone showed a slight benefit compared with placebo (lessening healing time by 0.8 day and pain duration by 1 day), it didn’t improve healing more than acyclovir alone. Other topical agents (penciclovir 1%; docosanol 10%) produced results similar to topical acyclovir.^7,8

RECOMMENDATIONS

No national guidelines on this topic exist. An online resource notes that most patients don’t require treatment for mild self-limited HSL.⁹ For patients with prodromal symptoms, the authors recommend episodic oral antiviral therapy. Patients who have no prodome but multiple painful or disfiguring lesions may choose to use chronic suppressive therapy with an oral antiviral drug.

EVIDENCE SUMMARY

A systematic review and meta-analysis of the effectiveness of oral and topical nucleoside antiviral agents to prevent recurrent HSL in immunocompetent people found 11 RCTs with a total of 1250 patients that compared an active drug against placebo.¹ The medications were topical 5% acyclovir, topical 1% penciclovir, and oral acyclovir, valacyclovir, or famciclovir in various doses. The primary outcome was recurrence of herpes simplex virus type 1 lesions during the treatment period. The relative risk (RR) of recurrence ranged from 0.22 to 1.22. Pooled results found a benefit favoring antiviral agents (RR of recurrence=0.70; 95% confidence interval [CI], 0.55-0.89).

Seven of the trials looked at acyclovir (5 oral, 2 topical). A subgroup analysis demonstrated that oral acyclovir (800-1000 mg/d) was more effective than placebo (RR=0.51; 95% CI, 0.29-0.88), whereas topical acyclovir wasn’t. Oral valacyclovir (2 studies; 500 mg/d for 4 months) also reduced recurrence (RR=0.65; 95% CI, 0.43-0.91). The authors of the meta-analysis noted that although 9 studies favored the use of an antiviral drug, only 4 showed statistically significant differences when compared with placebo, and none of them had a low risk of bias. They concluded that the review supported using oral acyclovir and valacyclovir to prevent recurrent HSL.¹

Oral antivirals produce variable treatment results

Three RCTs evaluated oral antiviral medications against placebo to treat recurrent HSL, with mixed results. The largest RCT found that valacyclovir (2000 mg twice in 24 hours, with or without an additional 1000 mg twice in another 24 hours) modestly but significantly reduced both healing time and duration of pain (by 0.5-0.8 day).² The second RCT showed that a higher, single dose of famciclovir (1500 mg) reduced healing time (by 1.8 days) and pain duration (by 1.2 days) and that a smaller, repeated dose (750 mg twice in 24 hours) reduced healing time alone (by 2.2 days).³

The third RCT demonstrated that acyclovir (400 mg 5 times a day for 5 days) reduced pain duration (by 0.9 day) but didn’t shorten healing time. If acyclovir was started during the prodrome, it decreased the time to disappearance of the lesion’s hard crust (2.1 days’ less time; P=.03), but the clinical significance of this finding is unclear.⁴

Topical treatment shows modest success

Two trials demonstrated that topical acyclovir (5% cream) modestly improved healing time and duration of pain (by as much as half a day). Patients in the first trial (paired RCTs reported together) began treatment within an hour of prodromal symptoms or signs, applying the medication 5 times daily for 4 days.⁵

Topical acyclovir, penciclovir, and docosanol modestly decrease healing time and pain duration—typically by less than a day—and require multiple doses per day.Patients in the second trial used ME-609 cream (5% acyclovir plus 1% hydrocortisone), 5% acyclovir cream, or placebo, all applied 5 times daily for 5 days.⁶ Although the cream with acyclovir and hydrocortisone showed a slight benefit compared with placebo (lessening healing time by 0.8 day and pain duration by 1 day), it didn’t improve healing more than acyclovir alone. Other topical agents (penciclovir 1%; docosanol 10%) produced results similar to topical acyclovir.^7,8

RECOMMENDATIONS

No national guidelines on this topic exist. An online resource notes that most patients don’t require treatment for mild self-limited HSL.⁹ For patients with prodromal symptoms, the authors recommend episodic oral antiviral therapy. Patients who have no prodome but multiple painful or disfiguring lesions may choose to use chronic suppressive therapy with an oral antiviral drug.

EVIDENCE SUMMARY

Because no randomized controlled trials have evaluated the efficacy of UTI treatment in lactating women, recommendations are extrapolated from studies in other populations and case reports.

Antibiotics: Comparable and effective

A 2010 Cochrane review examined 21 good-quality randomized trials that compared the effectiveness of TMP-SMX, β-lactam antibiotics, nitrofurantoin, and fluoroquinolones for uncomplicated UTIs in 6016 women.¹ The authors found no significant differences in short-term symptom cure rates: all antibiotics were very effective. Seven studies reported mixed (clinical and bacteriologic) cure rates.

Symptom cure rates for patients followed for as long as 2 weeks ranged from 78% to 95%; longer-term (as long as 8 weeks) symptom cure rates ranged from 82% to 91%. The review suggested that TMP-SMX may be slightly more likely to cause a rash than other antibiotics.¹

Antibiotic concentrations in breast milk

In a case series, TMP/SMX, 160/800 mg, given to 50 lactating women 2 times (40 women) or 3 times (10 women) daily resulted in an average breast milk concentration of 2 μg/mL of TMP and 4.6 μg/mL of SMX, corresponding to respective doses of 0.3 and 0.7 mg/kg/d for infants taking 150 mL breast milk/kg/d.² The authors state that this dose is safe for infants without G6PD deficiency. The study included only women with UTIs or other infections requiring antibiotic treatment.

A case series of 4 lactating mothers who received a single 100-mg oral dose of nitrofurantoin found that peak breast milk concentration occurred 4 hours later and averaged 2.4 μg/mL (standard deviation=1.7-3.2 μg/mL).³ The authors calculated a mean concentration over 12 hours of 1.3 μg nitrofurantoin/mL breast milk. This level would correspond to an estimated dose of 0.2 mg/kg/d for an infant consuming 150 mL/kg/d of breast milk whose mother takes 100 mg nitrofurantoin twice daily, much lower than the recommended pediatric dose of 5 to 7 mg/kg/d.

Data from a case series and a case report suggest the amount of ciprofloxacin transferred to breastfed infants is low. In the case series, researchers gave 10 lactating women 3 oral doses of ciprofloxacin, 750 mg, at 12-hour intervals and then measured ciprofloxacin levels in breast milk.⁴ The highest levels occurred 2 hours after the third dose and averaged 3.79 μg/mL. Average levels fell gradually to 0.02 μg/mL 24 hours after the third dose. Assuming a milk intake of 150 mL/kg/d, a breastfed infant would consume approximately 0.3 mg/kg/d, much lower than the 10 to 40 mg/kg/d dose recommended for treating sick infants.

A case report of a woman who took oral ciprofloxacin 500 mg/d for 10 days noted a breast milk ciprofloxacin concentration of 0.98 mg/L at 10.7 hours after the last dose.⁵ Ofloxacin, norfloxacin, and levofloxacin have been associated with lower milk concentrations than ciprofloxacin.⁶

Adverse effects

In a cohort study of 838 women from a program for pregnant and lactating women exposed to drugs and other substances, 2 of 12 mothers taking TMP/SMX reported poor feeding in their infants.⁷

The same program received reports of infants with diarrhea from mothers taking amoxicillin (3 of 25 infants), nitrofurantoin (2 of 6 infants), and cephalexin (2 of 7 infants), but no reports of other adverse effects. Another study demonstrated that nitrofurantoin is actively transported into the mother’s milk, making hemolytic anemia a possibility in G6PD-deficient infants.³

Data from a case series and a case report suggest the amount of ciprofloxacin transferred to breastfed infants is low.Studies indicate that adverse effects of fluoroquinolones in children are similar to those in adults despite a contraindication in children because of reports of arthropathy in young animals. One case of pseudomembranous colitis in a breastfeeding infant and 2 cases of green teeth in neonates have been reported with ciprofloxacin use.^6,8,9

RECOMMENDATIONS

The Infectious Disease Society of America recommends nitrofurantoin, TMP/SMX, or fosfomycin for first-line treatment of uncomplicated UTIs in women, although fosfomycin appears to be inferior to other standard short-course antibiotics based on FDA data. Fluoroquinolones and β-lactams are recommended alternative treatments.¹⁰

The American Academy of Pediatrics’ Committee on Drugs says that TMP/SMX (unless G6PD deficiency is present), amoxicillin, nitrofurantoin, ciprofloxacin, and ofloxacin usually are compatible with breastfeeding.¹¹

EVIDENCE SUMMARY

Because no randomized controlled trials have evaluated the efficacy of UTI treatment in lactating women, recommendations are extrapolated from studies in other populations and case reports.

Antibiotics: Comparable and effective

A 2010 Cochrane review examined 21 good-quality randomized trials that compared the effectiveness of TMP-SMX, β-lactam antibiotics, nitrofurantoin, and fluoroquinolones for uncomplicated UTIs in 6016 women.¹ The authors found no significant differences in short-term symptom cure rates: all antibiotics were very effective. Seven studies reported mixed (clinical and bacteriologic) cure rates.

Symptom cure rates for patients followed for as long as 2 weeks ranged from 78% to 95%; longer-term (as long as 8 weeks) symptom cure rates ranged from 82% to 91%. The review suggested that TMP-SMX may be slightly more likely to cause a rash than other antibiotics.¹

Antibiotic concentrations in breast milk

In a case series, TMP/SMX, 160/800 mg, given to 50 lactating women 2 times (40 women) or 3 times (10 women) daily resulted in an average breast milk concentration of 2 μg/mL of TMP and 4.6 μg/mL of SMX, corresponding to respective doses of 0.3 and 0.7 mg/kg/d for infants taking 150 mL breast milk/kg/d.² The authors state that this dose is safe for infants without G6PD deficiency. The study included only women with UTIs or other infections requiring antibiotic treatment.

A case series of 4 lactating mothers who received a single 100-mg oral dose of nitrofurantoin found that peak breast milk concentration occurred 4 hours later and averaged 2.4 μg/mL (standard deviation=1.7-3.2 μg/mL).³ The authors calculated a mean concentration over 12 hours of 1.3 μg nitrofurantoin/mL breast milk. This level would correspond to an estimated dose of 0.2 mg/kg/d for an infant consuming 150 mL/kg/d of breast milk whose mother takes 100 mg nitrofurantoin twice daily, much lower than the recommended pediatric dose of 5 to 7 mg/kg/d.

Data from a case series and a case report suggest the amount of ciprofloxacin transferred to breastfed infants is low. In the case series, researchers gave 10 lactating women 3 oral doses of ciprofloxacin, 750 mg, at 12-hour intervals and then measured ciprofloxacin levels in breast milk.⁴ The highest levels occurred 2 hours after the third dose and averaged 3.79 μg/mL. Average levels fell gradually to 0.02 μg/mL 24 hours after the third dose. Assuming a milk intake of 150 mL/kg/d, a breastfed infant would consume approximately 0.3 mg/kg/d, much lower than the 10 to 40 mg/kg/d dose recommended for treating sick infants.

A case report of a woman who took oral ciprofloxacin 500 mg/d for 10 days noted a breast milk ciprofloxacin concentration of 0.98 mg/L at 10.7 hours after the last dose.⁵ Ofloxacin, norfloxacin, and levofloxacin have been associated with lower milk concentrations than ciprofloxacin.⁶

Adverse effects

In a cohort study of 838 women from a program for pregnant and lactating women exposed to drugs and other substances, 2 of 12 mothers taking TMP/SMX reported poor feeding in their infants.⁷

The same program received reports of infants with diarrhea from mothers taking amoxicillin (3 of 25 infants), nitrofurantoin (2 of 6 infants), and cephalexin (2 of 7 infants), but no reports of other adverse effects. Another study demonstrated that nitrofurantoin is actively transported into the mother’s milk, making hemolytic anemia a possibility in G6PD-deficient infants.³

Data from a case series and a case report suggest the amount of ciprofloxacin transferred to breastfed infants is low.Studies indicate that adverse effects of fluoroquinolones in children are similar to those in adults despite a contraindication in children because of reports of arthropathy in young animals. One case of pseudomembranous colitis in a breastfeeding infant and 2 cases of green teeth in neonates have been reported with ciprofloxacin use.^6,8,9

RECOMMENDATIONS

The Infectious Disease Society of America recommends nitrofurantoin, TMP/SMX, or fosfomycin for first-line treatment of uncomplicated UTIs in women, although fosfomycin appears to be inferior to other standard short-course antibiotics based on FDA data. Fluoroquinolones and β-lactams are recommended alternative treatments.¹⁰

The American Academy of Pediatrics’ Committee on Drugs says that TMP/SMX (unless G6PD deficiency is present), amoxicillin, nitrofurantoin, ciprofloxacin, and ofloxacin usually are compatible with breastfeeding.¹¹

EVIDENCE SUMMARY

Because no randomized controlled trials have evaluated the efficacy of UTI treatment in lactating women, recommendations are extrapolated from studies in other populations and case reports.

Antibiotics: Comparable and effective

A 2010 Cochrane review examined 21 good-quality randomized trials that compared the effectiveness of TMP-SMX, β-lactam antibiotics, nitrofurantoin, and fluoroquinolones for uncomplicated UTIs in 6016 women.¹ The authors found no significant differences in short-term symptom cure rates: all antibiotics were very effective. Seven studies reported mixed (clinical and bacteriologic) cure rates.

Symptom cure rates for patients followed for as long as 2 weeks ranged from 78% to 95%; longer-term (as long as 8 weeks) symptom cure rates ranged from 82% to 91%. The review suggested that TMP-SMX may be slightly more likely to cause a rash than other antibiotics.¹

Antibiotic concentrations in breast milk

In a case series, TMP/SMX, 160/800 mg, given to 50 lactating women 2 times (40 women) or 3 times (10 women) daily resulted in an average breast milk concentration of 2 μg/mL of TMP and 4.6 μg/mL of SMX, corresponding to respective doses of 0.3 and 0.7 mg/kg/d for infants taking 150 mL breast milk/kg/d.² The authors state that this dose is safe for infants without G6PD deficiency. The study included only women with UTIs or other infections requiring antibiotic treatment.

A case series of 4 lactating mothers who received a single 100-mg oral dose of nitrofurantoin found that peak breast milk concentration occurred 4 hours later and averaged 2.4 μg/mL (standard deviation=1.7-3.2 μg/mL).³ The authors calculated a mean concentration over 12 hours of 1.3 μg nitrofurantoin/mL breast milk. This level would correspond to an estimated dose of 0.2 mg/kg/d for an infant consuming 150 mL/kg/d of breast milk whose mother takes 100 mg nitrofurantoin twice daily, much lower than the recommended pediatric dose of 5 to 7 mg/kg/d.

Data from a case series and a case report suggest the amount of ciprofloxacin transferred to breastfed infants is low. In the case series, researchers gave 10 lactating women 3 oral doses of ciprofloxacin, 750 mg, at 12-hour intervals and then measured ciprofloxacin levels in breast milk.⁴ The highest levels occurred 2 hours after the third dose and averaged 3.79 μg/mL. Average levels fell gradually to 0.02 μg/mL 24 hours after the third dose. Assuming a milk intake of 150 mL/kg/d, a breastfed infant would consume approximately 0.3 mg/kg/d, much lower than the 10 to 40 mg/kg/d dose recommended for treating sick infants.

A case report of a woman who took oral ciprofloxacin 500 mg/d for 10 days noted a breast milk ciprofloxacin concentration of 0.98 mg/L at 10.7 hours after the last dose.⁵ Ofloxacin, norfloxacin, and levofloxacin have been associated with lower milk concentrations than ciprofloxacin.⁶

Adverse effects

In a cohort study of 838 women from a program for pregnant and lactating women exposed to drugs and other substances, 2 of 12 mothers taking TMP/SMX reported poor feeding in their infants.⁷

The same program received reports of infants with diarrhea from mothers taking amoxicillin (3 of 25 infants), nitrofurantoin (2 of 6 infants), and cephalexin (2 of 7 infants), but no reports of other adverse effects. Another study demonstrated that nitrofurantoin is actively transported into the mother’s milk, making hemolytic anemia a possibility in G6PD-deficient infants.³

Data from a case series and a case report suggest the amount of ciprofloxacin transferred to breastfed infants is low.Studies indicate that adverse effects of fluoroquinolones in children are similar to those in adults despite a contraindication in children because of reports of arthropathy in young animals. One case of pseudomembranous colitis in a breastfeeding infant and 2 cases of green teeth in neonates have been reported with ciprofloxacin use.^6,8,9

RECOMMENDATIONS

The Infectious Disease Society of America recommends nitrofurantoin, TMP/SMX, or fosfomycin for first-line treatment of uncomplicated UTIs in women, although fosfomycin appears to be inferior to other standard short-course antibiotics based on FDA data. Fluoroquinolones and β-lactams are recommended alternative treatments.¹⁰

The American Academy of Pediatrics’ Committee on Drugs says that TMP/SMX (unless G6PD deficiency is present), amoxicillin, nitrofurantoin, ciprofloxacin, and ofloxacin usually are compatible with breastfeeding.¹¹

ABSTRACT

Purpose To assess the impact of a multicomponent intervention on 30-day hospital readmissions in a group of primary care practices that undertook practice transformation, compared with rates in usual-care practices that admitted patients to the same hospital service.

Methods Four primary care clinics enhanced patient care coordination with care managers and inpatient care teams, and developed and used hospital readmission reports to monitor readmission rates. Patient readmissions to the hospital were analyzed over a 12-month period from May 2012 through April 2013, among patients who fell into 2 groups. Group 1 patients were those cared for by the primary care clinics that implemented transformation activities and who were admitted to the hospital associated with the practices. Group 2 patients were seen at clinics in the same catchment area that did not undertake any known practice redesign activities (usual care group).

Results A total of 961 patients were included in analyses; 685 (71.3%) were in Group 1, and 276 (28.7%) were in Group 2. Readmissions among Group 1 patients decreased from 27% to 7.1% (P=.02), and readmissions in Group 2 were variable with a nonsignificant trend (P=.53). The unadjusted regression model that compared the interaction between Group 1 and Group 2 patients found a significant difference in readmissions (P=.05).

Conclusion Developing a multicomponent intervention appears to have a significant impact on reducing hospital readmissions. Primary care groups seeking to reduce hospital readmissions should consider implementing similar processes.

An analysis of Medicare claims data between 2003 and 2004 found that nearly 20% of the >11 million Medicare patients who had been discharged from a hospital were readmitted within 30 days, at a cost of $17.4 billion.¹ Certain patient subgroups were especially worrisome. Of those with congestive heart failure, for example, 50% were typically readmitted within 6 months of initial hospitalization.²

A longstanding issue comes to the fore. Concerns about hospital readmissions appeared in the literature nearly 40 years ago.³ In the 1990s, with the advent of managed care, organizations began “case management” to reduce preventable readmissions using several approaches, including enhanced primary care access.⁴ A meta-analysis at that time demonstrated some reduction in hospital readmissions associated with hospital-based case management interventions.⁵ Though quality improvement programs and case management have been assumed to reduce hospital readmissions, some studies have actually found the opposite,^6,7 or have yielded conflicting evidence.^8-13 Skyrocketing costs of health care have brought hospital readmissions to the forefront of health system redesign efforts.^14-16

Section 3025 of the Affordable Care Act added section 1886(q) to the Social Security Act establishing the Hospital Readmissions Reduction Program, which requires Centers for Medicare & Medicaid Services to reduce payments to hospitals with excess readmissions.¹⁷ This change was introduced on October 1, 2012 and has precipitated discussion across the country about the prevention of unnecessary hospital readmissions.^18,19

Compared with usual care, this multicomponent intervention more successfully reduced readmissions. Patient factors contributing to hospital readmissions. Concerns patients cite most frequently as contributors to relapse and readmission are 1) feeling unprepared for discharge; 2) difficulty performing activities of daily living; 3) trouble adhering to discharge medications; 4) difficulty accessing discharge medications; and 5) lack of social support.²⁰ While multiple tools have been developed to better assess unplanned readmissions—including the Identification of Seniors at Risk, the Flemish version of the Triage Risk Screening Tool, and Variable Indicative of Placement risk—none of these have accurately predicted unplanned readmission in older, hospitalized patients.²¹ Predicting which patients will require readmission remains elusive,²² though some new models show promise.²³ z

Targeted interventions that show promise. Postdischarge telephone follow-up has been shown to reduce hospital readmissions,^24,25 and a direct correlation has been observed between the timing of the intervention and readmission rates, with interventions implemented closer to the date of discharge being associated with greater reductions in the number of readmissions.²⁶ Additionally, multicomponent interventions with both pre- and postdischarge elements that specifically target high-risk populations appear to be more effective in reducing readmissions than single-component interventions.²⁷

Hansen et al²⁸ identified a number of predischarge, postdischarge, and bridging interventions that could potentially reduce hospital readmissions (TABLE 1). No single intervention implemented alone consistently reduced the risk for 30-day rehospitalization.²⁸ One multicomponent intervention that has reduced readmissions for patients with heart failure or acute myocardial infarction is a transition coach, who visits patients in the hospital and sees them again in clinic for follow-up appointments. The coach also calls patients between face-to-face visits to review treatment plans and answer questions.²⁹

The impetus for our study. The patient-centered medical home (PCMH) has been gaining traction as a mechanism to improve patient care while reducing health care spending.^30,31 An intensive multidimensional medical home model introduced into 11 primary care practices proved capable of significantly reducing admissions and readmissions for Medicare Advantage members.³² Additionally, intelligently leveraging clinical information technology is likely to be critical in reducing readmissions.³³ The purpose of our observational study was to examine the impact of a multicomponent intervention on 30-day hospital readmissions over 12 months.

METHODS

Study setting and preintervention practice routines in 2 patient groups

The study setting for Group 1 involved patients with assigned primary care providers (PCPs) in a university-based practice group at 4 outpatient clinics. The study setting for Group 2 included patients with assigned PCPs from county and community health centers, involving 12 primary care clinics in total. While the groups’ patient populations were distinguished for descriptive purposes, in practice the patients were admitted to the same inpatient treatment teams and university-based hospital in a metropolitan setting. For both groups, the primary care practices admitted patients to the hospital directly from clinic or through the emergency department (ED).

An admitting team from one of the inpatient services completed the admission, initiated treatment, and discharged patients. Preintervention, limited discharge case management occurred at the hospital, driven primarily by the treating team’s requests. The admitting team also attempted to schedule outpatient follow-up appointments with an available PCP at the patient’s primary clinic after discharge. Obstacles to successful appointment scheduling prior to discharge included but were not limited to discharges over weekends or holidays or after clinic hours. Additionally, for both groups, discharge summaries were sent to the PCP either electronically via the electronic medical record (EMR) or via system-generated automated fax.

Creating a culture of continuity in Group 1

Transformation of outpatient activities. We developed several important processes to transform the patient experience through hospitalization and discharge. Together, these processes created a “culture of continuity” to prevent avoidable readmissions. We introduced an innovative, systematic approach to notifying the clinic and primary care clinician about initial admission. We also gave notification immediately upon discharge, rather than waiting until after discharge, as had been occurring. This patient-centered change engaged the primary care team in the care of the patient while hospitalized and during discharge planning; it actively ensured that follow-up appointments occurred within 1 week after discharge. Prior to this intervention, there was no system for ensuring timely follow-up after hospital discharge. The new expectation for the ambulatory clinics was that clinic staff could “reach in” to the patient during the hospital stay and actively contact the patient before discharge to schedule a postdischarge appointment at the patient’s convenience. This patient-centered change engaged the primary care team in the care of the patient while hospitalized and during discharge planning. 

The 4 practices had embraced and implemented the PCMH model, a core component of which is care coordination.^34,35 Each clinic appointed a registered nurse (RN) to serve as a team-based care manager (CM) for patients being discharged from the hospital. Responsibilities included fielding calls or electronic communications from the inpatient team, developing a hospital follow-up workflow, developing a standardized list of questions to ask each patient after discharge, and calling patients to ensure a follow-up appointment was scheduled, ideally within 2 to 3 days and at least within 7 days of discharge. The CM prioritized scheduling follow-up appointments with the patient’s PCP to ensure the highest level of continuity.

In addition to patient-specific documents, CMs received electronic reports from inpatient teams (including from the ED, medical and surgical intensive care units, and surgery) listing all Group 1 patients discharged from the hospital. Reports were run daily and allowed the outpatient clinic staff and CMs to verify patients against previous lists of anticipated discharges, and to generate their own lists. The CMs would then make follow-up phone calls and ensure that appointments were scheduled for these patients.

Medical directors at the 4 clinics received monthly summary reports profiling clinical activities related to hospitalizations. A data team (led by author SF) created the reports, which initially focused on care delivered in ambulatory settings (and included the development of a “balanced scorecard” to assess quality of care, financial productivity, and operational efficiency³⁶). The data team developed new reports specifically for hospital admissions, discharges, and readmissions, identifying:
• all patients admitted by inpatient team
• the number and percentage of patients who were readmitted within 30 days
• the number and percentage of patients who had received a follow-up phone call or electronic communication from the outpatient team
• the number of patients who had follow-up visits after discharge within 7 and 30 days
• the number of patients who had clinic visits prior to readmission
• all patients discharged from any service within the prior 24 hours.

On the first or second day of admission, a follow-up document was electronically routed to the administrative support staff, office nurse, and primary care physician.These reports, which had patient drilldown capability, were forwarded to all providers and teams at each clinic by the medical director. Teams at each clinic were then charged with analyzing the readmissions, identifying high-risk patients, and improving the coordination of care for these patients, including the use of RN/clinician co-visits and proactive outreach from the team-based nurses and staff.

Transformation of inpatient activities. We reorganized inpatient teams to include clinician representatives from the clinics whose patients were being treated. This process ensured better continuity of experience and familiarity with the environment of care and discharge/follow-up processes for both patients and all providers.

Additionally, inpatient teams developed new workflows to ensure that all involved members of the outpatient team were well informed of the hospitalization process. On the first or second day of admission, a hospital follow-up document was electronically routed to the administrative support staff, the PCP team nurse, and the PCP (FIGURE 1). An integrated EMR created a link between the hospital and all ambulatory practices that allowed for real-time transmission of patient information. The document identified the timing of a follow-up appointment and requested a 48-hour phone call from the team nurse after hospital discharge. The inpatient team also included a concise summary of the hospitalization for the PCP, to aid in anticipating patient discharge and any impending needs. The document was retrievable and traceable in the EMR.

Study groups and statistical analysis

The Oregon Health & Science University’s Institutional Review Board (IRB#9768) determined this study was not human subjects research because the proposed activity did not meet the definition of human subject per 45 CFR 46.102(f). The board made this determination because our analysis file included only hospital readmission rates and no patient-level data.

Adult patients admitted by the inpatient teams consisted of 2 distinct populations: patients whose PCP practiced at one of the 4 outpatient clinics (Group 1 patients); and patients admitted from other, unaffiliated clinics (Group 2 patients). In contrast to the transformations in patient care described in Group 1, care provided to Group 2 patients was considered usual care, as there was no interface between outpatient and inpatient teams to revise operations. Patients in either group were excluded from analyses if they died during the hospitalization. Maternity patients were also excluded.

An integrated EMR created a link between the hospital and all ambulatory practices that allowed for real-time transmission of patient information. We identified the percentage of patients readmitted within 30 days of a hospital admission using administrative data sources, which underwent careful data checking and validation, and were sub-grouped according to whether the patients were in Group 1 or Group 2. We used group-specific and overall linear regression to examine the changes in percentage of readmission within 30 days of discharge in the 2 study groups over 12 months, including a model that specifically assessed the interaction between Group 1 readmission percentages and those in Group 2. We considered a P-value ≤.05 to be significant in this exploratory study.

RESULTS

Patient readmissions decreased significantly

Our analysis included 961 patients; 685 patients (71.3%) were in Group 1, and 276 (28.7%) were in Group 2 (Table 2). The distribution of patient gender and mean age was similar within groups for patients readmitted and not readmitted during the study period. Among patients readmitted, the mean hospital length of stay was 5.8 days and 7.1 days for Group 1 and Group 2, respectively. Among those not readmitted, the mean hospital length of stay was 4.3 and 4.9 in Group 1 and 2, respectively.

Multicomponent interventions are more successful at reducing readmissions than single-component interventions.The percentage of patients readmitted per month ranged from 28.1% to 7.1% in Group 1 and 27.8% to 5.9% in Group 2 (Figure 2). Patient readmissions in Group 1 decreased significantly from 27% in May 2012 to 7.1% in April 2013 with an R2 of 0.43 (P=.02). Readmissions of patients in Group 2 were more variable; 26.1% in May 2012 and 25.9% in April 2013 with a non-significant R2 of 0.04 (P=.53). The regression model (unadjusted) that compared the interaction between Group 1 and Group 2 readmissions over the study period was significant, indicating a decrease in readmissions in Group 1 and no strong correlation between usual care and readmissions over time in Group 2 (P=.05).

DISCUSSION

Implementing intensive coordinated care management and transition processes in a group of primary care clinics appears to significantly decrease hospital readmissions for patients in Group 1, compared with those in Group 2 who received usual care. While it is possible that some of the ambulatory practices in Group 2 admitting patients to the inpatient services were using or developing care coordination programs including hospital follow-up, none of these providers or groups interfaced with the inpatient teams in this study. We are, therefore, confident that Group 2 providers were not undertaking any new or novel activities that reached in to hospital inpatient services to improve care coordination.

Our findings are consistent with the literature review conducted by Scott et al,²⁷ which found that multicomponent interventions are more successful at reducing readmissions than single-component interventions. In our Group 1 clinics, we implemented 8 of the 12 predischarge, postdischarge, and bridging interventions identified by Hansen et al²⁸ (medication reconciliation, discharge planning, scheduling of a follow-up appointment before discharge, follow-up telephone calls, timely communication with ambulatory providers, timely ambulatory provider follow-up, physician continuity across the inpatient and outpatient setting, and patient-centered discharge instructions). 

Study strengths and weaknesses. The strengths of this study include means and quality of data capture for hospital readmission rates in the study setting. Limitations include the small sample sizes, which did not allow us to conduct a multivariable adjusted analysis that would have taken into account patient characteristics, seasons, and temporal correlations. These covariates might drive study findings in a way that results in us drawing inaccurate conclusions—the analysis we conducted (unadjusted) assumed that the events that occurred in each month were unrelated to what might have occurred in the prior month or subsequent month.

Patients in the 2 study groups did exhibit differences that could have contributed to our findings. For example, the average length of stay for Group 2 patients was longer by just over 1 day compared with that in Group 1. This may suggest Group 2 patients were sicker, and thus may have needed to be readmitted within 30 days of their discharge. We cannot know for certain that patients in Group 1 were less ill, as this would require a more discriminating study design. As with many studies, additional questions arise, but these serve to further a line of research that is vitally important.

Creating a culture of continuity is an important aspect of the patient-centered medical home.Another factor that could have affected our findings is that Group 1 patient readmission rates started off higher than the Group 2 patients, so there is a chance that regression to the mean rather than changes in clinical care could have contributed to some of the decrease in Group 1 readmission rates. There are potential subject-level, provider-level, and clinic-level factors that could have been used to adjust for potential confounding. Future studies could address these factors. Longer study follow-up would provide an even better picture of the difference between the groups.

A multicomponent intervention works. Creating a culture of continuity is an important aspect of PCMH. Not all primary care clinics or PCMHs may have built-in relationships for inpatient care of their patients. We would argue that outpatient adoption of the enhanced “reaching in” and a multicomponent intervention would have a significant positive impact on patient care and improve the transition from in- to outpatient care, and likely reduce readmissions.

CORRESPONDENCE
Brett White, MD, 4411 SW Vermont St, Portland, OR 97219; [email protected]

The authors gratefully acknowledge the clinic and inpatient physicians and staffs as well as the Research Program in the Department of Family Medicine, Oregon Health & Science University.

ABSTRACT

Purpose To assess the impact of a multicomponent intervention on 30-day hospital readmissions in a group of primary care practices that undertook practice transformation, compared with rates in usual-care practices that admitted patients to the same hospital service.

Methods Four primary care clinics enhanced patient care coordination with care managers and inpatient care teams, and developed and used hospital readmission reports to monitor readmission rates. Patient readmissions to the hospital were analyzed over a 12-month period from May 2012 through April 2013, among patients who fell into 2 groups. Group 1 patients were those cared for by the primary care clinics that implemented transformation activities and who were admitted to the hospital associated with the practices. Group 2 patients were seen at clinics in the same catchment area that did not undertake any known practice redesign activities (usual care group).

Results A total of 961 patients were included in analyses; 685 (71.3%) were in Group 1, and 276 (28.7%) were in Group 2. Readmissions among Group 1 patients decreased from 27% to 7.1% (P=.02), and readmissions in Group 2 were variable with a nonsignificant trend (P=.53). The unadjusted regression model that compared the interaction between Group 1 and Group 2 patients found a significant difference in readmissions (P=.05).

Conclusion Developing a multicomponent intervention appears to have a significant impact on reducing hospital readmissions. Primary care groups seeking to reduce hospital readmissions should consider implementing similar processes.

An analysis of Medicare claims data between 2003 and 2004 found that nearly 20% of the >11 million Medicare patients who had been discharged from a hospital were readmitted within 30 days, at a cost of $17.4 billion.¹ Certain patient subgroups were especially worrisome. Of those with congestive heart failure, for example, 50% were typically readmitted within 6 months of initial hospitalization.²

A longstanding issue comes to the fore. Concerns about hospital readmissions appeared in the literature nearly 40 years ago.³ In the 1990s, with the advent of managed care, organizations began “case management” to reduce preventable readmissions using several approaches, including enhanced primary care access.⁴ A meta-analysis at that time demonstrated some reduction in hospital readmissions associated with hospital-based case management interventions.⁵ Though quality improvement programs and case management have been assumed to reduce hospital readmissions, some studies have actually found the opposite,^6,7 or have yielded conflicting evidence.^8-13 Skyrocketing costs of health care have brought hospital readmissions to the forefront of health system redesign efforts.^14-16

Section 3025 of the Affordable Care Act added section 1886(q) to the Social Security Act establishing the Hospital Readmissions Reduction Program, which requires Centers for Medicare & Medicaid Services to reduce payments to hospitals with excess readmissions.¹⁷ This change was introduced on October 1, 2012 and has precipitated discussion across the country about the prevention of unnecessary hospital readmissions.^18,19

Compared with usual care, this multicomponent intervention more successfully reduced readmissions. Patient factors contributing to hospital readmissions. Concerns patients cite most frequently as contributors to relapse and readmission are 1) feeling unprepared for discharge; 2) difficulty performing activities of daily living; 3) trouble adhering to discharge medications; 4) difficulty accessing discharge medications; and 5) lack of social support.²⁰ While multiple tools have been developed to better assess unplanned readmissions—including the Identification of Seniors at Risk, the Flemish version of the Triage Risk Screening Tool, and Variable Indicative of Placement risk—none of these have accurately predicted unplanned readmission in older, hospitalized patients.²¹ Predicting which patients will require readmission remains elusive,²² though some new models show promise.²³ z

Targeted interventions that show promise. Postdischarge telephone follow-up has been shown to reduce hospital readmissions,^24,25 and a direct correlation has been observed between the timing of the intervention and readmission rates, with interventions implemented closer to the date of discharge being associated with greater reductions in the number of readmissions.²⁶ Additionally, multicomponent interventions with both pre- and postdischarge elements that specifically target high-risk populations appear to be more effective in reducing readmissions than single-component interventions.²⁷

Hansen et al²⁸ identified a number of predischarge, postdischarge, and bridging interventions that could potentially reduce hospital readmissions (TABLE 1). No single intervention implemented alone consistently reduced the risk for 30-day rehospitalization.²⁸ One multicomponent intervention that has reduced readmissions for patients with heart failure or acute myocardial infarction is a transition coach, who visits patients in the hospital and sees them again in clinic for follow-up appointments. The coach also calls patients between face-to-face visits to review treatment plans and answer questions.²⁹

The impetus for our study. The patient-centered medical home (PCMH) has been gaining traction as a mechanism to improve patient care while reducing health care spending.^30,31 An intensive multidimensional medical home model introduced into 11 primary care practices proved capable of significantly reducing admissions and readmissions for Medicare Advantage members.³² Additionally, intelligently leveraging clinical information technology is likely to be critical in reducing readmissions.³³ The purpose of our observational study was to examine the impact of a multicomponent intervention on 30-day hospital readmissions over 12 months.

METHODS

Study setting and preintervention practice routines in 2 patient groups

The study setting for Group 1 involved patients with assigned primary care providers (PCPs) in a university-based practice group at 4 outpatient clinics. The study setting for Group 2 included patients with assigned PCPs from county and community health centers, involving 12 primary care clinics in total. While the groups’ patient populations were distinguished for descriptive purposes, in practice the patients were admitted to the same inpatient treatment teams and university-based hospital in a metropolitan setting. For both groups, the primary care practices admitted patients to the hospital directly from clinic or through the emergency department (ED).

An admitting team from one of the inpatient services completed the admission, initiated treatment, and discharged patients. Preintervention, limited discharge case management occurred at the hospital, driven primarily by the treating team’s requests. The admitting team also attempted to schedule outpatient follow-up appointments with an available PCP at the patient’s primary clinic after discharge. Obstacles to successful appointment scheduling prior to discharge included but were not limited to discharges over weekends or holidays or after clinic hours. Additionally, for both groups, discharge summaries were sent to the PCP either electronically via the electronic medical record (EMR) or via system-generated automated fax.

Creating a culture of continuity in Group 1

Transformation of outpatient activities. We developed several important processes to transform the patient experience through hospitalization and discharge. Together, these processes created a “culture of continuity” to prevent avoidable readmissions. We introduced an innovative, systematic approach to notifying the clinic and primary care clinician about initial admission. We also gave notification immediately upon discharge, rather than waiting until after discharge, as had been occurring. This patient-centered change engaged the primary care team in the care of the patient while hospitalized and during discharge planning; it actively ensured that follow-up appointments occurred within 1 week after discharge. Prior to this intervention, there was no system for ensuring timely follow-up after hospital discharge. The new expectation for the ambulatory clinics was that clinic staff could “reach in” to the patient during the hospital stay and actively contact the patient before discharge to schedule a postdischarge appointment at the patient’s convenience. This patient-centered change engaged the primary care team in the care of the patient while hospitalized and during discharge planning. 

The 4 practices had embraced and implemented the PCMH model, a core component of which is care coordination.^34,35 Each clinic appointed a registered nurse (RN) to serve as a team-based care manager (CM) for patients being discharged from the hospital. Responsibilities included fielding calls or electronic communications from the inpatient team, developing a hospital follow-up workflow, developing a standardized list of questions to ask each patient after discharge, and calling patients to ensure a follow-up appointment was scheduled, ideally within 2 to 3 days and at least within 7 days of discharge. The CM prioritized scheduling follow-up appointments with the patient’s PCP to ensure the highest level of continuity.

In addition to patient-specific documents, CMs received electronic reports from inpatient teams (including from the ED, medical and surgical intensive care units, and surgery) listing all Group 1 patients discharged from the hospital. Reports were run daily and allowed the outpatient clinic staff and CMs to verify patients against previous lists of anticipated discharges, and to generate their own lists. The CMs would then make follow-up phone calls and ensure that appointments were scheduled for these patients.

Medical directors at the 4 clinics received monthly summary reports profiling clinical activities related to hospitalizations. A data team (led by author SF) created the reports, which initially focused on care delivered in ambulatory settings (and included the development of a “balanced scorecard” to assess quality of care, financial productivity, and operational efficiency³⁶). The data team developed new reports specifically for hospital admissions, discharges, and readmissions, identifying:
• all patients admitted by inpatient team
• the number and percentage of patients who were readmitted within 30 days
• the number and percentage of patients who had received a follow-up phone call or electronic communication from the outpatient team
• the number of patients who had follow-up visits after discharge within 7 and 30 days
• the number of patients who had clinic visits prior to readmission
• all patients discharged from any service within the prior 24 hours.

On the first or second day of admission, a follow-up document was electronically routed to the administrative support staff, office nurse, and primary care physician.These reports, which had patient drilldown capability, were forwarded to all providers and teams at each clinic by the medical director. Teams at each clinic were then charged with analyzing the readmissions, identifying high-risk patients, and improving the coordination of care for these patients, including the use of RN/clinician co-visits and proactive outreach from the team-based nurses and staff.

Transformation of inpatient activities. We reorganized inpatient teams to include clinician representatives from the clinics whose patients were being treated. This process ensured better continuity of experience and familiarity with the environment of care and discharge/follow-up processes for both patients and all providers.

Additionally, inpatient teams developed new workflows to ensure that all involved members of the outpatient team were well informed of the hospitalization process. On the first or second day of admission, a hospital follow-up document was electronically routed to the administrative support staff, the PCP team nurse, and the PCP (FIGURE 1). An integrated EMR created a link between the hospital and all ambulatory practices that allowed for real-time transmission of patient information. The document identified the timing of a follow-up appointment and requested a 48-hour phone call from the team nurse after hospital discharge. The inpatient team also included a concise summary of the hospitalization for the PCP, to aid in anticipating patient discharge and any impending needs. The document was retrievable and traceable in the EMR.

Study groups and statistical analysis

The Oregon Health & Science University’s Institutional Review Board (IRB#9768) determined this study was not human subjects research because the proposed activity did not meet the definition of human subject per 45 CFR 46.102(f). The board made this determination because our analysis file included only hospital readmission rates and no patient-level data.

Adult patients admitted by the inpatient teams consisted of 2 distinct populations: patients whose PCP practiced at one of the 4 outpatient clinics (Group 1 patients); and patients admitted from other, unaffiliated clinics (Group 2 patients). In contrast to the transformations in patient care described in Group 1, care provided to Group 2 patients was considered usual care, as there was no interface between outpatient and inpatient teams to revise operations. Patients in either group were excluded from analyses if they died during the hospitalization. Maternity patients were also excluded.

An integrated EMR created a link between the hospital and all ambulatory practices that allowed for real-time transmission of patient information. We identified the percentage of patients readmitted within 30 days of a hospital admission using administrative data sources, which underwent careful data checking and validation, and were sub-grouped according to whether the patients were in Group 1 or Group 2. We used group-specific and overall linear regression to examine the changes in percentage of readmission within 30 days of discharge in the 2 study groups over 12 months, including a model that specifically assessed the interaction between Group 1 readmission percentages and those in Group 2. We considered a P-value ≤.05 to be significant in this exploratory study.

RESULTS

Patient readmissions decreased significantly

Our analysis included 961 patients; 685 patients (71.3%) were in Group 1, and 276 (28.7%) were in Group 2 (Table 2). The distribution of patient gender and mean age was similar within groups for patients readmitted and not readmitted during the study period. Among patients readmitted, the mean hospital length of stay was 5.8 days and 7.1 days for Group 1 and Group 2, respectively. Among those not readmitted, the mean hospital length of stay was 4.3 and 4.9 in Group 1 and 2, respectively.

Multicomponent interventions are more successful at reducing readmissions than single-component interventions.The percentage of patients readmitted per month ranged from 28.1% to 7.1% in Group 1 and 27.8% to 5.9% in Group 2 (Figure 2). Patient readmissions in Group 1 decreased significantly from 27% in May 2012 to 7.1% in April 2013 with an R2 of 0.43 (P=.02). Readmissions of patients in Group 2 were more variable; 26.1% in May 2012 and 25.9% in April 2013 with a non-significant R2 of 0.04 (P=.53). The regression model (unadjusted) that compared the interaction between Group 1 and Group 2 readmissions over the study period was significant, indicating a decrease in readmissions in Group 1 and no strong correlation between usual care and readmissions over time in Group 2 (P=.05).

DISCUSSION

Implementing intensive coordinated care management and transition processes in a group of primary care clinics appears to significantly decrease hospital readmissions for patients in Group 1, compared with those in Group 2 who received usual care. While it is possible that some of the ambulatory practices in Group 2 admitting patients to the inpatient services were using or developing care coordination programs including hospital follow-up, none of these providers or groups interfaced with the inpatient teams in this study. We are, therefore, confident that Group 2 providers were not undertaking any new or novel activities that reached in to hospital inpatient services to improve care coordination.

Our findings are consistent with the literature review conducted by Scott et al,²⁷ which found that multicomponent interventions are more successful at reducing readmissions than single-component interventions. In our Group 1 clinics, we implemented 8 of the 12 predischarge, postdischarge, and bridging interventions identified by Hansen et al²⁸ (medication reconciliation, discharge planning, scheduling of a follow-up appointment before discharge, follow-up telephone calls, timely communication with ambulatory providers, timely ambulatory provider follow-up, physician continuity across the inpatient and outpatient setting, and patient-centered discharge instructions). 

Study strengths and weaknesses. The strengths of this study include means and quality of data capture for hospital readmission rates in the study setting. Limitations include the small sample sizes, which did not allow us to conduct a multivariable adjusted analysis that would have taken into account patient characteristics, seasons, and temporal correlations. These covariates might drive study findings in a way that results in us drawing inaccurate conclusions—the analysis we conducted (unadjusted) assumed that the events that occurred in each month were unrelated to what might have occurred in the prior month or subsequent month.

Patients in the 2 study groups did exhibit differences that could have contributed to our findings. For example, the average length of stay for Group 2 patients was longer by just over 1 day compared with that in Group 1. This may suggest Group 2 patients were sicker, and thus may have needed to be readmitted within 30 days of their discharge. We cannot know for certain that patients in Group 1 were less ill, as this would require a more discriminating study design. As with many studies, additional questions arise, but these serve to further a line of research that is vitally important.

Creating a culture of continuity is an important aspect of the patient-centered medical home.Another factor that could have affected our findings is that Group 1 patient readmission rates started off higher than the Group 2 patients, so there is a chance that regression to the mean rather than changes in clinical care could have contributed to some of the decrease in Group 1 readmission rates. There are potential subject-level, provider-level, and clinic-level factors that could have been used to adjust for potential confounding. Future studies could address these factors. Longer study follow-up would provide an even better picture of the difference between the groups.

A multicomponent intervention works. Creating a culture of continuity is an important aspect of PCMH. Not all primary care clinics or PCMHs may have built-in relationships for inpatient care of their patients. We would argue that outpatient adoption of the enhanced “reaching in” and a multicomponent intervention would have a significant positive impact on patient care and improve the transition from in- to outpatient care, and likely reduce readmissions.

CORRESPONDENCE
Brett White, MD, 4411 SW Vermont St, Portland, OR 97219; [email protected]

The authors gratefully acknowledge the clinic and inpatient physicians and staffs as well as the Research Program in the Department of Family Medicine, Oregon Health & Science University.

ABSTRACT

Purpose To assess the impact of a multicomponent intervention on 30-day hospital readmissions in a group of primary care practices that undertook practice transformation, compared with rates in usual-care practices that admitted patients to the same hospital service.

Methods Four primary care clinics enhanced patient care coordination with care managers and inpatient care teams, and developed and used hospital readmission reports to monitor readmission rates. Patient readmissions to the hospital were analyzed over a 12-month period from May 2012 through April 2013, among patients who fell into 2 groups. Group 1 patients were those cared for by the primary care clinics that implemented transformation activities and who were admitted to the hospital associated with the practices. Group 2 patients were seen at clinics in the same catchment area that did not undertake any known practice redesign activities (usual care group).

Results A total of 961 patients were included in analyses; 685 (71.3%) were in Group 1, and 276 (28.7%) were in Group 2. Readmissions among Group 1 patients decreased from 27% to 7.1% (P=.02), and readmissions in Group 2 were variable with a nonsignificant trend (P=.53). The unadjusted regression model that compared the interaction between Group 1 and Group 2 patients found a significant difference in readmissions (P=.05).

Conclusion Developing a multicomponent intervention appears to have a significant impact on reducing hospital readmissions. Primary care groups seeking to reduce hospital readmissions should consider implementing similar processes.

An analysis of Medicare claims data between 2003 and 2004 found that nearly 20% of the >11 million Medicare patients who had been discharged from a hospital were readmitted within 30 days, at a cost of $17.4 billion.¹ Certain patient subgroups were especially worrisome. Of those with congestive heart failure, for example, 50% were typically readmitted within 6 months of initial hospitalization.²

A longstanding issue comes to the fore. Concerns about hospital readmissions appeared in the literature nearly 40 years ago.³ In the 1990s, with the advent of managed care, organizations began “case management” to reduce preventable readmissions using several approaches, including enhanced primary care access.⁴ A meta-analysis at that time demonstrated some reduction in hospital readmissions associated with hospital-based case management interventions.⁵ Though quality improvement programs and case management have been assumed to reduce hospital readmissions, some studies have actually found the opposite,^6,7 or have yielded conflicting evidence.^8-13 Skyrocketing costs of health care have brought hospital readmissions to the forefront of health system redesign efforts.^14-16

Section 3025 of the Affordable Care Act added section 1886(q) to the Social Security Act establishing the Hospital Readmissions Reduction Program, which requires Centers for Medicare & Medicaid Services to reduce payments to hospitals with excess readmissions.¹⁷ This change was introduced on October 1, 2012 and has precipitated discussion across the country about the prevention of unnecessary hospital readmissions.^18,19

Compared with usual care, this multicomponent intervention more successfully reduced readmissions. Patient factors contributing to hospital readmissions. Concerns patients cite most frequently as contributors to relapse and readmission are 1) feeling unprepared for discharge; 2) difficulty performing activities of daily living; 3) trouble adhering to discharge medications; 4) difficulty accessing discharge medications; and 5) lack of social support.²⁰ While multiple tools have been developed to better assess unplanned readmissions—including the Identification of Seniors at Risk, the Flemish version of the Triage Risk Screening Tool, and Variable Indicative of Placement risk—none of these have accurately predicted unplanned readmission in older, hospitalized patients.²¹ Predicting which patients will require readmission remains elusive,²² though some new models show promise.²³ z

Targeted interventions that show promise. Postdischarge telephone follow-up has been shown to reduce hospital readmissions,^24,25 and a direct correlation has been observed between the timing of the intervention and readmission rates, with interventions implemented closer to the date of discharge being associated with greater reductions in the number of readmissions.²⁶ Additionally, multicomponent interventions with both pre- and postdischarge elements that specifically target high-risk populations appear to be more effective in reducing readmissions than single-component interventions.²⁷

Hansen et al²⁸ identified a number of predischarge, postdischarge, and bridging interventions that could potentially reduce hospital readmissions (TABLE 1). No single intervention implemented alone consistently reduced the risk for 30-day rehospitalization.²⁸ One multicomponent intervention that has reduced readmissions for patients with heart failure or acute myocardial infarction is a transition coach, who visits patients in the hospital and sees them again in clinic for follow-up appointments. The coach also calls patients between face-to-face visits to review treatment plans and answer questions.²⁹

The impetus for our study. The patient-centered medical home (PCMH) has been gaining traction as a mechanism to improve patient care while reducing health care spending.^30,31 An intensive multidimensional medical home model introduced into 11 primary care practices proved capable of significantly reducing admissions and readmissions for Medicare Advantage members.³² Additionally, intelligently leveraging clinical information technology is likely to be critical in reducing readmissions.³³ The purpose of our observational study was to examine the impact of a multicomponent intervention on 30-day hospital readmissions over 12 months.

METHODS

Study setting and preintervention practice routines in 2 patient groups

The study setting for Group 1 involved patients with assigned primary care providers (PCPs) in a university-based practice group at 4 outpatient clinics. The study setting for Group 2 included patients with assigned PCPs from county and community health centers, involving 12 primary care clinics in total. While the groups’ patient populations were distinguished for descriptive purposes, in practice the patients were admitted to the same inpatient treatment teams and university-based hospital in a metropolitan setting. For both groups, the primary care practices admitted patients to the hospital directly from clinic or through the emergency department (ED).

An admitting team from one of the inpatient services completed the admission, initiated treatment, and discharged patients. Preintervention, limited discharge case management occurred at the hospital, driven primarily by the treating team’s requests. The admitting team also attempted to schedule outpatient follow-up appointments with an available PCP at the patient’s primary clinic after discharge. Obstacles to successful appointment scheduling prior to discharge included but were not limited to discharges over weekends or holidays or after clinic hours. Additionally, for both groups, discharge summaries were sent to the PCP either electronically via the electronic medical record (EMR) or via system-generated automated fax.

Creating a culture of continuity in Group 1

Transformation of outpatient activities. We developed several important processes to transform the patient experience through hospitalization and discharge. Together, these processes created a “culture of continuity” to prevent avoidable readmissions. We introduced an innovative, systematic approach to notifying the clinic and primary care clinician about initial admission. We also gave notification immediately upon discharge, rather than waiting until after discharge, as had been occurring. This patient-centered change engaged the primary care team in the care of the patient while hospitalized and during discharge planning; it actively ensured that follow-up appointments occurred within 1 week after discharge. Prior to this intervention, there was no system for ensuring timely follow-up after hospital discharge. The new expectation for the ambulatory clinics was that clinic staff could “reach in” to the patient during the hospital stay and actively contact the patient before discharge to schedule a postdischarge appointment at the patient’s convenience. This patient-centered change engaged the primary care team in the care of the patient while hospitalized and during discharge planning. 

The 4 practices had embraced and implemented the PCMH model, a core component of which is care coordination.^34,35 Each clinic appointed a registered nurse (RN) to serve as a team-based care manager (CM) for patients being discharged from the hospital. Responsibilities included fielding calls or electronic communications from the inpatient team, developing a hospital follow-up workflow, developing a standardized list of questions to ask each patient after discharge, and calling patients to ensure a follow-up appointment was scheduled, ideally within 2 to 3 days and at least within 7 days of discharge. The CM prioritized scheduling follow-up appointments with the patient’s PCP to ensure the highest level of continuity.

In addition to patient-specific documents, CMs received electronic reports from inpatient teams (including from the ED, medical and surgical intensive care units, and surgery) listing all Group 1 patients discharged from the hospital. Reports were run daily and allowed the outpatient clinic staff and CMs to verify patients against previous lists of anticipated discharges, and to generate their own lists. The CMs would then make follow-up phone calls and ensure that appointments were scheduled for these patients.

Medical directors at the 4 clinics received monthly summary reports profiling clinical activities related to hospitalizations. A data team (led by author SF) created the reports, which initially focused on care delivered in ambulatory settings (and included the development of a “balanced scorecard” to assess quality of care, financial productivity, and operational efficiency³⁶). The data team developed new reports specifically for hospital admissions, discharges, and readmissions, identifying:
• all patients admitted by inpatient team
• the number and percentage of patients who were readmitted within 30 days
• the number and percentage of patients who had received a follow-up phone call or electronic communication from the outpatient team
• the number of patients who had follow-up visits after discharge within 7 and 30 days
• the number of patients who had clinic visits prior to readmission
• all patients discharged from any service within the prior 24 hours.

On the first or second day of admission, a follow-up document was electronically routed to the administrative support staff, office nurse, and primary care physician.These reports, which had patient drilldown capability, were forwarded to all providers and teams at each clinic by the medical director. Teams at each clinic were then charged with analyzing the readmissions, identifying high-risk patients, and improving the coordination of care for these patients, including the use of RN/clinician co-visits and proactive outreach from the team-based nurses and staff.

Transformation of inpatient activities. We reorganized inpatient teams to include clinician representatives from the clinics whose patients were being treated. This process ensured better continuity of experience and familiarity with the environment of care and discharge/follow-up processes for both patients and all providers.

Additionally, inpatient teams developed new workflows to ensure that all involved members of the outpatient team were well informed of the hospitalization process. On the first or second day of admission, a hospital follow-up document was electronically routed to the administrative support staff, the PCP team nurse, and the PCP (FIGURE 1). An integrated EMR created a link between the hospital and all ambulatory practices that allowed for real-time transmission of patient information. The document identified the timing of a follow-up appointment and requested a 48-hour phone call from the team nurse after hospital discharge. The inpatient team also included a concise summary of the hospitalization for the PCP, to aid in anticipating patient discharge and any impending needs. The document was retrievable and traceable in the EMR.

Study groups and statistical analysis

The Oregon Health & Science University’s Institutional Review Board (IRB#9768) determined this study was not human subjects research because the proposed activity did not meet the definition of human subject per 45 CFR 46.102(f). The board made this determination because our analysis file included only hospital readmission rates and no patient-level data.

Adult patients admitted by the inpatient teams consisted of 2 distinct populations: patients whose PCP practiced at one of the 4 outpatient clinics (Group 1 patients); and patients admitted from other, unaffiliated clinics (Group 2 patients). In contrast to the transformations in patient care described in Group 1, care provided to Group 2 patients was considered usual care, as there was no interface between outpatient and inpatient teams to revise operations. Patients in either group were excluded from analyses if they died during the hospitalization. Maternity patients were also excluded.

An integrated EMR created a link between the hospital and all ambulatory practices that allowed for real-time transmission of patient information. We identified the percentage of patients readmitted within 30 days of a hospital admission using administrative data sources, which underwent careful data checking and validation, and were sub-grouped according to whether the patients were in Group 1 or Group 2. We used group-specific and overall linear regression to examine the changes in percentage of readmission within 30 days of discharge in the 2 study groups over 12 months, including a model that specifically assessed the interaction between Group 1 readmission percentages and those in Group 2. We considered a P-value ≤.05 to be significant in this exploratory study.

RESULTS

Patient readmissions decreased significantly

Our analysis included 961 patients; 685 patients (71.3%) were in Group 1, and 276 (28.7%) were in Group 2 (Table 2). The distribution of patient gender and mean age was similar within groups for patients readmitted and not readmitted during the study period. Among patients readmitted, the mean hospital length of stay was 5.8 days and 7.1 days for Group 1 and Group 2, respectively. Among those not readmitted, the mean hospital length of stay was 4.3 and 4.9 in Group 1 and 2, respectively.

Multicomponent interventions are more successful at reducing readmissions than single-component interventions.The percentage of patients readmitted per month ranged from 28.1% to 7.1% in Group 1 and 27.8% to 5.9% in Group 2 (Figure 2). Patient readmissions in Group 1 decreased significantly from 27% in May 2012 to 7.1% in April 2013 with an R2 of 0.43 (P=.02). Readmissions of patients in Group 2 were more variable; 26.1% in May 2012 and 25.9% in April 2013 with a non-significant R2 of 0.04 (P=.53). The regression model (unadjusted) that compared the interaction between Group 1 and Group 2 readmissions over the study period was significant, indicating a decrease in readmissions in Group 1 and no strong correlation between usual care and readmissions over time in Group 2 (P=.05).

DISCUSSION

Implementing intensive coordinated care management and transition processes in a group of primary care clinics appears to significantly decrease hospital readmissions for patients in Group 1, compared with those in Group 2 who received usual care. While it is possible that some of the ambulatory practices in Group 2 admitting patients to the inpatient services were using or developing care coordination programs including hospital follow-up, none of these providers or groups interfaced with the inpatient teams in this study. We are, therefore, confident that Group 2 providers were not undertaking any new or novel activities that reached in to hospital inpatient services to improve care coordination.

Our findings are consistent with the literature review conducted by Scott et al,²⁷ which found that multicomponent interventions are more successful at reducing readmissions than single-component interventions. In our Group 1 clinics, we implemented 8 of the 12 predischarge, postdischarge, and bridging interventions identified by Hansen et al²⁸ (medication reconciliation, discharge planning, scheduling of a follow-up appointment before discharge, follow-up telephone calls, timely communication with ambulatory providers, timely ambulatory provider follow-up, physician continuity across the inpatient and outpatient setting, and patient-centered discharge instructions). 

Study strengths and weaknesses. The strengths of this study include means and quality of data capture for hospital readmission rates in the study setting. Limitations include the small sample sizes, which did not allow us to conduct a multivariable adjusted analysis that would have taken into account patient characteristics, seasons, and temporal correlations. These covariates might drive study findings in a way that results in us drawing inaccurate conclusions—the analysis we conducted (unadjusted) assumed that the events that occurred in each month were unrelated to what might have occurred in the prior month or subsequent month.

Patients in the 2 study groups did exhibit differences that could have contributed to our findings. For example, the average length of stay for Group 2 patients was longer by just over 1 day compared with that in Group 1. This may suggest Group 2 patients were sicker, and thus may have needed to be readmitted within 30 days of their discharge. We cannot know for certain that patients in Group 1 were less ill, as this would require a more discriminating study design. As with many studies, additional questions arise, but these serve to further a line of research that is vitally important.

Creating a culture of continuity is an important aspect of the patient-centered medical home.Another factor that could have affected our findings is that Group 1 patient readmission rates started off higher than the Group 2 patients, so there is a chance that regression to the mean rather than changes in clinical care could have contributed to some of the decrease in Group 1 readmission rates. There are potential subject-level, provider-level, and clinic-level factors that could have been used to adjust for potential confounding. Future studies could address these factors. Longer study follow-up would provide an even better picture of the difference between the groups.

A multicomponent intervention works. Creating a culture of continuity is an important aspect of PCMH. Not all primary care clinics or PCMHs may have built-in relationships for inpatient care of their patients. We would argue that outpatient adoption of the enhanced “reaching in” and a multicomponent intervention would have a significant positive impact on patient care and improve the transition from in- to outpatient care, and likely reduce readmissions.

CORRESPONDENCE
Brett White, MD, 4411 SW Vermont St, Portland, OR 97219; [email protected]

The authors gratefully acknowledge the clinic and inpatient physicians and staffs as well as the Research Program in the Department of Family Medicine, Oregon Health & Science University.

To the Editor: Regarding the case of tetany presented by Drs. Shaheen and Merugu in the June 2013 issue of Cleveland Clinic Journal of Medicine (pages 360–362), their clinical discussion was right on, but they did not mention the clinical use of and need for ionized calcium levels in a case like this and the follow-up to confirm this was not a patient with latent hypoparathyroidism.

There is often a major discrepancy between the total calcium (no matter how it is “corrected”) and the free (ionized) calcium value, and the need to follow it during the correction phase of both hypercalcemia and hypocalcemia is critical.

To the Editor: Regarding the case of tetany presented by Drs. Shaheen and Merugu in the June 2013 issue of Cleveland Clinic Journal of Medicine (pages 360–362), their clinical discussion was right on, but they did not mention the clinical use of and need for ionized calcium levels in a case like this and the follow-up to confirm this was not a patient with latent hypoparathyroidism.

There is often a major discrepancy between the total calcium (no matter how it is “corrected”) and the free (ionized) calcium value, and the need to follow it during the correction phase of both hypercalcemia and hypocalcemia is critical.

To the Editor: Regarding the case of tetany presented by Drs. Shaheen and Merugu in the June 2013 issue of Cleveland Clinic Journal of Medicine (pages 360–362), their clinical discussion was right on, but they did not mention the clinical use of and need for ionized calcium levels in a case like this and the follow-up to confirm this was not a patient with latent hypoparathyroidism.

There is often a major discrepancy between the total calcium (no matter how it is “corrected”) and the free (ionized) calcium value, and the need to follow it during the correction phase of both hypercalcemia and hypocalcemia is critical.

In Reply: Generally, it is preferable to measure the ionized calcium directly, particularly if there is uncertainty about whether the corrected serum calcium is reflective of the ionized calcium, if the patient’s symptoms are atypical, or if a reliable laboratory is available to measure ionized calcium.

Direct measurement of the ionized calcium concentration could be favored compared with measuring the corrected calcium in patients with symptoms of hypocalcemia in the setting of a normal total calcium concentration. Symptomatic hypocalcemia with normal total calcium but low ionized calcium can occasionally occur in patients with acute respiratory alkalosis due to increased binding of calcium to albumin. Thus, respiratory alkalosis may cause an acute decrease in ionized calcium. Furthermore, the ionized fraction can change without an alteration in the total serum calcium concentration, as with hyperparathyroidism, which increases the ionized calcium at the expense of that bound to albumin, and hyperphosphatemia, which increases the fraction bound to inorganic anions, decreasing ionized calcium. In patients who have chronic kidney disease and a low serum bicarbonate or a low serum albumin, or both, measuring the ionized calcium is preferable to measuring the total calcium in order to diagnose hypocalcemia or hypercalcemia.

The patient was given oral magnesium, potassium, calcium, and vitamin D to continue at home. In addition, she was advised to avoid excessive alcohol consumption, and she was followed by her primary care doctor. All the laboratory values normalized within 1 month of abstinence from alcohol, and she has been well since. We agree regarding the importance of checking on the ionized calcium to confirm the hypocalcemia and normalization after treatment as stated above. Ionized calcium was never checked during the hospital stay or during the follow-up after the discharge.

In Reply: Generally, it is preferable to measure the ionized calcium directly, particularly if there is uncertainty about whether the corrected serum calcium is reflective of the ionized calcium, if the patient’s symptoms are atypical, or if a reliable laboratory is available to measure ionized calcium.

Direct measurement of the ionized calcium concentration could be favored compared with measuring the corrected calcium in patients with symptoms of hypocalcemia in the setting of a normal total calcium concentration. Symptomatic hypocalcemia with normal total calcium but low ionized calcium can occasionally occur in patients with acute respiratory alkalosis due to increased binding of calcium to albumin. Thus, respiratory alkalosis may cause an acute decrease in ionized calcium. Furthermore, the ionized fraction can change without an alteration in the total serum calcium concentration, as with hyperparathyroidism, which increases the ionized calcium at the expense of that bound to albumin, and hyperphosphatemia, which increases the fraction bound to inorganic anions, decreasing ionized calcium. In patients who have chronic kidney disease and a low serum bicarbonate or a low serum albumin, or both, measuring the ionized calcium is preferable to measuring the total calcium in order to diagnose hypocalcemia or hypercalcemia.

The patient was given oral magnesium, potassium, calcium, and vitamin D to continue at home. In addition, she was advised to avoid excessive alcohol consumption, and she was followed by her primary care doctor. All the laboratory values normalized within 1 month of abstinence from alcohol, and she has been well since. We agree regarding the importance of checking on the ionized calcium to confirm the hypocalcemia and normalization after treatment as stated above. Ionized calcium was never checked during the hospital stay or during the follow-up after the discharge.

In Reply: Generally, it is preferable to measure the ionized calcium directly, particularly if there is uncertainty about whether the corrected serum calcium is reflective of the ionized calcium, if the patient’s symptoms are atypical, or if a reliable laboratory is available to measure ionized calcium.

Direct measurement of the ionized calcium concentration could be favored compared with measuring the corrected calcium in patients with symptoms of hypocalcemia in the setting of a normal total calcium concentration. Symptomatic hypocalcemia with normal total calcium but low ionized calcium can occasionally occur in patients with acute respiratory alkalosis due to increased binding of calcium to albumin. Thus, respiratory alkalosis may cause an acute decrease in ionized calcium. Furthermore, the ionized fraction can change without an alteration in the total serum calcium concentration, as with hyperparathyroidism, which increases the ionized calcium at the expense of that bound to albumin, and hyperphosphatemia, which increases the fraction bound to inorganic anions, decreasing ionized calcium. In patients who have chronic kidney disease and a low serum bicarbonate or a low serum albumin, or both, measuring the ionized calcium is preferable to measuring the total calcium in order to diagnose hypocalcemia or hypercalcemia.

The patient was given oral magnesium, potassium, calcium, and vitamin D to continue at home. In addition, she was advised to avoid excessive alcohol consumption, and she was followed by her primary care doctor. All the laboratory values normalized within 1 month of abstinence from alcohol, and she has been well since. We agree regarding the importance of checking on the ionized calcium to confirm the hypocalcemia and normalization after treatment as stated above. Ionized calcium was never checked during the hospital stay or during the follow-up after the discharge.

To the Editor: We found Dr. Vouyiouklis’s article about the recently approved sodium-glucose cotransport 2 (SGLT) inhibitor canagliflozin very useful. However, we strongly believe there are some issues that should be addressed.

In discussing the canagliflozin trials, Dr. Vouyiouklis did not mention a phase III randomized, double-blind, double-arm study, in which canagliflozin (100 and 300 mg) in addition to metformin was compared with placebo and sitagliptin (100 mg) in patients with type 2 diabetes.¹ This study recruited 1,284 participants in 22 countries. At week 52, hemoglobin A_1c levels had declined by 0.73% in the sitagliptin group, 0.73% in the canagliflozin 100 mg group, and 0.88% in the canagliflozin 300 mg group. Thus, canagliflozin 100 mg demonstrated noninferiority, and canagliflozin 300 mg demonstrated superiority. In addition, as previously described by other trials, a significant statistical reduction was observed in weight and blood pressure with modest elevations in LDL cholesterol and the incidence of mycotic urinary infections.

Current guidelines and recommendations give a wide variety of therapeutic options as the second step if lifestyle interventions and metformin fail to achieve glycemic control.² The best combination regimen is still debated and, because of their excellent side-effect profile, dipeptidyl peptidase-4 inhibitors (gliptins) are one of the most used therapeutic classes. We believe this study adds important evidence that could help with decision-making in routine clinical practice.

Also, canagliflozin’s favorable effects on weight and blood pressure inevitably lead to the question, Are the weight loss and decreased systolic blood pressure due to osmotic diuresis or to lean or body fat weight loss? The mechanism of action of SGLT2 inhibitors, per se, favors osmotic diuresis, and several trials have demonstrated this same effect, as well as postural dizziness and orthostatic hypotension.^3,4 Until now, the exact cause of this weight loss has not been elucidated, and no trial has demonstrated with precision a reduction in lean or fat body weight as a direct effect of SGLT2 inhibitors. This, in addition to LDL elevation, could have important clinical implications, as diuretic osmosis will subsequently activate the renin-angiotensin-aldosterone system. This might initially blunt this blood pressure reduction and promote parasympathetic inhibition, sympathetic activation, and myocardial and vascular fibrosis that can potentially lead in the long term to adverse cardiovascular outcomes.⁵

To the Editor: We found Dr. Vouyiouklis’s article about the recently approved sodium-glucose cotransport 2 (SGLT) inhibitor canagliflozin very useful. However, we strongly believe there are some issues that should be addressed.

In discussing the canagliflozin trials, Dr. Vouyiouklis did not mention a phase III randomized, double-blind, double-arm study, in which canagliflozin (100 and 300 mg) in addition to metformin was compared with placebo and sitagliptin (100 mg) in patients with type 2 diabetes.¹ This study recruited 1,284 participants in 22 countries. At week 52, hemoglobin A_1c levels had declined by 0.73% in the sitagliptin group, 0.73% in the canagliflozin 100 mg group, and 0.88% in the canagliflozin 300 mg group. Thus, canagliflozin 100 mg demonstrated noninferiority, and canagliflozin 300 mg demonstrated superiority. In addition, as previously described by other trials, a significant statistical reduction was observed in weight and blood pressure with modest elevations in LDL cholesterol and the incidence of mycotic urinary infections.

Current guidelines and recommendations give a wide variety of therapeutic options as the second step if lifestyle interventions and metformin fail to achieve glycemic control.² The best combination regimen is still debated and, because of their excellent side-effect profile, dipeptidyl peptidase-4 inhibitors (gliptins) are one of the most used therapeutic classes. We believe this study adds important evidence that could help with decision-making in routine clinical practice.

Also, canagliflozin’s favorable effects on weight and blood pressure inevitably lead to the question, Are the weight loss and decreased systolic blood pressure due to osmotic diuresis or to lean or body fat weight loss? The mechanism of action of SGLT2 inhibitors, per se, favors osmotic diuresis, and several trials have demonstrated this same effect, as well as postural dizziness and orthostatic hypotension.^3,4 Until now, the exact cause of this weight loss has not been elucidated, and no trial has demonstrated with precision a reduction in lean or fat body weight as a direct effect of SGLT2 inhibitors. This, in addition to LDL elevation, could have important clinical implications, as diuretic osmosis will subsequently activate the renin-angiotensin-aldosterone system. This might initially blunt this blood pressure reduction and promote parasympathetic inhibition, sympathetic activation, and myocardial and vascular fibrosis that can potentially lead in the long term to adverse cardiovascular outcomes.⁵

To the Editor: We found Dr. Vouyiouklis’s article about the recently approved sodium-glucose cotransport 2 (SGLT) inhibitor canagliflozin very useful. However, we strongly believe there are some issues that should be addressed.

In discussing the canagliflozin trials, Dr. Vouyiouklis did not mention a phase III randomized, double-blind, double-arm study, in which canagliflozin (100 and 300 mg) in addition to metformin was compared with placebo and sitagliptin (100 mg) in patients with type 2 diabetes.¹ This study recruited 1,284 participants in 22 countries. At week 52, hemoglobin A_1c levels had declined by 0.73% in the sitagliptin group, 0.73% in the canagliflozin 100 mg group, and 0.88% in the canagliflozin 300 mg group. Thus, canagliflozin 100 mg demonstrated noninferiority, and canagliflozin 300 mg demonstrated superiority. In addition, as previously described by other trials, a significant statistical reduction was observed in weight and blood pressure with modest elevations in LDL cholesterol and the incidence of mycotic urinary infections.

Current guidelines and recommendations give a wide variety of therapeutic options as the second step if lifestyle interventions and metformin fail to achieve glycemic control.² The best combination regimen is still debated and, because of their excellent side-effect profile, dipeptidyl peptidase-4 inhibitors (gliptins) are one of the most used therapeutic classes. We believe this study adds important evidence that could help with decision-making in routine clinical practice.

Also, canagliflozin’s favorable effects on weight and blood pressure inevitably lead to the question, Are the weight loss and decreased systolic blood pressure due to osmotic diuresis or to lean or body fat weight loss? The mechanism of action of SGLT2 inhibitors, per se, favors osmotic diuresis, and several trials have demonstrated this same effect, as well as postural dizziness and orthostatic hypotension.^3,4 Until now, the exact cause of this weight loss has not been elucidated, and no trial has demonstrated with precision a reduction in lean or fat body weight as a direct effect of SGLT2 inhibitors. This, in addition to LDL elevation, could have important clinical implications, as diuretic osmosis will subsequently activate the renin-angiotensin-aldosterone system. This might initially blunt this blood pressure reduction and promote parasympathetic inhibition, sympathetic activation, and myocardial and vascular fibrosis that can potentially lead in the long term to adverse cardiovascular outcomes.⁵

To the Editor: In a recent CCJM review of canagliflozin,¹ this novel antihyperglycemic medication was noted to be associated with a dose-dependent increase in low-density lipoprotein (LDL) cholesterol, with an increase in LDL of 8.3 mg/dL (0.215 mmol/L) seen with the 300-mg/day dose of canagliflozin.

The Cholesterol Treatment Trialists’ (CTT) meta-analysis² showed a significant 21% proportional reduction in major vascular events per 1.0 mmol/L reduction in LDL cholesterol in people with diabetes treated with statins over an average of 4.3 years. If we assume that raising LDL cholesterol by 1.0 mmol/L has the opposite effect, then patients taking 300 mg per day of canagliflozin would be expected to suffer an increase in major vascular events of about 4.5% over 4.3 years. Put another way, for every 22 diabetic patients treated with canagliflozin over 4.3 years, one additional major vascular event would be expected on the basis of the associated increase in LDL cholesterol.

The CTT data also showed a significant 9% decrease in all-cause mortality for every 1.0 mmol/L decrease in LDL cholesterol. Again, assuming that raising LDL has the opposite effect of lowering it, then we should expect an additional death for each 52 diabetic patients treated with 300 mg/day of canagliflozin per day for 4.3 years.

The hypotensive side effect of canagliflozin might tend to mitigate some of the above adverse effects, as might its antihyperglycemic effect. Still, it would seem prudent to use this novel agent only as a second- or third-line choice, particularly in diabetic patients who have already suffered a major vascular event.

To the Editor: In a recent CCJM review of canagliflozin,¹ this novel antihyperglycemic medication was noted to be associated with a dose-dependent increase in low-density lipoprotein (LDL) cholesterol, with an increase in LDL of 8.3 mg/dL (0.215 mmol/L) seen with the 300-mg/day dose of canagliflozin.

The Cholesterol Treatment Trialists’ (CTT) meta-analysis² showed a significant 21% proportional reduction in major vascular events per 1.0 mmol/L reduction in LDL cholesterol in people with diabetes treated with statins over an average of 4.3 years. If we assume that raising LDL cholesterol by 1.0 mmol/L has the opposite effect, then patients taking 300 mg per day of canagliflozin would be expected to suffer an increase in major vascular events of about 4.5% over 4.3 years. Put another way, for every 22 diabetic patients treated with canagliflozin over 4.3 years, one additional major vascular event would be expected on the basis of the associated increase in LDL cholesterol.

The CTT data also showed a significant 9% decrease in all-cause mortality for every 1.0 mmol/L decrease in LDL cholesterol. Again, assuming that raising LDL has the opposite effect of lowering it, then we should expect an additional death for each 52 diabetic patients treated with 300 mg/day of canagliflozin per day for 4.3 years.

The hypotensive side effect of canagliflozin might tend to mitigate some of the above adverse effects, as might its antihyperglycemic effect. Still, it would seem prudent to use this novel agent only as a second- or third-line choice, particularly in diabetic patients who have already suffered a major vascular event.

To the Editor: In a recent CCJM review of canagliflozin,¹ this novel antihyperglycemic medication was noted to be associated with a dose-dependent increase in low-density lipoprotein (LDL) cholesterol, with an increase in LDL of 8.3 mg/dL (0.215 mmol/L) seen with the 300-mg/day dose of canagliflozin.

The Cholesterol Treatment Trialists’ (CTT) meta-analysis² showed a significant 21% proportional reduction in major vascular events per 1.0 mmol/L reduction in LDL cholesterol in people with diabetes treated with statins over an average of 4.3 years. If we assume that raising LDL cholesterol by 1.0 mmol/L has the opposite effect, then patients taking 300 mg per day of canagliflozin would be expected to suffer an increase in major vascular events of about 4.5% over 4.3 years. Put another way, for every 22 diabetic patients treated with canagliflozin over 4.3 years, one additional major vascular event would be expected on the basis of the associated increase in LDL cholesterol.

The CTT data also showed a significant 9% decrease in all-cause mortality for every 1.0 mmol/L decrease in LDL cholesterol. Again, assuming that raising LDL has the opposite effect of lowering it, then we should expect an additional death for each 52 diabetic patients treated with 300 mg/day of canagliflozin per day for 4.3 years.

The hypotensive side effect of canagliflozin might tend to mitigate some of the above adverse effects, as might its antihyperglycemic effect. Still, it would seem prudent to use this novel agent only as a second- or third-line choice, particularly in diabetic patients who have already suffered a major vascular event.

In Reply: I would like to thank these readers very much for their response and comments.

Additional data provided from the study conducted by Lavalle-González et al evaluating the efficacy and safety of canagliflozin (100-mg and 300-mg doses) vs placebo and sitagliptin in patients with type 2 diabetes showed similar findings in weight and blood pressure reduction with slight LDL elevation with the studies mentioned in my article.¹ At 52 weeks, as noted, canagliflozin 100 mg demonstrated noninferiority, and canagliflozin 300 mg showed a statistically significant superiority to sitagliptin in lowering hemoglobin A_1c (a change of −0.73% with canagliflozin 100 mg, −0.88% with canagliflozin 300 mg, and −0.73% with sitagliptin), which may be considered in treatment decisions along with the other possible effects of this drug.¹

The decision to use canagliflozin as second-or third-line therapy should be individualized after considering all of the patient’s risk factors as well as the potential benefit vs side effectsof this drug. Metformin remains my first-line choice in the management of type 2 diabetes. In my clinical practice, thus far, I have not used canagliflozin in patients with known coronary disease or a history of cardiovascular events. I have ensured that the LDL is certainly below goal before starting any patient on this drug, and I have followed the LDL closely, without hesitating to increase the statin drug to keep the LDL below goal. I agree that the slight increase of LDL is of concern, and certainly long-term studies are necessary to see whether there will be any increase in cardiovascular events from the use of canagliflozin.

In Reply: I would like to thank these readers very much for their response and comments.

Additional data provided from the study conducted by Lavalle-González et al evaluating the efficacy and safety of canagliflozin (100-mg and 300-mg doses) vs placebo and sitagliptin in patients with type 2 diabetes showed similar findings in weight and blood pressure reduction with slight LDL elevation with the studies mentioned in my article.¹ At 52 weeks, as noted, canagliflozin 100 mg demonstrated noninferiority, and canagliflozin 300 mg showed a statistically significant superiority to sitagliptin in lowering hemoglobin A_1c (a change of −0.73% with canagliflozin 100 mg, −0.88% with canagliflozin 300 mg, and −0.73% with sitagliptin), which may be considered in treatment decisions along with the other possible effects of this drug.¹

The decision to use canagliflozin as second-or third-line therapy should be individualized after considering all of the patient’s risk factors as well as the potential benefit vs side effectsof this drug. Metformin remains my first-line choice in the management of type 2 diabetes. In my clinical practice, thus far, I have not used canagliflozin in patients with known coronary disease or a history of cardiovascular events. I have ensured that the LDL is certainly below goal before starting any patient on this drug, and I have followed the LDL closely, without hesitating to increase the statin drug to keep the LDL below goal. I agree that the slight increase of LDL is of concern, and certainly long-term studies are necessary to see whether there will be any increase in cardiovascular events from the use of canagliflozin.

In Reply: I would like to thank these readers very much for their response and comments.

Additional data provided from the study conducted by Lavalle-González et al evaluating the efficacy and safety of canagliflozin (100-mg and 300-mg doses) vs placebo and sitagliptin in patients with type 2 diabetes showed similar findings in weight and blood pressure reduction with slight LDL elevation with the studies mentioned in my article.¹ At 52 weeks, as noted, canagliflozin 100 mg demonstrated noninferiority, and canagliflozin 300 mg showed a statistically significant superiority to sitagliptin in lowering hemoglobin A_1c (a change of −0.73% with canagliflozin 100 mg, −0.88% with canagliflozin 300 mg, and −0.73% with sitagliptin), which may be considered in treatment decisions along with the other possible effects of this drug.¹

The decision to use canagliflozin as second-or third-line therapy should be individualized after considering all of the patient’s risk factors as well as the potential benefit vs side effectsof this drug. Metformin remains my first-line choice in the management of type 2 diabetes. In my clinical practice, thus far, I have not used canagliflozin in patients with known coronary disease or a history of cardiovascular events. I have ensured that the LDL is certainly below goal before starting any patient on this drug, and I have followed the LDL closely, without hesitating to increase the statin drug to keep the LDL below goal. I agree that the slight increase of LDL is of concern, and certainly long-term studies are necessary to see whether there will be any increase in cardiovascular events from the use of canagliflozin.