Clinical Inquiries

Evidence summary

Inhaled corticosteroids are the primary therapy for asthma and are commonly prescribed for chronic obstructive pulmonary disease. The use of oral steroids is a well-known risk factor for osteoporosis, but the effects of inhaled corticosteroids on bone mineral density (BMD) are not well defined.

No significant changes seen in BMD at moderate doses

Our search found evidence pertaining to the use of inhaled pulmonary steroids, but no evidence meeting our inclusion criteria about the effect of inhaled nasal steroids. We located a Cochrane review, 1 other meta-analysis, and 2 individual RCTs that were not included in the systematic reviews. Three of the 7 RCTs included in the 2002 Cochrane review met our inclusion criteria for evaluating the impact of inhaled corticosteroids on BMD or fracture rate for adults with asthma or COPD.

All 3 RCTs (792 subjects total) examined the effect of conventional doses of inhaled corticosteroids on BMD and 2 of the RCTs (892 participants total) collected fracture data. No demonstrable effect was seen on vertebral fracture (odds ratio [OR]=1.87; 95% confidence interval [CI], 0.5–7.03) or BMD at 2 years follow-up.¹ The subjects were otherwise healthy people with asthma or COPD with an average age of 40 years; men outnumbered women 2 to 1.

A fair-quality 2004 meta-analysis of 14 randomized trials (2300 participants) included 2 studies (448 subjects) that overlapped with the Cochrane review. There were no significant changes in BMD with moderately high doses of inhaled corticosteroids at 1 to 3 years follow-up.²

Annual changes in lumbar and femoral neck BMD (–0.23% and –0.17%, respectively) were not statistically significant. Mean changes in lumbar BMD were not significantly different from controls (–0.02). A fair-quality 2004 RCT did not demonstrate any clinically relevant effect on BMD at 2 years follow-up. This study used 800 mcg/day of fluticasone for patients with mild asthma.³

BMD changes found at higher doses

There is, however, some evidence that higher doses of inhaled corticosteroids can result in adverse BMD changes. In a high-quality RCT of 412 participants, aged 40 to 69 years, with mild to moderate COPD, use of higher-dose triamcinolone (1200 mcg/day) was associated with decreased lumbar and femoral neck BMD over 3 to 4 years.⁴ The differences in BMD between the inhaled corticosteroids and placebo groups at the femoral neck and lumbar spine were 1.78% (P<.001) and 1.33% (P=.007), respectively. However, the risk of fracture or height loss did not increase at follow-up.

A large fair-quality RCT from 2001 included in both meta-analyses demonstrated a dose-related fall in BMD within the subjects over 2 years at the lumbar spine (standard deviation, 3.4%; P<.010). This finding remained statistically significant after adjusting for asthma severity, but BMD changes were not different between the inhaled corticosteroids and placebo groups. However, this finding may be the result of higher oral corticosteroids use in the reference group.⁵

Limitations of these studies

These studies, though, have limitations. The follow-up periods for all of these studies are less than 5 years, and thus the longer-term effects of prolonged use of inhaled corticosteroids on BMD or fracture risk cannot be determined with this evidence. Furthermore, the study populations were relatively young, with few other risk factors (they were, for example, predominantly male) than populations at highest risk for osteoporosis and fracture. These factors limit interpretation of the data for long-term inhaled corticosteroids use, particularly in populations with higher baseline osteoporosis risk—older persons with chronic lung disease who take inhaled corticosteroids for more than 2 to 3 years. We need better and longer-term studies to help advise our patients about the risks and benefits of inhaled corticosteroids therapy.

Recommendations from others

The New Zealand Guideline Group says the risk of reduced BMD increased with long-term, high-dose inhaled corticosteroids.⁶ The Institute for Clinical Systems Improvement guidelines recommends considering osteoporosis prevention measures for those who have been (or will be) taking a daily high-dose inhaled glucocorticoid for several years as glucocorticoid use compounds fracture risk beyond that determined solely by BMD.⁷

Evidence summary

Inhaled corticosteroids are the primary therapy for asthma and are commonly prescribed for chronic obstructive pulmonary disease. The use of oral steroids is a well-known risk factor for osteoporosis, but the effects of inhaled corticosteroids on bone mineral density (BMD) are not well defined.

No significant changes seen in BMD at moderate doses

Our search found evidence pertaining to the use of inhaled pulmonary steroids, but no evidence meeting our inclusion criteria about the effect of inhaled nasal steroids. We located a Cochrane review, 1 other meta-analysis, and 2 individual RCTs that were not included in the systematic reviews. Three of the 7 RCTs included in the 2002 Cochrane review met our inclusion criteria for evaluating the impact of inhaled corticosteroids on BMD or fracture rate for adults with asthma or COPD.

All 3 RCTs (792 subjects total) examined the effect of conventional doses of inhaled corticosteroids on BMD and 2 of the RCTs (892 participants total) collected fracture data. No demonstrable effect was seen on vertebral fracture (odds ratio [OR]=1.87; 95% confidence interval [CI], 0.5–7.03) or BMD at 2 years follow-up.¹ The subjects were otherwise healthy people with asthma or COPD with an average age of 40 years; men outnumbered women 2 to 1.

A fair-quality 2004 meta-analysis of 14 randomized trials (2300 participants) included 2 studies (448 subjects) that overlapped with the Cochrane review. There were no significant changes in BMD with moderately high doses of inhaled corticosteroids at 1 to 3 years follow-up.²

Annual changes in lumbar and femoral neck BMD (–0.23% and –0.17%, respectively) were not statistically significant. Mean changes in lumbar BMD were not significantly different from controls (–0.02). A fair-quality 2004 RCT did not demonstrate any clinically relevant effect on BMD at 2 years follow-up. This study used 800 mcg/day of fluticasone for patients with mild asthma.³

BMD changes found at higher doses

There is, however, some evidence that higher doses of inhaled corticosteroids can result in adverse BMD changes. In a high-quality RCT of 412 participants, aged 40 to 69 years, with mild to moderate COPD, use of higher-dose triamcinolone (1200 mcg/day) was associated with decreased lumbar and femoral neck BMD over 3 to 4 years.⁴ The differences in BMD between the inhaled corticosteroids and placebo groups at the femoral neck and lumbar spine were 1.78% (P<.001) and 1.33% (P=.007), respectively. However, the risk of fracture or height loss did not increase at follow-up.

A large fair-quality RCT from 2001 included in both meta-analyses demonstrated a dose-related fall in BMD within the subjects over 2 years at the lumbar spine (standard deviation, 3.4%; P<.010). This finding remained statistically significant after adjusting for asthma severity, but BMD changes were not different between the inhaled corticosteroids and placebo groups. However, this finding may be the result of higher oral corticosteroids use in the reference group.⁵

Limitations of these studies

These studies, though, have limitations. The follow-up periods for all of these studies are less than 5 years, and thus the longer-term effects of prolonged use of inhaled corticosteroids on BMD or fracture risk cannot be determined with this evidence. Furthermore, the study populations were relatively young, with few other risk factors (they were, for example, predominantly male) than populations at highest risk for osteoporosis and fracture. These factors limit interpretation of the data for long-term inhaled corticosteroids use, particularly in populations with higher baseline osteoporosis risk—older persons with chronic lung disease who take inhaled corticosteroids for more than 2 to 3 years. We need better and longer-term studies to help advise our patients about the risks and benefits of inhaled corticosteroids therapy.

Recommendations from others

The New Zealand Guideline Group says the risk of reduced BMD increased with long-term, high-dose inhaled corticosteroids.⁶ The Institute for Clinical Systems Improvement guidelines recommends considering osteoporosis prevention measures for those who have been (or will be) taking a daily high-dose inhaled glucocorticoid for several years as glucocorticoid use compounds fracture risk beyond that determined solely by BMD.⁷

Evidence summary

Inhaled corticosteroids are the primary therapy for asthma and are commonly prescribed for chronic obstructive pulmonary disease. The use of oral steroids is a well-known risk factor for osteoporosis, but the effects of inhaled corticosteroids on bone mineral density (BMD) are not well defined.

No significant changes seen in BMD at moderate doses

Our search found evidence pertaining to the use of inhaled pulmonary steroids, but no evidence meeting our inclusion criteria about the effect of inhaled nasal steroids. We located a Cochrane review, 1 other meta-analysis, and 2 individual RCTs that were not included in the systematic reviews. Three of the 7 RCTs included in the 2002 Cochrane review met our inclusion criteria for evaluating the impact of inhaled corticosteroids on BMD or fracture rate for adults with asthma or COPD.

All 3 RCTs (792 subjects total) examined the effect of conventional doses of inhaled corticosteroids on BMD and 2 of the RCTs (892 participants total) collected fracture data. No demonstrable effect was seen on vertebral fracture (odds ratio [OR]=1.87; 95% confidence interval [CI], 0.5–7.03) or BMD at 2 years follow-up.¹ The subjects were otherwise healthy people with asthma or COPD with an average age of 40 years; men outnumbered women 2 to 1.

A fair-quality 2004 meta-analysis of 14 randomized trials (2300 participants) included 2 studies (448 subjects) that overlapped with the Cochrane review. There were no significant changes in BMD with moderately high doses of inhaled corticosteroids at 1 to 3 years follow-up.²

Annual changes in lumbar and femoral neck BMD (–0.23% and –0.17%, respectively) were not statistically significant. Mean changes in lumbar BMD were not significantly different from controls (–0.02). A fair-quality 2004 RCT did not demonstrate any clinically relevant effect on BMD at 2 years follow-up. This study used 800 mcg/day of fluticasone for patients with mild asthma.³

BMD changes found at higher doses

There is, however, some evidence that higher doses of inhaled corticosteroids can result in adverse BMD changes. In a high-quality RCT of 412 participants, aged 40 to 69 years, with mild to moderate COPD, use of higher-dose triamcinolone (1200 mcg/day) was associated with decreased lumbar and femoral neck BMD over 3 to 4 years.⁴ The differences in BMD between the inhaled corticosteroids and placebo groups at the femoral neck and lumbar spine were 1.78% (P<.001) and 1.33% (P=.007), respectively. However, the risk of fracture or height loss did not increase at follow-up.

A large fair-quality RCT from 2001 included in both meta-analyses demonstrated a dose-related fall in BMD within the subjects over 2 years at the lumbar spine (standard deviation, 3.4%; P<.010). This finding remained statistically significant after adjusting for asthma severity, but BMD changes were not different between the inhaled corticosteroids and placebo groups. However, this finding may be the result of higher oral corticosteroids use in the reference group.⁵

Limitations of these studies

These studies, though, have limitations. The follow-up periods for all of these studies are less than 5 years, and thus the longer-term effects of prolonged use of inhaled corticosteroids on BMD or fracture risk cannot be determined with this evidence. Furthermore, the study populations were relatively young, with few other risk factors (they were, for example, predominantly male) than populations at highest risk for osteoporosis and fracture. These factors limit interpretation of the data for long-term inhaled corticosteroids use, particularly in populations with higher baseline osteoporosis risk—older persons with chronic lung disease who take inhaled corticosteroids for more than 2 to 3 years. We need better and longer-term studies to help advise our patients about the risks and benefits of inhaled corticosteroids therapy.

Recommendations from others

The New Zealand Guideline Group says the risk of reduced BMD increased with long-term, high-dose inhaled corticosteroids.⁶ The Institute for Clinical Systems Improvement guidelines recommends considering osteoporosis prevention measures for those who have been (or will be) taking a daily high-dose inhaled glucocorticoid for several years as glucocorticoid use compounds fracture risk beyond that determined solely by BMD.⁷

Evidence summary

Three large cohort studies determined that African Americans have a higher prevalence of hypertension and worse cardiovascular and renal outcomes when compared with white Americans. For African American patients, the standard blood pressure goals apply: below 140/90 mm Hg with uncomplicated hypertension and below 130/80 with diabetes or renal disease.¹

Dietary interventions

An RCT compared the effects of consuming the DASH diet (consisting of 4–5 servings of fruit, 4–5 servings of vegetables, 2–3 servings of low-fat dairy per day, and <25% fat) with a typical high-fat control diet among 459 adults with normal or elevated blood pressure.² Among 133 patients with hypertension, the DASH diet reduced systolic and diastolic blood pressure by 11.4 mm Hg (97.5% confidence interval [CI], –15.9 to –6.9) and 5.5 mm Hg (97.5% CI, –8.2 to –2.7) respectively when compared with the control diet. Among African Americans with hypertension, the DASH diet was even more beneficial, reducing their systolic and diastolic blood pressure by 13.2 mm Hg and 6.1 mm Hg respectively.¹

Another RCT studied the effect of different levels of dietary sodium in conjunction with the DASH diet.³ A total of 412 participants were randomly assigned to eat either a control diet or the DASH diet. Within the assigned diet, participants ate foods with high (150 mmol/d), intermediate (100 mmol/d), and low (50 mmol/d) levels of sodium in random order. In this study, low-sodium DASH diet was associated with additional lowering of blood pressure, an effect that was also found to be stronger for African Americans patients than others.³ When compared with the combination of the control diet and a high level of sodium, the DASH diet and a low level of sodium lowered systolic blood pressure by 11.5 mm Hg for participants with hypertension (12.6 mm Hg for blacks; 9.5 mm Hg for others), and by 7.1 mm Hg for participants without hypertension (7.2 mm Hg for blacks; 6.9 mm Hg for others).³

Medical interventions

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial⁴ (ALLHAT) and African American Study of Kidney Disease and Hypertension⁵ (AASK) have demonstrated the benefit of blood pressure reduction using specific classes of antihypertensive agents.

The ALLHAT trial, a double-blind RCT of 42,448 high-risk hypertensive patients aged >55 years, compared chlorthalidone (a thiazide-type diuretic) with amlodipine (Norvasc), lisinopril (Prinivil, Zestril), or doxazosin (Cardura). In this study, which included 36% African Americans, chlorthalidone, lisinopril, and amlodipine did not differ in preventing major cardiovascular events. However, lisinopril was associated with an increased risk for heart failure (relative risk [RR] for African Americans=1.32; 95% CI, 1.11–1.58) and stroke (RR for African Americans=1.4; 95% CI, 1.17–1.68), and amlodipine was associated with a higher risk of heart failure (RR in African Americans=1.47; 95% CI, 1.24–1.74). Additionally, ACE inhibitor–induced angioedema or cough occurred more frequently among African American patients than white patients.⁴

Although a randomized controlled trial⁵ and a review of multiple studies⁶ demonstrated that African Americans may be less responsive to monotherapy with ACE inhibitors, the AASK trial confirmed that ACE inhibitors can provide significant clinical benefits for African Americans with hypertensive renal disease. AASK, a double-blind RCT of 1094 African American patients with renal insufficiency, compared the effects of an ACE inhibitor (ramipril [Altace]), a dihydropyridine calcium channel blocker (amlodipine), or a beta blocker (metoprolol [Lopressor]) on the progression of hypertensive renal disease.

The study showed a 44% relative risk reduction (95% CI, 13%–65%; number needed to treat [NNT]=25) in progression to end-stage renal disease, and a significant decrease in the combined endpoints of glomerular filtration rate events (decrease >50%), end-stage renal disease, and death (decreased by 38%) in the ramipril group compared with the amlodipine group (95% CI, 13%–56%; NNT=56 per patient-year).^5,7 Metoprolol appeared to have intermediate outcomes.⁸

Recommendations from others

Both the International Society on Hypertension in Blacks (ISHIB) guidelines¹ and the JNC 7⁹ recommend therapeutic lifestyle modification that includes DASH diet, dietary sodium restriction, and weight reduction. Both guidelines recognize the importance of thiazide diuretics and recommend its use as first-line therapy or as a part of combination therapy for hypertension among African Americans. They also recommend initiating therapy with 2 agents for blood pressure significantly above target level (20/10 mm Hg above target per JNC 7, 15/10 mm Hg above target per ISHIB).

The ISHIB report emphasizes the need for not overlooking renal protection with an ACE inhibitor for African Americans with renal disease. The American Diabetes Association recommends that all patients with diabetes and hypertension be treated with a regimen that includes either an ACE inhibitor or an ARB.¹⁰

Evidence summary

Three large cohort studies determined that African Americans have a higher prevalence of hypertension and worse cardiovascular and renal outcomes when compared with white Americans. For African American patients, the standard blood pressure goals apply: below 140/90 mm Hg with uncomplicated hypertension and below 130/80 with diabetes or renal disease.¹

Dietary interventions

An RCT compared the effects of consuming the DASH diet (consisting of 4–5 servings of fruit, 4–5 servings of vegetables, 2–3 servings of low-fat dairy per day, and <25% fat) with a typical high-fat control diet among 459 adults with normal or elevated blood pressure.² Among 133 patients with hypertension, the DASH diet reduced systolic and diastolic blood pressure by 11.4 mm Hg (97.5% confidence interval [CI], –15.9 to –6.9) and 5.5 mm Hg (97.5% CI, –8.2 to –2.7) respectively when compared with the control diet. Among African Americans with hypertension, the DASH diet was even more beneficial, reducing their systolic and diastolic blood pressure by 13.2 mm Hg and 6.1 mm Hg respectively.¹

Another RCT studied the effect of different levels of dietary sodium in conjunction with the DASH diet.³ A total of 412 participants were randomly assigned to eat either a control diet or the DASH diet. Within the assigned diet, participants ate foods with high (150 mmol/d), intermediate (100 mmol/d), and low (50 mmol/d) levels of sodium in random order. In this study, low-sodium DASH diet was associated with additional lowering of blood pressure, an effect that was also found to be stronger for African Americans patients than others.³ When compared with the combination of the control diet and a high level of sodium, the DASH diet and a low level of sodium lowered systolic blood pressure by 11.5 mm Hg for participants with hypertension (12.6 mm Hg for blacks; 9.5 mm Hg for others), and by 7.1 mm Hg for participants without hypertension (7.2 mm Hg for blacks; 6.9 mm Hg for others).³

Medical interventions

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial⁴ (ALLHAT) and African American Study of Kidney Disease and Hypertension⁵ (AASK) have demonstrated the benefit of blood pressure reduction using specific classes of antihypertensive agents.

The ALLHAT trial, a double-blind RCT of 42,448 high-risk hypertensive patients aged >55 years, compared chlorthalidone (a thiazide-type diuretic) with amlodipine (Norvasc), lisinopril (Prinivil, Zestril), or doxazosin (Cardura). In this study, which included 36% African Americans, chlorthalidone, lisinopril, and amlodipine did not differ in preventing major cardiovascular events. However, lisinopril was associated with an increased risk for heart failure (relative risk [RR] for African Americans=1.32; 95% CI, 1.11–1.58) and stroke (RR for African Americans=1.4; 95% CI, 1.17–1.68), and amlodipine was associated with a higher risk of heart failure (RR in African Americans=1.47; 95% CI, 1.24–1.74). Additionally, ACE inhibitor–induced angioedema or cough occurred more frequently among African American patients than white patients.⁴

Although a randomized controlled trial⁵ and a review of multiple studies⁶ demonstrated that African Americans may be less responsive to monotherapy with ACE inhibitors, the AASK trial confirmed that ACE inhibitors can provide significant clinical benefits for African Americans with hypertensive renal disease. AASK, a double-blind RCT of 1094 African American patients with renal insufficiency, compared the effects of an ACE inhibitor (ramipril [Altace]), a dihydropyridine calcium channel blocker (amlodipine), or a beta blocker (metoprolol [Lopressor]) on the progression of hypertensive renal disease.

The study showed a 44% relative risk reduction (95% CI, 13%–65%; number needed to treat [NNT]=25) in progression to end-stage renal disease, and a significant decrease in the combined endpoints of glomerular filtration rate events (decrease >50%), end-stage renal disease, and death (decreased by 38%) in the ramipril group compared with the amlodipine group (95% CI, 13%–56%; NNT=56 per patient-year).^5,7 Metoprolol appeared to have intermediate outcomes.⁸

Recommendations from others

Both the International Society on Hypertension in Blacks (ISHIB) guidelines¹ and the JNC 7⁹ recommend therapeutic lifestyle modification that includes DASH diet, dietary sodium restriction, and weight reduction. Both guidelines recognize the importance of thiazide diuretics and recommend its use as first-line therapy or as a part of combination therapy for hypertension among African Americans. They also recommend initiating therapy with 2 agents for blood pressure significantly above target level (20/10 mm Hg above target per JNC 7, 15/10 mm Hg above target per ISHIB).

The ISHIB report emphasizes the need for not overlooking renal protection with an ACE inhibitor for African Americans with renal disease. The American Diabetes Association recommends that all patients with diabetes and hypertension be treated with a regimen that includes either an ACE inhibitor or an ARB.¹⁰

Evidence summary

Three large cohort studies determined that African Americans have a higher prevalence of hypertension and worse cardiovascular and renal outcomes when compared with white Americans. For African American patients, the standard blood pressure goals apply: below 140/90 mm Hg with uncomplicated hypertension and below 130/80 with diabetes or renal disease.¹

Dietary interventions

An RCT compared the effects of consuming the DASH diet (consisting of 4–5 servings of fruit, 4–5 servings of vegetables, 2–3 servings of low-fat dairy per day, and <25% fat) with a typical high-fat control diet among 459 adults with normal or elevated blood pressure.² Among 133 patients with hypertension, the DASH diet reduced systolic and diastolic blood pressure by 11.4 mm Hg (97.5% confidence interval [CI], –15.9 to –6.9) and 5.5 mm Hg (97.5% CI, –8.2 to –2.7) respectively when compared with the control diet. Among African Americans with hypertension, the DASH diet was even more beneficial, reducing their systolic and diastolic blood pressure by 13.2 mm Hg and 6.1 mm Hg respectively.¹

Another RCT studied the effect of different levels of dietary sodium in conjunction with the DASH diet.³ A total of 412 participants were randomly assigned to eat either a control diet or the DASH diet. Within the assigned diet, participants ate foods with high (150 mmol/d), intermediate (100 mmol/d), and low (50 mmol/d) levels of sodium in random order. In this study, low-sodium DASH diet was associated with additional lowering of blood pressure, an effect that was also found to be stronger for African Americans patients than others.³ When compared with the combination of the control diet and a high level of sodium, the DASH diet and a low level of sodium lowered systolic blood pressure by 11.5 mm Hg for participants with hypertension (12.6 mm Hg for blacks; 9.5 mm Hg for others), and by 7.1 mm Hg for participants without hypertension (7.2 mm Hg for blacks; 6.9 mm Hg for others).³

Medical interventions

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial⁴ (ALLHAT) and African American Study of Kidney Disease and Hypertension⁵ (AASK) have demonstrated the benefit of blood pressure reduction using specific classes of antihypertensive agents.

The ALLHAT trial, a double-blind RCT of 42,448 high-risk hypertensive patients aged >55 years, compared chlorthalidone (a thiazide-type diuretic) with amlodipine (Norvasc), lisinopril (Prinivil, Zestril), or doxazosin (Cardura). In this study, which included 36% African Americans, chlorthalidone, lisinopril, and amlodipine did not differ in preventing major cardiovascular events. However, lisinopril was associated with an increased risk for heart failure (relative risk [RR] for African Americans=1.32; 95% CI, 1.11–1.58) and stroke (RR for African Americans=1.4; 95% CI, 1.17–1.68), and amlodipine was associated with a higher risk of heart failure (RR in African Americans=1.47; 95% CI, 1.24–1.74). Additionally, ACE inhibitor–induced angioedema or cough occurred more frequently among African American patients than white patients.⁴

Although a randomized controlled trial⁵ and a review of multiple studies⁶ demonstrated that African Americans may be less responsive to monotherapy with ACE inhibitors, the AASK trial confirmed that ACE inhibitors can provide significant clinical benefits for African Americans with hypertensive renal disease. AASK, a double-blind RCT of 1094 African American patients with renal insufficiency, compared the effects of an ACE inhibitor (ramipril [Altace]), a dihydropyridine calcium channel blocker (amlodipine), or a beta blocker (metoprolol [Lopressor]) on the progression of hypertensive renal disease.

The study showed a 44% relative risk reduction (95% CI, 13%–65%; number needed to treat [NNT]=25) in progression to end-stage renal disease, and a significant decrease in the combined endpoints of glomerular filtration rate events (decrease >50%), end-stage renal disease, and death (decreased by 38%) in the ramipril group compared with the amlodipine group (95% CI, 13%–56%; NNT=56 per patient-year).^5,7 Metoprolol appeared to have intermediate outcomes.⁸

Recommendations from others

Both the International Society on Hypertension in Blacks (ISHIB) guidelines¹ and the JNC 7⁹ recommend therapeutic lifestyle modification that includes DASH diet, dietary sodium restriction, and weight reduction. Both guidelines recognize the importance of thiazide diuretics and recommend its use as first-line therapy or as a part of combination therapy for hypertension among African Americans. They also recommend initiating therapy with 2 agents for blood pressure significantly above target level (20/10 mm Hg above target per JNC 7, 15/10 mm Hg above target per ISHIB).

The ISHIB report emphasizes the need for not overlooking renal protection with an ACE inhibitor for African Americans with renal disease. The American Diabetes Association recommends that all patients with diabetes and hypertension be treated with a regimen that includes either an ACE inhibitor or an ARB.¹⁰

Evidence summary

Limited research exists in this area. Practice today is guided by clinical judgment, anecdotal evidence, and historical teaching. Assessment for inflammation and malignancy risk factors contributes to the diagnosis.

Lymph nodes with concomitant malignancy risk factors warrant immediate evaluation. For lymph nodes without signs or symptoms of inflammation or malignancy, observation for 4 to 6 weeks has been recommended. Further evaluation with imaging or biopsy is indicated if the node persists beyond 4 to 6 weeks, continues to enlarge, is located within the supraclavicular fossa, or is >3 cm.¹

A study of 550 patients identified 5 significant predictors of malignancy: male gender (risk ratio [RR]=2.72; 95% confidence interval [CI], 1.63–4.56), increasing age (RR=1.05; 95% CI, 1.04–1.07), white ethnicity (RR=3.01; 95% CI, 1.19–7.6), supraclavicular lymph nodes (RR=3.72; 95% CI, 1.52–9.12), and 2 or more regions of lymph nodes (RR=6.41; 95% CI, 2.82–14.58).⁵

For lymph nodes with inflammatory symptoms, further evaluation (including imaging) is indicated if there is no response to antibiotics. CT with contrast is considered the gold standard. However, a study of 50 patients with lymphadenopathy on CT demonstrated the sensitivity of ultrasound was 92% in identifying the same nodes.³ Another study demonstrated an ultrasound sensitivity of 100% and specificity of 97% for 154 patients with lymphadenopathy.⁵

Histologic evaluation after excisional biopsy is the gold standard for diagnosis. Fine-needle aspiration is an alternate, minimally invasive option for further work-up. Fine-needle aspiration had a sensitivity of 49% and specificity of 97% in a study of 550 patients.⁵ In a study of 309 patients with supraclavicular lymphadenopathy, fine-needle aspiration had a sensitivity of 97%, a specificity of 98%, and a positive predictive value of 98%. A study of 94 patients found that clinical exam alone was 78% sensitive in diagnosing the cause of lymphadenopathy; this improved to 93% sensitivity with fine-needle aspiration.⁶

Fine-needle aspiration has a higher rate of false negatives. A study of 1103 patients found a 97% sensitivity (3.4% false-negative rate) and a 99% specificity (0.9% false-positive rate) for fine-needle aspiration.⁴ In cases where pathology is equivocal, or where concern for malignancy is exceptionally high, excisional biopsy provides a more definitive diagnosis.

Recommendations from others

Cecil’s Textbook of Medicine recommends observing the nodes when they are soft and smaller than 2 to 3 cm and the patient has no obvious systemic illness. They note that performing a complete blood count and peripheral smear exam can aid in diagnosing systemic illness and that antibiotics are often given. They suggest performing a biopsy if the lymph node does not regress within a few weeks or if it grows. They also say the art of medicine is at play here and that if patients are particularly anxious, biopsy may be done more quickly.⁷

Harrison’s Manual of Medicine specifies that nodes >4 cm located in the subclavicular or scalene area or hard nodes fixed to surrounding tissues should be biopsied immediately, and that tender nodes are most often benign.⁸

Evidence summary

Limited research exists in this area. Practice today is guided by clinical judgment, anecdotal evidence, and historical teaching. Assessment for inflammation and malignancy risk factors contributes to the diagnosis.

Lymph nodes with concomitant malignancy risk factors warrant immediate evaluation. For lymph nodes without signs or symptoms of inflammation or malignancy, observation for 4 to 6 weeks has been recommended. Further evaluation with imaging or biopsy is indicated if the node persists beyond 4 to 6 weeks, continues to enlarge, is located within the supraclavicular fossa, or is >3 cm.¹

A study of 550 patients identified 5 significant predictors of malignancy: male gender (risk ratio [RR]=2.72; 95% confidence interval [CI], 1.63–4.56), increasing age (RR=1.05; 95% CI, 1.04–1.07), white ethnicity (RR=3.01; 95% CI, 1.19–7.6), supraclavicular lymph nodes (RR=3.72; 95% CI, 1.52–9.12), and 2 or more regions of lymph nodes (RR=6.41; 95% CI, 2.82–14.58).⁵

For lymph nodes with inflammatory symptoms, further evaluation (including imaging) is indicated if there is no response to antibiotics. CT with contrast is considered the gold standard. However, a study of 50 patients with lymphadenopathy on CT demonstrated the sensitivity of ultrasound was 92% in identifying the same nodes.³ Another study demonstrated an ultrasound sensitivity of 100% and specificity of 97% for 154 patients with lymphadenopathy.⁵

Histologic evaluation after excisional biopsy is the gold standard for diagnosis. Fine-needle aspiration is an alternate, minimally invasive option for further work-up. Fine-needle aspiration had a sensitivity of 49% and specificity of 97% in a study of 550 patients.⁵ In a study of 309 patients with supraclavicular lymphadenopathy, fine-needle aspiration had a sensitivity of 97%, a specificity of 98%, and a positive predictive value of 98%. A study of 94 patients found that clinical exam alone was 78% sensitive in diagnosing the cause of lymphadenopathy; this improved to 93% sensitivity with fine-needle aspiration.⁶

Fine-needle aspiration has a higher rate of false negatives. A study of 1103 patients found a 97% sensitivity (3.4% false-negative rate) and a 99% specificity (0.9% false-positive rate) for fine-needle aspiration.⁴ In cases where pathology is equivocal, or where concern for malignancy is exceptionally high, excisional biopsy provides a more definitive diagnosis.

Recommendations from others

Cecil’s Textbook of Medicine recommends observing the nodes when they are soft and smaller than 2 to 3 cm and the patient has no obvious systemic illness. They note that performing a complete blood count and peripheral smear exam can aid in diagnosing systemic illness and that antibiotics are often given. They suggest performing a biopsy if the lymph node does not regress within a few weeks or if it grows. They also say the art of medicine is at play here and that if patients are particularly anxious, biopsy may be done more quickly.⁷

Harrison’s Manual of Medicine specifies that nodes >4 cm located in the subclavicular or scalene area or hard nodes fixed to surrounding tissues should be biopsied immediately, and that tender nodes are most often benign.⁸

Evidence summary

Limited research exists in this area. Practice today is guided by clinical judgment, anecdotal evidence, and historical teaching. Assessment for inflammation and malignancy risk factors contributes to the diagnosis.

Lymph nodes with concomitant malignancy risk factors warrant immediate evaluation. For lymph nodes without signs or symptoms of inflammation or malignancy, observation for 4 to 6 weeks has been recommended. Further evaluation with imaging or biopsy is indicated if the node persists beyond 4 to 6 weeks, continues to enlarge, is located within the supraclavicular fossa, or is >3 cm.¹

A study of 550 patients identified 5 significant predictors of malignancy: male gender (risk ratio [RR]=2.72; 95% confidence interval [CI], 1.63–4.56), increasing age (RR=1.05; 95% CI, 1.04–1.07), white ethnicity (RR=3.01; 95% CI, 1.19–7.6), supraclavicular lymph nodes (RR=3.72; 95% CI, 1.52–9.12), and 2 or more regions of lymph nodes (RR=6.41; 95% CI, 2.82–14.58).⁵

For lymph nodes with inflammatory symptoms, further evaluation (including imaging) is indicated if there is no response to antibiotics. CT with contrast is considered the gold standard. However, a study of 50 patients with lymphadenopathy on CT demonstrated the sensitivity of ultrasound was 92% in identifying the same nodes.³ Another study demonstrated an ultrasound sensitivity of 100% and specificity of 97% for 154 patients with lymphadenopathy.⁵

Histologic evaluation after excisional biopsy is the gold standard for diagnosis. Fine-needle aspiration is an alternate, minimally invasive option for further work-up. Fine-needle aspiration had a sensitivity of 49% and specificity of 97% in a study of 550 patients.⁵ In a study of 309 patients with supraclavicular lymphadenopathy, fine-needle aspiration had a sensitivity of 97%, a specificity of 98%, and a positive predictive value of 98%. A study of 94 patients found that clinical exam alone was 78% sensitive in diagnosing the cause of lymphadenopathy; this improved to 93% sensitivity with fine-needle aspiration.⁶

Fine-needle aspiration has a higher rate of false negatives. A study of 1103 patients found a 97% sensitivity (3.4% false-negative rate) and a 99% specificity (0.9% false-positive rate) for fine-needle aspiration.⁴ In cases where pathology is equivocal, or where concern for malignancy is exceptionally high, excisional biopsy provides a more definitive diagnosis.

Recommendations from others

Cecil’s Textbook of Medicine recommends observing the nodes when they are soft and smaller than 2 to 3 cm and the patient has no obvious systemic illness. They note that performing a complete blood count and peripheral smear exam can aid in diagnosing systemic illness and that antibiotics are often given. They suggest performing a biopsy if the lymph node does not regress within a few weeks or if it grows. They also say the art of medicine is at play here and that if patients are particularly anxious, biopsy may be done more quickly.⁷

Harrison’s Manual of Medicine specifies that nodes >4 cm located in the subclavicular or scalene area or hard nodes fixed to surrounding tissues should be biopsied immediately, and that tender nodes are most often benign.⁸

Evidence Summary

Our comprehensive literature search found no studies that provide direct evidence for or against continuing to monitor microalbuminuria among patients with diabetes already on ACE inhibitor or ARB therapy. We reviewed and included indirect evidence and expert opinion to answer this clinical question.

Diabetes mellitus is the leading cause of end-stage renal disease in the Western world.¹ The prevalence of diabetic nephropathy continues to rise along with the rapidly rising prevalence of obesity and diabetes, with 40% of patients with diabetes at risk of developing nephropathy. One study that followed 5097 patients with type 2 diabetes over a median of 10.4 years found that 2% of patients progressed from normal levels of urinary protein to microalbuminuria; 2.8% changed from microalbuminuria to macroalbuminuria (urine albumin >300 mg in a 24-hour period); and 2.3% progressed to chronic renal disease (creatinine ≥2 mg/dL) from macroalbuminuria per year.² Chronic renal disease is more likely to occur in those patients whose hypertension or hyperglycemia is poorly controlled.

For patients with diabetes who develop microalbuminuria, the evidence is good for starting ACE inhibitors or ARBs for renal protection.^3,4 The American Diabetes Association (ADA) also recommends that patients with diabetes and hypertension and those aged >55 years with other cardiovascular risk factors (history of cardiovascular disease, dyslipidemia, or tobacco use) be started on ACE inhibitors or ARBs.¹ There is also good evidence that screening for microalbuminuria can identify those who might benefit from treatments that delay the onset of nephropathy.⁵

Recent studies have raised the possibility of further benefit in prevention and treatment of diabetic nephropathy by maximizing doses of ACE inhibitors or ARBs, and even from the dual blockade attained from using both. For example, during a 2-year trial—in which 590 patients with diabetes and microalbuminuria were randomized to receive placebo, 150 mg irbesartan, or 300 mg irbesartan—14.9% of the placebo group, 9.7% of the 150-mg group, and only 5.2% of the 300-mg group progressed to overt nephropathy.⁶ In very small randomized trial of 20 patients with type 2 diabetes, adding 16 mg of candesartan to the maximal dose of an ACE inhibitor decreased albuminuria an additional 28%.⁷

Experts argue that it may benefit patients to continue regular surveillance for the presence or progression of microalbuminuria even if they are already taking an ACE inhibitor or ARB so that therapy can be maximized.^1,8 However, no direct evidence supports this recommendation.

Recommendations from others

The ADA suggests that clinicians perform a test each year for microalbuminuria among patients with type 1 diabetes of ≥5 years duration, and in all patients with type 2 diabetes at diagnosis and during pregnancy. They also recommend continued surveillance of proteinuria to assess both response to therapy and progression of disease.¹

The National Kidney Foundation recommends continued surveillance of microalbuminuria to assess progression of chronic kidney disease and response to therapy.⁸

Evidence Summary

Our comprehensive literature search found no studies that provide direct evidence for or against continuing to monitor microalbuminuria among patients with diabetes already on ACE inhibitor or ARB therapy. We reviewed and included indirect evidence and expert opinion to answer this clinical question.

Diabetes mellitus is the leading cause of end-stage renal disease in the Western world.¹ The prevalence of diabetic nephropathy continues to rise along with the rapidly rising prevalence of obesity and diabetes, with 40% of patients with diabetes at risk of developing nephropathy. One study that followed 5097 patients with type 2 diabetes over a median of 10.4 years found that 2% of patients progressed from normal levels of urinary protein to microalbuminuria; 2.8% changed from microalbuminuria to macroalbuminuria (urine albumin >300 mg in a 24-hour period); and 2.3% progressed to chronic renal disease (creatinine ≥2 mg/dL) from macroalbuminuria per year.² Chronic renal disease is more likely to occur in those patients whose hypertension or hyperglycemia is poorly controlled.

For patients with diabetes who develop microalbuminuria, the evidence is good for starting ACE inhibitors or ARBs for renal protection.^3,4 The American Diabetes Association (ADA) also recommends that patients with diabetes and hypertension and those aged >55 years with other cardiovascular risk factors (history of cardiovascular disease, dyslipidemia, or tobacco use) be started on ACE inhibitors or ARBs.¹ There is also good evidence that screening for microalbuminuria can identify those who might benefit from treatments that delay the onset of nephropathy.⁵

Recent studies have raised the possibility of further benefit in prevention and treatment of diabetic nephropathy by maximizing doses of ACE inhibitors or ARBs, and even from the dual blockade attained from using both. For example, during a 2-year trial—in which 590 patients with diabetes and microalbuminuria were randomized to receive placebo, 150 mg irbesartan, or 300 mg irbesartan—14.9% of the placebo group, 9.7% of the 150-mg group, and only 5.2% of the 300-mg group progressed to overt nephropathy.⁶ In very small randomized trial of 20 patients with type 2 diabetes, adding 16 mg of candesartan to the maximal dose of an ACE inhibitor decreased albuminuria an additional 28%.⁷

Experts argue that it may benefit patients to continue regular surveillance for the presence or progression of microalbuminuria even if they are already taking an ACE inhibitor or ARB so that therapy can be maximized.^1,8 However, no direct evidence supports this recommendation.

Recommendations from others

The ADA suggests that clinicians perform a test each year for microalbuminuria among patients with type 1 diabetes of ≥5 years duration, and in all patients with type 2 diabetes at diagnosis and during pregnancy. They also recommend continued surveillance of proteinuria to assess both response to therapy and progression of disease.¹

The National Kidney Foundation recommends continued surveillance of microalbuminuria to assess progression of chronic kidney disease and response to therapy.⁸

Evidence Summary

Our comprehensive literature search found no studies that provide direct evidence for or against continuing to monitor microalbuminuria among patients with diabetes already on ACE inhibitor or ARB therapy. We reviewed and included indirect evidence and expert opinion to answer this clinical question.

Diabetes mellitus is the leading cause of end-stage renal disease in the Western world.¹ The prevalence of diabetic nephropathy continues to rise along with the rapidly rising prevalence of obesity and diabetes, with 40% of patients with diabetes at risk of developing nephropathy. One study that followed 5097 patients with type 2 diabetes over a median of 10.4 years found that 2% of patients progressed from normal levels of urinary protein to microalbuminuria; 2.8% changed from microalbuminuria to macroalbuminuria (urine albumin >300 mg in a 24-hour period); and 2.3% progressed to chronic renal disease (creatinine ≥2 mg/dL) from macroalbuminuria per year.² Chronic renal disease is more likely to occur in those patients whose hypertension or hyperglycemia is poorly controlled.

For patients with diabetes who develop microalbuminuria, the evidence is good for starting ACE inhibitors or ARBs for renal protection.^3,4 The American Diabetes Association (ADA) also recommends that patients with diabetes and hypertension and those aged >55 years with other cardiovascular risk factors (history of cardiovascular disease, dyslipidemia, or tobacco use) be started on ACE inhibitors or ARBs.¹ There is also good evidence that screening for microalbuminuria can identify those who might benefit from treatments that delay the onset of nephropathy.⁵

Recent studies have raised the possibility of further benefit in prevention and treatment of diabetic nephropathy by maximizing doses of ACE inhibitors or ARBs, and even from the dual blockade attained from using both. For example, during a 2-year trial—in which 590 patients with diabetes and microalbuminuria were randomized to receive placebo, 150 mg irbesartan, or 300 mg irbesartan—14.9% of the placebo group, 9.7% of the 150-mg group, and only 5.2% of the 300-mg group progressed to overt nephropathy.⁶ In very small randomized trial of 20 patients with type 2 diabetes, adding 16 mg of candesartan to the maximal dose of an ACE inhibitor decreased albuminuria an additional 28%.⁷

Experts argue that it may benefit patients to continue regular surveillance for the presence or progression of microalbuminuria even if they are already taking an ACE inhibitor or ARB so that therapy can be maximized.^1,8 However, no direct evidence supports this recommendation.

Recommendations from others

The ADA suggests that clinicians perform a test each year for microalbuminuria among patients with type 1 diabetes of ≥5 years duration, and in all patients with type 2 diabetes at diagnosis and during pregnancy. They also recommend continued surveillance of proteinuria to assess both response to therapy and progression of disease.¹

The National Kidney Foundation recommends continued surveillance of microalbuminuria to assess progression of chronic kidney disease and response to therapy.⁸

Evidence summary

Topical antibiotics for prophylaxis

Numerous studies support the prophylactic application of topical antibiotics to wounds that are clean. Topical bacitracin zinc (Bacitracin), a triple ointment of neomycin sulfate, bacitracin zinc, and polymyxin B sulfate (Neosporin), and silver sulfadiazine (Silvadene) were compared with petrolatum as a control in a well-conducted RCT of 426 patients with uncomplicated wounds seen at a military community hospital. Wound infection rates were 17.6% (19/108) for petrolatum, 5.5% (6/109) for Bacitracin (number needed to treat [NNT]=8), 4.5% (5/110) for Neosporin (NNT=8), and 12.1% (12/99) for Silvadene (NNT=18).¹ Most (60%) of the infections were “stitch abscesses” and were treated with local care only. There was no difference in rates of more serious infections between groups. One patient (0.9%) developed a hypersensitivity reaction to Neosporin.

A clinical trial compared the efficacy of a cetrimide, bacitracin zinc, and polymyxin B sulfate gel (a combination not available in the US) with placebo and povidone-iodine cream in preventing infections in 177 minor wounds (cuts, grazes, scrapes, and scratches) among children. The antibiotic gel was found to be superior to placebo and equivalent to povidone-iodine, in that it reduced clinical infections from 12.5% to 1.6% (absolute risk reduction [ARR]=0.109; 95% confidence interval [CI], 0.011–0.207; NNT=11).²

A double-blind study of 59 patients found Neosporin superior to placebo ointment in the prevention of streptococcal pyoderma for children with minor wounds. Infection occurred in 47% of placebo-treated children compared with 15% treated with the triple-antibiotic ointment (NNT=32; P=.01).³

A small randomized prospective trial of 99 patients, who self-reported compliance with wound care and dressing changes, compared Neosporin with mupirocin (Bactroban) in preventing infections in uncomplicated soft tissue wounds. The study found no statistical difference in infection rates, and the authors recommend the more cost-effective Neosporin, as well as a larger trial to confirm the results.⁴

Another randomized controlled trial of 933 outpatients—with a total of 1249 wounds from sterile dermatologic surgeries—compared white petrolatum with bacitracin zinc ointment prophylaxis. The study found no statistically significant differences in post-procedure infection rates, though only 13 patients developed an infection (2% in petrolatum group vs. 0.9% in bacitracin zinc group; 95% CI for the difference, –0.4 to 2.7).⁵

Topical antibiotics for treatment

Topical antimicrobials are appealing for the treatment of secondarily infected wounds for the sake of convenience and because they may reduce the risk of adverse effects.

An open randomized trial with 48 volunteers compared the effects of Neosporin with several antiseptics (3% hydrogen peroxide, 1% povidone-iodine, 0.25% acetic acid, 0.5% sodium hydrochloride) and a wound protectant (Johnson & Johnson First Aid Cream without antimicrobial agent) on blister wounds (6 blisters per volunteer) intentionally contaminated with S aureus. Only Neosporin eliminated the infection after 2 applications (at 16 and 24 hours). Both the antibiotic ointment and the wound protectant led to faster wound healing by about 4 days compared with the antiseptics or no treatment.⁶

Another study with 2 parallel, identical RCTs of a total of 706 patients found mupirocin cream (Bactroban) to be equivalent to oral cephalexin in the treatment of secondarily infected minor wounds, such as small lacerations, abrasions, or sutured wounds. Clinical success (95.1% for mupirocin and 95.3% for cephalexin), bacteriologic success (96.9% for mupirocin and 98.9% for cephalexin), as well as the intention-to-treat success rate of 83% at follow-up were equivalent in the 2 groups.⁷

A small but well-designed study of 62 patients with major contaminated wounds failed to show any additional benefit when topical piperacillin/tazobactam (not available in US as a topical agent) was added to parenteral piperacillin/tazobactam (Zosyn) alone. Two of 31 patients on just parenteral antibiotics and 3 of 31 patients on both topical and parenteral antibiotics developed wound infections (P>.05).⁸

Finally, topical antibiotics also appear to aid in the healing of chronic wounds. However, these findings are difficult to interpret in light of small sample size and other methodological problems. A systematic review of the treatment of chronic wounds, such as diabetic foot ulcers, found 30 trials, including 25 RCTs, mostly of low quality. Little evidence supports the routine use of systemic antibiotics for patients with chronic wounds; however, some topical antiseptic and antimicrobial agents may hasten the healing of these wounds. Topical preparations that may be helpful include dimethyl sulfoxide (Rimso-50), silver sulfadiazine (Silvadene), benzoyl peroxide (Benzac, Brevoxyl, Desquam, Triaz, ZoDerm), oxyquinoline (Trimo-san Vaginal Jelly), and gentamicin (Garamycin).⁹

Honey may also make an acceptable wound dressing for chronic wounds, as it has been repeatedly shown to suppress bacterial growth. Infection with Clostridium spores does not appear to be a concern when treating chronic wounds with honey.^10,11

Recommendations from others

Guidelines for antibiotic prophylaxis of surgical wounds uniformly recommend prophylaxis for all clean-contaminated, contaminated, and dirty procedures. Prophylaxis is considered optional for most clean procedures, although it may be indicated for certain at-risk patients and for clean procedures that fulfill specific risk criteria.¹²

The Infectious Diseases Society of America recommends mupirocin as the best topical agent for the treatment and prevention of S aureus and S pyogenes infections, followed by bacitracin zinc and neomycin, although resistance is emerging.¹³ Expert and consensus opinion from the Canadian Chronic Wound Advisory Board and the International Wound Bed Preparation Advisory Board for wound care management of infected chronic wounds recommend that since bacterial infection can develop gradually, good-quality wound cultures should be used in conjunction with clinical assessment. Iodine and silver-based dressings, topical antibiotics, and systemic antibiotics can be helpful.¹⁴

Evidence summary

Topical antibiotics for prophylaxis

Numerous studies support the prophylactic application of topical antibiotics to wounds that are clean. Topical bacitracin zinc (Bacitracin), a triple ointment of neomycin sulfate, bacitracin zinc, and polymyxin B sulfate (Neosporin), and silver sulfadiazine (Silvadene) were compared with petrolatum as a control in a well-conducted RCT of 426 patients with uncomplicated wounds seen at a military community hospital. Wound infection rates were 17.6% (19/108) for petrolatum, 5.5% (6/109) for Bacitracin (number needed to treat [NNT]=8), 4.5% (5/110) for Neosporin (NNT=8), and 12.1% (12/99) for Silvadene (NNT=18).¹ Most (60%) of the infections were “stitch abscesses” and were treated with local care only. There was no difference in rates of more serious infections between groups. One patient (0.9%) developed a hypersensitivity reaction to Neosporin.

A clinical trial compared the efficacy of a cetrimide, bacitracin zinc, and polymyxin B sulfate gel (a combination not available in the US) with placebo and povidone-iodine cream in preventing infections in 177 minor wounds (cuts, grazes, scrapes, and scratches) among children. The antibiotic gel was found to be superior to placebo and equivalent to povidone-iodine, in that it reduced clinical infections from 12.5% to 1.6% (absolute risk reduction [ARR]=0.109; 95% confidence interval [CI], 0.011–0.207; NNT=11).²

A double-blind study of 59 patients found Neosporin superior to placebo ointment in the prevention of streptococcal pyoderma for children with minor wounds. Infection occurred in 47% of placebo-treated children compared with 15% treated with the triple-antibiotic ointment (NNT=32; P=.01).³

A small randomized prospective trial of 99 patients, who self-reported compliance with wound care and dressing changes, compared Neosporin with mupirocin (Bactroban) in preventing infections in uncomplicated soft tissue wounds. The study found no statistical difference in infection rates, and the authors recommend the more cost-effective Neosporin, as well as a larger trial to confirm the results.⁴

Another randomized controlled trial of 933 outpatients—with a total of 1249 wounds from sterile dermatologic surgeries—compared white petrolatum with bacitracin zinc ointment prophylaxis. The study found no statistically significant differences in post-procedure infection rates, though only 13 patients developed an infection (2% in petrolatum group vs. 0.9% in bacitracin zinc group; 95% CI for the difference, –0.4 to 2.7).⁵

Topical antibiotics for treatment

Topical antimicrobials are appealing for the treatment of secondarily infected wounds for the sake of convenience and because they may reduce the risk of adverse effects.

An open randomized trial with 48 volunteers compared the effects of Neosporin with several antiseptics (3% hydrogen peroxide, 1% povidone-iodine, 0.25% acetic acid, 0.5% sodium hydrochloride) and a wound protectant (Johnson & Johnson First Aid Cream without antimicrobial agent) on blister wounds (6 blisters per volunteer) intentionally contaminated with S aureus. Only Neosporin eliminated the infection after 2 applications (at 16 and 24 hours). Both the antibiotic ointment and the wound protectant led to faster wound healing by about 4 days compared with the antiseptics or no treatment.⁶

Another study with 2 parallel, identical RCTs of a total of 706 patients found mupirocin cream (Bactroban) to be equivalent to oral cephalexin in the treatment of secondarily infected minor wounds, such as small lacerations, abrasions, or sutured wounds. Clinical success (95.1% for mupirocin and 95.3% for cephalexin), bacteriologic success (96.9% for mupirocin and 98.9% for cephalexin), as well as the intention-to-treat success rate of 83% at follow-up were equivalent in the 2 groups.⁷

A small but well-designed study of 62 patients with major contaminated wounds failed to show any additional benefit when topical piperacillin/tazobactam (not available in US as a topical agent) was added to parenteral piperacillin/tazobactam (Zosyn) alone. Two of 31 patients on just parenteral antibiotics and 3 of 31 patients on both topical and parenteral antibiotics developed wound infections (P>.05).⁸

Finally, topical antibiotics also appear to aid in the healing of chronic wounds. However, these findings are difficult to interpret in light of small sample size and other methodological problems. A systematic review of the treatment of chronic wounds, such as diabetic foot ulcers, found 30 trials, including 25 RCTs, mostly of low quality. Little evidence supports the routine use of systemic antibiotics for patients with chronic wounds; however, some topical antiseptic and antimicrobial agents may hasten the healing of these wounds. Topical preparations that may be helpful include dimethyl sulfoxide (Rimso-50), silver sulfadiazine (Silvadene), benzoyl peroxide (Benzac, Brevoxyl, Desquam, Triaz, ZoDerm), oxyquinoline (Trimo-san Vaginal Jelly), and gentamicin (Garamycin).⁹

Honey may also make an acceptable wound dressing for chronic wounds, as it has been repeatedly shown to suppress bacterial growth. Infection with Clostridium spores does not appear to be a concern when treating chronic wounds with honey.^10,11

Recommendations from others

Guidelines for antibiotic prophylaxis of surgical wounds uniformly recommend prophylaxis for all clean-contaminated, contaminated, and dirty procedures. Prophylaxis is considered optional for most clean procedures, although it may be indicated for certain at-risk patients and for clean procedures that fulfill specific risk criteria.¹²

The Infectious Diseases Society of America recommends mupirocin as the best topical agent for the treatment and prevention of S aureus and S pyogenes infections, followed by bacitracin zinc and neomycin, although resistance is emerging.¹³ Expert and consensus opinion from the Canadian Chronic Wound Advisory Board and the International Wound Bed Preparation Advisory Board for wound care management of infected chronic wounds recommend that since bacterial infection can develop gradually, good-quality wound cultures should be used in conjunction with clinical assessment. Iodine and silver-based dressings, topical antibiotics, and systemic antibiotics can be helpful.¹⁴

Evidence summary

Topical antibiotics for prophylaxis

Numerous studies support the prophylactic application of topical antibiotics to wounds that are clean. Topical bacitracin zinc (Bacitracin), a triple ointment of neomycin sulfate, bacitracin zinc, and polymyxin B sulfate (Neosporin), and silver sulfadiazine (Silvadene) were compared with petrolatum as a control in a well-conducted RCT of 426 patients with uncomplicated wounds seen at a military community hospital. Wound infection rates were 17.6% (19/108) for petrolatum, 5.5% (6/109) for Bacitracin (number needed to treat [NNT]=8), 4.5% (5/110) for Neosporin (NNT=8), and 12.1% (12/99) for Silvadene (NNT=18).¹ Most (60%) of the infections were “stitch abscesses” and were treated with local care only. There was no difference in rates of more serious infections between groups. One patient (0.9%) developed a hypersensitivity reaction to Neosporin.

A clinical trial compared the efficacy of a cetrimide, bacitracin zinc, and polymyxin B sulfate gel (a combination not available in the US) with placebo and povidone-iodine cream in preventing infections in 177 minor wounds (cuts, grazes, scrapes, and scratches) among children. The antibiotic gel was found to be superior to placebo and equivalent to povidone-iodine, in that it reduced clinical infections from 12.5% to 1.6% (absolute risk reduction [ARR]=0.109; 95% confidence interval [CI], 0.011–0.207; NNT=11).²

A double-blind study of 59 patients found Neosporin superior to placebo ointment in the prevention of streptococcal pyoderma for children with minor wounds. Infection occurred in 47% of placebo-treated children compared with 15% treated with the triple-antibiotic ointment (NNT=32; P=.01).³

A small randomized prospective trial of 99 patients, who self-reported compliance with wound care and dressing changes, compared Neosporin with mupirocin (Bactroban) in preventing infections in uncomplicated soft tissue wounds. The study found no statistical difference in infection rates, and the authors recommend the more cost-effective Neosporin, as well as a larger trial to confirm the results.⁴

Another randomized controlled trial of 933 outpatients—with a total of 1249 wounds from sterile dermatologic surgeries—compared white petrolatum with bacitracin zinc ointment prophylaxis. The study found no statistically significant differences in post-procedure infection rates, though only 13 patients developed an infection (2% in petrolatum group vs. 0.9% in bacitracin zinc group; 95% CI for the difference, –0.4 to 2.7).⁵

Topical antibiotics for treatment

Topical antimicrobials are appealing for the treatment of secondarily infected wounds for the sake of convenience and because they may reduce the risk of adverse effects.

An open randomized trial with 48 volunteers compared the effects of Neosporin with several antiseptics (3% hydrogen peroxide, 1% povidone-iodine, 0.25% acetic acid, 0.5% sodium hydrochloride) and a wound protectant (Johnson & Johnson First Aid Cream without antimicrobial agent) on blister wounds (6 blisters per volunteer) intentionally contaminated with S aureus. Only Neosporin eliminated the infection after 2 applications (at 16 and 24 hours). Both the antibiotic ointment and the wound protectant led to faster wound healing by about 4 days compared with the antiseptics or no treatment.⁶

Another study with 2 parallel, identical RCTs of a total of 706 patients found mupirocin cream (Bactroban) to be equivalent to oral cephalexin in the treatment of secondarily infected minor wounds, such as small lacerations, abrasions, or sutured wounds. Clinical success (95.1% for mupirocin and 95.3% for cephalexin), bacteriologic success (96.9% for mupirocin and 98.9% for cephalexin), as well as the intention-to-treat success rate of 83% at follow-up were equivalent in the 2 groups.⁷

A small but well-designed study of 62 patients with major contaminated wounds failed to show any additional benefit when topical piperacillin/tazobactam (not available in US as a topical agent) was added to parenteral piperacillin/tazobactam (Zosyn) alone. Two of 31 patients on just parenteral antibiotics and 3 of 31 patients on both topical and parenteral antibiotics developed wound infections (P>.05).⁸

Finally, topical antibiotics also appear to aid in the healing of chronic wounds. However, these findings are difficult to interpret in light of small sample size and other methodological problems. A systematic review of the treatment of chronic wounds, such as diabetic foot ulcers, found 30 trials, including 25 RCTs, mostly of low quality. Little evidence supports the routine use of systemic antibiotics for patients with chronic wounds; however, some topical antiseptic and antimicrobial agents may hasten the healing of these wounds. Topical preparations that may be helpful include dimethyl sulfoxide (Rimso-50), silver sulfadiazine (Silvadene), benzoyl peroxide (Benzac, Brevoxyl, Desquam, Triaz, ZoDerm), oxyquinoline (Trimo-san Vaginal Jelly), and gentamicin (Garamycin).⁹

Honey may also make an acceptable wound dressing for chronic wounds, as it has been repeatedly shown to suppress bacterial growth. Infection with Clostridium spores does not appear to be a concern when treating chronic wounds with honey.^10,11

Recommendations from others

Guidelines for antibiotic prophylaxis of surgical wounds uniformly recommend prophylaxis for all clean-contaminated, contaminated, and dirty procedures. Prophylaxis is considered optional for most clean procedures, although it may be indicated for certain at-risk patients and for clean procedures that fulfill specific risk criteria.¹²

The Infectious Diseases Society of America recommends mupirocin as the best topical agent for the treatment and prevention of S aureus and S pyogenes infections, followed by bacitracin zinc and neomycin, although resistance is emerging.¹³ Expert and consensus opinion from the Canadian Chronic Wound Advisory Board and the International Wound Bed Preparation Advisory Board for wound care management of infected chronic wounds recommend that since bacterial infection can develop gradually, good-quality wound cultures should be used in conjunction with clinical assessment. Iodine and silver-based dressings, topical antibiotics, and systemic antibiotics can be helpful.¹⁴

Evidence Summary

A pilot study evaluated the yield of testing patients for other STIs among patients with genital chlamydia diagnosed during opportunistic screening. The study screened patients of both sexes in primary health care settings, as well as men attending a genitourinary medicine clinic. All patients testing positive in the community were advised to attend the genitourinary medicine clinic for STI screening, partner notification, and testing of patients and their contacts. More than 90% of the patients testing positive for chlamydia attended the genitourinary medicine clinic for management (total numbers seen in the clinic; women n=1245 [957 screened in the community] and men n=490 [280 screened in the community]).

At the clinic, further workup included evaluation and testing for chlamydia, gonorrhea, trichomonas, and bacterial vaginosis. Of the patients whose initial screening was in the genitourinary medicine clinic, 28% had an additional STI. Of the patients initially screened in the community setting, 4% had another STI. Partner testing showed that 55% of male partners of female patients had an STI and 76% of female partners of male patients had one or more STI.¹

The high prevalence of coinfection of chlamydia and gonorrhea has been shown in several studies. One cross-sectional study of new clients to a hospital-based STI clinic with gonorrhea, chlamydia, or both infections found 39% of 1239 women and 24% of 1141 heterosexual men with gonorrhea also had chlamydia. Thirteen percent of females and 19% of heterosexual males with chlamydia also had gonorrhea. More than half of the women and a third of the men aged 15 to 19 had both gonorrhea and chlamydia. Patients with both STIs tended to be younger than those with one.² A study of the prevalence rate of chlamydia, gonorrhea, and their coinfection in an adolescent population (women n=131,915 and men n=71,074) of juvenile detention centers between 1997 and 2002 found that 18% of women and 13% of males with chlamydia were coinfected with gonorrhea.³ In non–STI clinic settings, gonorrhea has been found in 9% of men^4,5 and 6% of women⁵ with chlamydia.

Recommendations from others

The American Academy of Family Physicians (AAFP) strongly recommends testing for chlamydia in all sexually active women aged 25 years or younger and those at increased risk. The AAFP recommends screening all sexually active women for gonorrhea if they are at increased risk for infection; strongly recommends screening persons at increased risk for syphilis infection; and strongly recommends screening for HIV for persons seeking treatment for STIs.⁶

The CDC guidelines recommend evaluation, testing and treatment of partners of persons with chlamydia. As well as testing for other STIs, the guidelines suggest Pap smear screening for women who have not been adequately screened, as they often are at high risk for later cervical cancer.⁷ All patients seeking treatment for STDs, including all patients attending STD clinics, should be screened routinely for HIV during each visit for a new complaint, regardless of whether the patient is known or suspected to have specific behavior risks for HIV infection.⁸

The Institute for Clinical Systems Improvement recommends screening for chlamydia and gonorrhea for all sexually active women aged 25 years and younger and other asymptomatic women at risk for infection. Routine screening for HIV is also recommended to all persons at high risk, including those seeking treatment for any STI.⁹

Evidence Summary

A pilot study evaluated the yield of testing patients for other STIs among patients with genital chlamydia diagnosed during opportunistic screening. The study screened patients of both sexes in primary health care settings, as well as men attending a genitourinary medicine clinic. All patients testing positive in the community were advised to attend the genitourinary medicine clinic for STI screening, partner notification, and testing of patients and their contacts. More than 90% of the patients testing positive for chlamydia attended the genitourinary medicine clinic for management (total numbers seen in the clinic; women n=1245 [957 screened in the community] and men n=490 [280 screened in the community]).

At the clinic, further workup included evaluation and testing for chlamydia, gonorrhea, trichomonas, and bacterial vaginosis. Of the patients whose initial screening was in the genitourinary medicine clinic, 28% had an additional STI. Of the patients initially screened in the community setting, 4% had another STI. Partner testing showed that 55% of male partners of female patients had an STI and 76% of female partners of male patients had one or more STI.¹

The high prevalence of coinfection of chlamydia and gonorrhea has been shown in several studies. One cross-sectional study of new clients to a hospital-based STI clinic with gonorrhea, chlamydia, or both infections found 39% of 1239 women and 24% of 1141 heterosexual men with gonorrhea also had chlamydia. Thirteen percent of females and 19% of heterosexual males with chlamydia also had gonorrhea. More than half of the women and a third of the men aged 15 to 19 had both gonorrhea and chlamydia. Patients with both STIs tended to be younger than those with one.² A study of the prevalence rate of chlamydia, gonorrhea, and their coinfection in an adolescent population (women n=131,915 and men n=71,074) of juvenile detention centers between 1997 and 2002 found that 18% of women and 13% of males with chlamydia were coinfected with gonorrhea.³ In non–STI clinic settings, gonorrhea has been found in 9% of men^4,5 and 6% of women⁵ with chlamydia.

Recommendations from others

The American Academy of Family Physicians (AAFP) strongly recommends testing for chlamydia in all sexually active women aged 25 years or younger and those at increased risk. The AAFP recommends screening all sexually active women for gonorrhea if they are at increased risk for infection; strongly recommends screening persons at increased risk for syphilis infection; and strongly recommends screening for HIV for persons seeking treatment for STIs.⁶

The CDC guidelines recommend evaluation, testing and treatment of partners of persons with chlamydia. As well as testing for other STIs, the guidelines suggest Pap smear screening for women who have not been adequately screened, as they often are at high risk for later cervical cancer.⁷ All patients seeking treatment for STDs, including all patients attending STD clinics, should be screened routinely for HIV during each visit for a new complaint, regardless of whether the patient is known or suspected to have specific behavior risks for HIV infection.⁸

The Institute for Clinical Systems Improvement recommends screening for chlamydia and gonorrhea for all sexually active women aged 25 years and younger and other asymptomatic women at risk for infection. Routine screening for HIV is also recommended to all persons at high risk, including those seeking treatment for any STI.⁹

Evidence Summary

A pilot study evaluated the yield of testing patients for other STIs among patients with genital chlamydia diagnosed during opportunistic screening. The study screened patients of both sexes in primary health care settings, as well as men attending a genitourinary medicine clinic. All patients testing positive in the community were advised to attend the genitourinary medicine clinic for STI screening, partner notification, and testing of patients and their contacts. More than 90% of the patients testing positive for chlamydia attended the genitourinary medicine clinic for management (total numbers seen in the clinic; women n=1245 [957 screened in the community] and men n=490 [280 screened in the community]).

At the clinic, further workup included evaluation and testing for chlamydia, gonorrhea, trichomonas, and bacterial vaginosis. Of the patients whose initial screening was in the genitourinary medicine clinic, 28% had an additional STI. Of the patients initially screened in the community setting, 4% had another STI. Partner testing showed that 55% of male partners of female patients had an STI and 76% of female partners of male patients had one or more STI.¹

The high prevalence of coinfection of chlamydia and gonorrhea has been shown in several studies. One cross-sectional study of new clients to a hospital-based STI clinic with gonorrhea, chlamydia, or both infections found 39% of 1239 women and 24% of 1141 heterosexual men with gonorrhea also had chlamydia. Thirteen percent of females and 19% of heterosexual males with chlamydia also had gonorrhea. More than half of the women and a third of the men aged 15 to 19 had both gonorrhea and chlamydia. Patients with both STIs tended to be younger than those with one.² A study of the prevalence rate of chlamydia, gonorrhea, and their coinfection in an adolescent population (women n=131,915 and men n=71,074) of juvenile detention centers between 1997 and 2002 found that 18% of women and 13% of males with chlamydia were coinfected with gonorrhea.³ In non–STI clinic settings, gonorrhea has been found in 9% of men^4,5 and 6% of women⁵ with chlamydia.

Recommendations from others

The American Academy of Family Physicians (AAFP) strongly recommends testing for chlamydia in all sexually active women aged 25 years or younger and those at increased risk. The AAFP recommends screening all sexually active women for gonorrhea if they are at increased risk for infection; strongly recommends screening persons at increased risk for syphilis infection; and strongly recommends screening for HIV for persons seeking treatment for STIs.⁶

The CDC guidelines recommend evaluation, testing and treatment of partners of persons with chlamydia. As well as testing for other STIs, the guidelines suggest Pap smear screening for women who have not been adequately screened, as they often are at high risk for later cervical cancer.⁷ All patients seeking treatment for STDs, including all patients attending STD clinics, should be screened routinely for HIV during each visit for a new complaint, regardless of whether the patient is known or suspected to have specific behavior risks for HIV infection.⁸

The Institute for Clinical Systems Improvement recommends screening for chlamydia and gonorrhea for all sexually active women aged 25 years and younger and other asymptomatic women at risk for infection. Routine screening for HIV is also recommended to all persons at high risk, including those seeking treatment for any STI.⁹

Evidence Summary

A low-normal B₁₂ level is 150 to 350 pg/mL. Levels less than 150 pg/mL indicate deficiency. Levels greater than 350 pg/mL indicate adequate B₁₂ supply.²

Vitamin B₁₂ is a necessary coenzyme in the metabolism of methylmalonic acid to succinyl choline, and is also a necessary coenzyme with folate in the metabolism of homocysteine to methionine. Therefore, a vitamin B₁₂ deficiency leads to elevated levels of unmetabolized methylmalonic acid and homocysteine. At a local lab the normal range of methylmalonic acid is 0.00 to 0.40 umol/L, and homocysteine’s normal range is 4.0 to 10.0 mmol/L. Normal levels might vary by laboratory. Other conditions, such as renal insufficiency, may also cause elevation of methylmalonic acid and homocysteine.³

Holotranscobalamin may become a first-choice assay for diagnosing early vitamin B₁₂ deficiency. Studies have shown that it compares favorably with current combined measures (B₁₂ levels, methylmalonic acid, homocysteine). Like current assays, holotranscobalamin is also affected by renal function. It requires further investigation to establish relevant cutoff levels before it can be recommended as a diagnostic strategy.⁴

Oral vitamin B₁₂ at doses of 1000 to 2000 mcg/d is a simple and cost-effective treatment option for any B₁₂-deficient person, and may actually be superior to intramuscular replacement.^5,6 A Cochrane Collaboration review of oral vitamin B₁₂ replacement found that these high doses seemed as effective as intramuscular vitamin B₁₂ in all B₁₂-deficient patients—even those with pernicious anemia, Crohn’s disease, ileal resection, or malabsorption states. The authors of the review recommend a “further large, pragmatic trial in a primary care setting” to determine whether oral vitamin B₁₂ is effective for patients with major common cases of malabsorption and to provide additional evidence for cost effectiveness.⁶

Recommendations from Others

Current guidelines recommend giving vitamin B₁₂ if methylmalonic acid or both methylmalonic acid and homocysteine are elevated. Give folate if only homocysteine is elevated. Give vitamin B₁₂ if homocysteine elevation persists in spite of adequate folate replacement.²

Monitor for correction of low-normal B₁₂ and metabolites with follow-up blood test after 1 to 2 months of treatment. The negative predictive value of normal metabolites (methylmalonic acid and homocysteine) is unknown.

Individuals with normal vitamin B₁₂ levels and metabolites but significant B₁₂ deficiency signs and symptoms have responded dramatically to B₁₂ replacement.⁷ Therefore, it is reasonable to treat and monitor for response as an alternative approach to the evaluation of a low-normal B₁₂ level. Pennypacker et al² state that “the ultimate gold standard for vitamin B₁₂ deficiency may be the reduction in homocysteine and methylmalonic acid concentrations and improvement in clinical symptoms or signs in response to vitamin B₁₂ treatment.”

Evidence Summary

A low-normal B₁₂ level is 150 to 350 pg/mL. Levels less than 150 pg/mL indicate deficiency. Levels greater than 350 pg/mL indicate adequate B₁₂ supply.²

Vitamin B₁₂ is a necessary coenzyme in the metabolism of methylmalonic acid to succinyl choline, and is also a necessary coenzyme with folate in the metabolism of homocysteine to methionine. Therefore, a vitamin B₁₂ deficiency leads to elevated levels of unmetabolized methylmalonic acid and homocysteine. At a local lab the normal range of methylmalonic acid is 0.00 to 0.40 umol/L, and homocysteine’s normal range is 4.0 to 10.0 mmol/L. Normal levels might vary by laboratory. Other conditions, such as renal insufficiency, may also cause elevation of methylmalonic acid and homocysteine.³

Holotranscobalamin may become a first-choice assay for diagnosing early vitamin B₁₂ deficiency. Studies have shown that it compares favorably with current combined measures (B₁₂ levels, methylmalonic acid, homocysteine). Like current assays, holotranscobalamin is also affected by renal function. It requires further investigation to establish relevant cutoff levels before it can be recommended as a diagnostic strategy.⁴

Oral vitamin B₁₂ at doses of 1000 to 2000 mcg/d is a simple and cost-effective treatment option for any B₁₂-deficient person, and may actually be superior to intramuscular replacement.^5,6 A Cochrane Collaboration review of oral vitamin B₁₂ replacement found that these high doses seemed as effective as intramuscular vitamin B₁₂ in all B₁₂-deficient patients—even those with pernicious anemia, Crohn’s disease, ileal resection, or malabsorption states. The authors of the review recommend a “further large, pragmatic trial in a primary care setting” to determine whether oral vitamin B₁₂ is effective for patients with major common cases of malabsorption and to provide additional evidence for cost effectiveness.⁶

Recommendations from Others

Current guidelines recommend giving vitamin B₁₂ if methylmalonic acid or both methylmalonic acid and homocysteine are elevated. Give folate if only homocysteine is elevated. Give vitamin B₁₂ if homocysteine elevation persists in spite of adequate folate replacement.²

Monitor for correction of low-normal B₁₂ and metabolites with follow-up blood test after 1 to 2 months of treatment. The negative predictive value of normal metabolites (methylmalonic acid and homocysteine) is unknown.

Individuals with normal vitamin B₁₂ levels and metabolites but significant B₁₂ deficiency signs and symptoms have responded dramatically to B₁₂ replacement.⁷ Therefore, it is reasonable to treat and monitor for response as an alternative approach to the evaluation of a low-normal B₁₂ level. Pennypacker et al² state that “the ultimate gold standard for vitamin B₁₂ deficiency may be the reduction in homocysteine and methylmalonic acid concentrations and improvement in clinical symptoms or signs in response to vitamin B₁₂ treatment.”

Evidence Summary

A low-normal B₁₂ level is 150 to 350 pg/mL. Levels less than 150 pg/mL indicate deficiency. Levels greater than 350 pg/mL indicate adequate B₁₂ supply.²

Vitamin B₁₂ is a necessary coenzyme in the metabolism of methylmalonic acid to succinyl choline, and is also a necessary coenzyme with folate in the metabolism of homocysteine to methionine. Therefore, a vitamin B₁₂ deficiency leads to elevated levels of unmetabolized methylmalonic acid and homocysteine. At a local lab the normal range of methylmalonic acid is 0.00 to 0.40 umol/L, and homocysteine’s normal range is 4.0 to 10.0 mmol/L. Normal levels might vary by laboratory. Other conditions, such as renal insufficiency, may also cause elevation of methylmalonic acid and homocysteine.³

Holotranscobalamin may become a first-choice assay for diagnosing early vitamin B₁₂ deficiency. Studies have shown that it compares favorably with current combined measures (B₁₂ levels, methylmalonic acid, homocysteine). Like current assays, holotranscobalamin is also affected by renal function. It requires further investigation to establish relevant cutoff levels before it can be recommended as a diagnostic strategy.⁴

Oral vitamin B₁₂ at doses of 1000 to 2000 mcg/d is a simple and cost-effective treatment option for any B₁₂-deficient person, and may actually be superior to intramuscular replacement.^5,6 A Cochrane Collaboration review of oral vitamin B₁₂ replacement found that these high doses seemed as effective as intramuscular vitamin B₁₂ in all B₁₂-deficient patients—even those with pernicious anemia, Crohn’s disease, ileal resection, or malabsorption states. The authors of the review recommend a “further large, pragmatic trial in a primary care setting” to determine whether oral vitamin B₁₂ is effective for patients with major common cases of malabsorption and to provide additional evidence for cost effectiveness.⁶

Recommendations from Others

Current guidelines recommend giving vitamin B₁₂ if methylmalonic acid or both methylmalonic acid and homocysteine are elevated. Give folate if only homocysteine is elevated. Give vitamin B₁₂ if homocysteine elevation persists in spite of adequate folate replacement.²

Monitor for correction of low-normal B₁₂ and metabolites with follow-up blood test after 1 to 2 months of treatment. The negative predictive value of normal metabolites (methylmalonic acid and homocysteine) is unknown.

Individuals with normal vitamin B₁₂ levels and metabolites but significant B₁₂ deficiency signs and symptoms have responded dramatically to B₁₂ replacement.⁷ Therefore, it is reasonable to treat and monitor for response as an alternative approach to the evaluation of a low-normal B₁₂ level. Pennypacker et al² state that “the ultimate gold standard for vitamin B₁₂ deficiency may be the reduction in homocysteine and methylmalonic acid concentrations and improvement in clinical symptoms or signs in response to vitamin B₁₂ treatment.”

Evidence Summary

Heart rate varies by age; however, tachycardia in adults is usually defined as a rate exceeding 100 beats/minute.¹ Tachycardia at rest requires a diagnostic evaluation. However, our search found no systematic reviews, randomized trials, or prospective cohort studies relevant to this question. The highest level of evidence we located was an international practice guideline developed by the American College of Cardiology, the American Heart Association Task Force on Practice Guidelines, and the European Society of Cardiology Committee for Practice Guidelines.¹

This joint guideline recommends that the diagnostic evaluation of a hemodynamically stable patient should begin with a clinical history, physical examination with relevant labs, and 12-lead ECG.¹ Many patients with tachycardia are asymptomatic; however, common symptoms and complaints include palpitations, fatigue, lightheadedness, chest discomfort, dyspnea, presyncope, or syncope.¹ If the patient has experienced symptoms, it is of crucial importance to obtain a clinical history describing the pattern in terms of the number of episodes, duration, frequency, mode of onset, and possible triggers.¹

The main goals of the physical examination, labs, and the 12-lead ECG are to determine if the patient has a sinus or non-sinus tachycardia and to look for other findings that may suggest either a cause for the tachycardia or any complications resulting from the tachycardia.

First, determine if the patient’s heartbeat is regular or irregular. Atrial flutter and atrial fibrillation are common causes of an irregular heartbeat that can easily be diagnosed with a 12-lead ECG. Second, determine the width of the QRS interval: narrow QRS complex tachycardias are supraventricular (from the sinus node, the atria, and the atrioventricular junction) in origin, and wide QRS complex tachycardias are usually ventricular (from all sites below the AV junction).^2,3 If an irregular heartbeat or wide-complex tachycardia is detected, appropriate management (including possible urgent referrals) should begin immediately.¹ A stable patient with a regular rhythm and a narrow QRS complex can be further investigated at a more relaxed pace.

Refer to the TABLE for a listing of common secondary causes for sinus tachycardia, which should direct lab investigations. If no secondary cause is easily identifiable, a 24-hour monitor is recommended as the next step.

TABLE
Potential secondary causes of resting sinus tachycardia^5-7

Recommendations from others

Textbook chapters and other review articles regarding this topic describe a similar initial evaluation and provide further details about interpreting the 12-lead ECG.^2-7 The most relevant and recent review article suggests that further investigation of narrow QRS complex tachycardias with a regular rate currently involves 4 diagnostic categories: normal sinus tachycardia (ie, secondary cause can be identified), inappropriate sinus tachycardia (IST), postural orthostatic tachycardia syndrome (POTS), and sinus node reentry tachycardia (SNRT).⁴

If a secondary cause is identified, it should be treated appropriately. If no underlying cause is discovered, a 24-hour Holter monitor is recommended.

Persistent sinus tachycardia (sometimes with nocturnal normalization of heart rate) is diagnosed as IST.⁴ If the monitor shows paroxysmal episodes of sinus tachycardia, determine if they are triggered by orthostasis and relieved by recumbency (confirm with head upright tilt test) to make the diagnosis of POTS. If it is not POTS, the recordings from the 24-hour Holter monitor help make the diagnosis of SNRT, which consists of sudden, paroxysmal, and usually nonsustained tachycardia.⁴ The FIGURE shows an algorithm of one common diagnostic strategy for evaluation of tachycardia.^2-7

FIGURE
Diagnostic algorithm for evaluating tachycardias⁴

Evidence Summary

Heart rate varies by age; however, tachycardia in adults is usually defined as a rate exceeding 100 beats/minute.¹ Tachycardia at rest requires a diagnostic evaluation. However, our search found no systematic reviews, randomized trials, or prospective cohort studies relevant to this question. The highest level of evidence we located was an international practice guideline developed by the American College of Cardiology, the American Heart Association Task Force on Practice Guidelines, and the European Society of Cardiology Committee for Practice Guidelines.¹

This joint guideline recommends that the diagnostic evaluation of a hemodynamically stable patient should begin with a clinical history, physical examination with relevant labs, and 12-lead ECG.¹ Many patients with tachycardia are asymptomatic; however, common symptoms and complaints include palpitations, fatigue, lightheadedness, chest discomfort, dyspnea, presyncope, or syncope.¹ If the patient has experienced symptoms, it is of crucial importance to obtain a clinical history describing the pattern in terms of the number of episodes, duration, frequency, mode of onset, and possible triggers.¹

The main goals of the physical examination, labs, and the 12-lead ECG are to determine if the patient has a sinus or non-sinus tachycardia and to look for other findings that may suggest either a cause for the tachycardia or any complications resulting from the tachycardia.

First, determine if the patient’s heartbeat is regular or irregular. Atrial flutter and atrial fibrillation are common causes of an irregular heartbeat that can easily be diagnosed with a 12-lead ECG. Second, determine the width of the QRS interval: narrow QRS complex tachycardias are supraventricular (from the sinus node, the atria, and the atrioventricular junction) in origin, and wide QRS complex tachycardias are usually ventricular (from all sites below the AV junction).^2,3 If an irregular heartbeat or wide-complex tachycardia is detected, appropriate management (including possible urgent referrals) should begin immediately.¹ A stable patient with a regular rhythm and a narrow QRS complex can be further investigated at a more relaxed pace.

Refer to the TABLE for a listing of common secondary causes for sinus tachycardia, which should direct lab investigations. If no secondary cause is easily identifiable, a 24-hour monitor is recommended as the next step.

TABLE
Potential secondary causes of resting sinus tachycardia^5-7

Recommendations from others

Textbook chapters and other review articles regarding this topic describe a similar initial evaluation and provide further details about interpreting the 12-lead ECG.^2-7 The most relevant and recent review article suggests that further investigation of narrow QRS complex tachycardias with a regular rate currently involves 4 diagnostic categories: normal sinus tachycardia (ie, secondary cause can be identified), inappropriate sinus tachycardia (IST), postural orthostatic tachycardia syndrome (POTS), and sinus node reentry tachycardia (SNRT).⁴

If a secondary cause is identified, it should be treated appropriately. If no underlying cause is discovered, a 24-hour Holter monitor is recommended.

Persistent sinus tachycardia (sometimes with nocturnal normalization of heart rate) is diagnosed as IST.⁴ If the monitor shows paroxysmal episodes of sinus tachycardia, determine if they are triggered by orthostasis and relieved by recumbency (confirm with head upright tilt test) to make the diagnosis of POTS. If it is not POTS, the recordings from the 24-hour Holter monitor help make the diagnosis of SNRT, which consists of sudden, paroxysmal, and usually nonsustained tachycardia.⁴ The FIGURE shows an algorithm of one common diagnostic strategy for evaluation of tachycardia.^2-7

FIGURE
Diagnostic algorithm for evaluating tachycardias⁴

Evidence Summary

Heart rate varies by age; however, tachycardia in adults is usually defined as a rate exceeding 100 beats/minute.¹ Tachycardia at rest requires a diagnostic evaluation. However, our search found no systematic reviews, randomized trials, or prospective cohort studies relevant to this question. The highest level of evidence we located was an international practice guideline developed by the American College of Cardiology, the American Heart Association Task Force on Practice Guidelines, and the European Society of Cardiology Committee for Practice Guidelines.¹

This joint guideline recommends that the diagnostic evaluation of a hemodynamically stable patient should begin with a clinical history, physical examination with relevant labs, and 12-lead ECG.¹ Many patients with tachycardia are asymptomatic; however, common symptoms and complaints include palpitations, fatigue, lightheadedness, chest discomfort, dyspnea, presyncope, or syncope.¹ If the patient has experienced symptoms, it is of crucial importance to obtain a clinical history describing the pattern in terms of the number of episodes, duration, frequency, mode of onset, and possible triggers.¹

The main goals of the physical examination, labs, and the 12-lead ECG are to determine if the patient has a sinus or non-sinus tachycardia and to look for other findings that may suggest either a cause for the tachycardia or any complications resulting from the tachycardia.

First, determine if the patient’s heartbeat is regular or irregular. Atrial flutter and atrial fibrillation are common causes of an irregular heartbeat that can easily be diagnosed with a 12-lead ECG. Second, determine the width of the QRS interval: narrow QRS complex tachycardias are supraventricular (from the sinus node, the atria, and the atrioventricular junction) in origin, and wide QRS complex tachycardias are usually ventricular (from all sites below the AV junction).^2,3 If an irregular heartbeat or wide-complex tachycardia is detected, appropriate management (including possible urgent referrals) should begin immediately.¹ A stable patient with a regular rhythm and a narrow QRS complex can be further investigated at a more relaxed pace.

Refer to the TABLE for a listing of common secondary causes for sinus tachycardia, which should direct lab investigations. If no secondary cause is easily identifiable, a 24-hour monitor is recommended as the next step.

TABLE
Potential secondary causes of resting sinus tachycardia^5-7

Recommendations from others

Textbook chapters and other review articles regarding this topic describe a similar initial evaluation and provide further details about interpreting the 12-lead ECG.^2-7 The most relevant and recent review article suggests that further investigation of narrow QRS complex tachycardias with a regular rate currently involves 4 diagnostic categories: normal sinus tachycardia (ie, secondary cause can be identified), inappropriate sinus tachycardia (IST), postural orthostatic tachycardia syndrome (POTS), and sinus node reentry tachycardia (SNRT).⁴

If a secondary cause is identified, it should be treated appropriately. If no underlying cause is discovered, a 24-hour Holter monitor is recommended.

Persistent sinus tachycardia (sometimes with nocturnal normalization of heart rate) is diagnosed as IST.⁴ If the monitor shows paroxysmal episodes of sinus tachycardia, determine if they are triggered by orthostasis and relieved by recumbency (confirm with head upright tilt test) to make the diagnosis of POTS. If it is not POTS, the recordings from the 24-hour Holter monitor help make the diagnosis of SNRT, which consists of sudden, paroxysmal, and usually nonsustained tachycardia.⁴ The FIGURE shows an algorithm of one common diagnostic strategy for evaluation of tachycardia.^2-7

FIGURE
Diagnostic algorithm for evaluating tachycardias⁴

Evidence summary

No randomized controlled trials have identified the optimal management of patients with asymptomatic ischemia on EST. EST is not generally recommended for asymptomatic persons because of its limited predictive value. EST may sometimes be useful for predicting mortality risk among patients who plan to begin exercise programs, or whose jobs affect public safety, or who have conditions such as diabetes or chronic renal insufficiency.¹

For example, a prospective cohort study of 613 patients with suspected coronary artery disease investigated EST duration, presence of angina, and ST-segment depression as predictors of mortality.² Patients with asymptomatic ischemia (2 mm of ischemic depression) whose EST lasted 15 minutes (DTS=+5, low risk) had a 5-year cardiac mortality of less than 1%, compared with 2% for those whose EST was tolerated for only 7 minutes (DTS=–3, intermediate risk).² (See TABLE for DTS formula.)

Later prospective cohort studies^3,4 confirmed that a low-risk DTS was associated with high 5-year survival—eg, 97% among 2758 patients (median age 49, 70% male, 30% prior myocardial infarction, 49% with angina).³ Those with an intermediate- or high-risk DTS had corresponding survival rates of 90% and 65%, respectively. The DTS was further analyzed in a 5-year follow-up of 9454 patients, 88% of whom were low-risk (75% undergoing screening EST).⁴ Most patients (1406 of 1477) with ST-segment depression ≥1 mm had asymptomatic ischemia, only 71 having EST-induced angina. A low-risk DTS was associated with 98% survival, compared with 92% for patients with an intermediate- or high-risk DTS.⁴

Patients with an intermediate-risk DTS, and normal or near-normal perfusion imaging without cardiomegaly, also comprised a low-risk group with 5-year cardiac survival of 99.5%.⁵ Post-EST heart rate recovery and the Chronotropic Index are enhancements to the DTS.⁶ Used singly or in combination, these tools provided more accurate estimates of 5-year all-cause mortality among 9454 patients referred for EST (TABLE).

Two other prospective cohort studies of middle-aged men with EST showing asymptomatic ischemia did not employ the above enhancements but reported major impact of cardiac risk factors on mortality. Among 25,927 healthy men followed for an average of 8.4 years, the age-adjusted risk of death from all causes of those with asymptomatic ischemia increased from 2-fold (95% confidence interval [CI], 1.1–3.8, P=.03) with no risk factors to 4 (95% CI, 2.7–5.4) with 1 risk factor, 5 (95% CI, 3.3–6.9) with 2 risk factors, and 8 (95% CI, 5.4–12.8) with 3 or more risk factors (P<.0001).⁷ Other investigators found increased mortality from coronary artery disease to be associated with smoking (relative risk [RR]=5.0 [95% CI, 2.1–11.9]), hypercholesterolemia (RR=7.6 [95% CI, 3.0–19.5]) and hypertension (RR=6.7 [95% CI, 2.9–16.0]).⁸

While risk factor reduction seems logical for all patients who have asymptomatic ischemia, actual evidence of benefit is limited. In the MRFIT study,⁹ high-risk men with asymptomatic ischemia were randomized to either usual care or a special intervention to reduce smoking, blood cholesterol, and diastolic blood pressure. The intervention group had lower cardiac mortality than men who received usual care (22 vs 53 per 1000, P<.002).⁹ As observed in 2 large prospective cohort studies, one of which documented abnormal EST in 17%, males who improved their fitness had 23% (95% CI, 4–42) and 44% (95% CI, 5–59) lower mortality over 18 years of mean follow-up, respectively.^10,11 Smoking cessation is also important, associated with 41% lower mortality (95% CI, 20–57).¹¹

Most of the evidence underlying the above recommendations derives from studies of men and hence may not apply directly to women. The American Heart Association’s guidelines¹² for cardiovascular disease prevention in women do not consider EST results in risk assessment. They rely instead on the Framingham Risk Score to stratify women’s 10-year risk of coronary events as low (<10%), intermediate (10%–20%), and high (>20%), and prioritize recommendations for risk factor reduction according to these levels.¹²

TABLE
Duke Treadmill Scores: 5-year all-cause mortality

Recommendations from others

American College of Cardiology/American Heart Association (ACC/AHA) guidelines¹ favor medical treatment for low-risk patients with asymptomatic ischemia (annual cardiac mortality ≤1%—ie, DTS ≥5, or normal HRR or normal CI). The ACC/AHA recommend perfusion imaging (or exercise echocardiography) for patients with asymptomatic ischemia who have intermediate or high-risk DTS.¹ Such imaging can refine prognosis, guide therapy with aspirin, beta blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors, and possibly identify patients who might benefit from coronary angiography and revascularization (AHA/ACC Recommendation Class IIa–IIb, Level of Evidence B–C).

Evidence summary

No randomized controlled trials have identified the optimal management of patients with asymptomatic ischemia on EST. EST is not generally recommended for asymptomatic persons because of its limited predictive value. EST may sometimes be useful for predicting mortality risk among patients who plan to begin exercise programs, or whose jobs affect public safety, or who have conditions such as diabetes or chronic renal insufficiency.¹

For example, a prospective cohort study of 613 patients with suspected coronary artery disease investigated EST duration, presence of angina, and ST-segment depression as predictors of mortality.² Patients with asymptomatic ischemia (2 mm of ischemic depression) whose EST lasted 15 minutes (DTS=+5, low risk) had a 5-year cardiac mortality of less than 1%, compared with 2% for those whose EST was tolerated for only 7 minutes (DTS=–3, intermediate risk).² (See TABLE for DTS formula.)

Later prospective cohort studies^3,4 confirmed that a low-risk DTS was associated with high 5-year survival—eg, 97% among 2758 patients (median age 49, 70% male, 30% prior myocardial infarction, 49% with angina).³ Those with an intermediate- or high-risk DTS had corresponding survival rates of 90% and 65%, respectively. The DTS was further analyzed in a 5-year follow-up of 9454 patients, 88% of whom were low-risk (75% undergoing screening EST).⁴ Most patients (1406 of 1477) with ST-segment depression ≥1 mm had asymptomatic ischemia, only 71 having EST-induced angina. A low-risk DTS was associated with 98% survival, compared with 92% for patients with an intermediate- or high-risk DTS.⁴

Patients with an intermediate-risk DTS, and normal or near-normal perfusion imaging without cardiomegaly, also comprised a low-risk group with 5-year cardiac survival of 99.5%.⁵ Post-EST heart rate recovery and the Chronotropic Index are enhancements to the DTS.⁶ Used singly or in combination, these tools provided more accurate estimates of 5-year all-cause mortality among 9454 patients referred for EST (TABLE).

Two other prospective cohort studies of middle-aged men with EST showing asymptomatic ischemia did not employ the above enhancements but reported major impact of cardiac risk factors on mortality. Among 25,927 healthy men followed for an average of 8.4 years, the age-adjusted risk of death from all causes of those with asymptomatic ischemia increased from 2-fold (95% confidence interval [CI], 1.1–3.8, P=.03) with no risk factors to 4 (95% CI, 2.7–5.4) with 1 risk factor, 5 (95% CI, 3.3–6.9) with 2 risk factors, and 8 (95% CI, 5.4–12.8) with 3 or more risk factors (P<.0001).⁷ Other investigators found increased mortality from coronary artery disease to be associated with smoking (relative risk [RR]=5.0 [95% CI, 2.1–11.9]), hypercholesterolemia (RR=7.6 [95% CI, 3.0–19.5]) and hypertension (RR=6.7 [95% CI, 2.9–16.0]).⁸

While risk factor reduction seems logical for all patients who have asymptomatic ischemia, actual evidence of benefit is limited. In the MRFIT study,⁹ high-risk men with asymptomatic ischemia were randomized to either usual care or a special intervention to reduce smoking, blood cholesterol, and diastolic blood pressure. The intervention group had lower cardiac mortality than men who received usual care (22 vs 53 per 1000, P<.002).⁹ As observed in 2 large prospective cohort studies, one of which documented abnormal EST in 17%, males who improved their fitness had 23% (95% CI, 4–42) and 44% (95% CI, 5–59) lower mortality over 18 years of mean follow-up, respectively.^10,11 Smoking cessation is also important, associated with 41% lower mortality (95% CI, 20–57).¹¹

Most of the evidence underlying the above recommendations derives from studies of men and hence may not apply directly to women. The American Heart Association’s guidelines¹² for cardiovascular disease prevention in women do not consider EST results in risk assessment. They rely instead on the Framingham Risk Score to stratify women’s 10-year risk of coronary events as low (<10%), intermediate (10%–20%), and high (>20%), and prioritize recommendations for risk factor reduction according to these levels.¹²

TABLE
Duke Treadmill Scores: 5-year all-cause mortality

Recommendations from others

American College of Cardiology/American Heart Association (ACC/AHA) guidelines¹ favor medical treatment for low-risk patients with asymptomatic ischemia (annual cardiac mortality ≤1%—ie, DTS ≥5, or normal HRR or normal CI). The ACC/AHA recommend perfusion imaging (or exercise echocardiography) for patients with asymptomatic ischemia who have intermediate or high-risk DTS.¹ Such imaging can refine prognosis, guide therapy with aspirin, beta blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors, and possibly identify patients who might benefit from coronary angiography and revascularization (AHA/ACC Recommendation Class IIa–IIb, Level of Evidence B–C).

Evidence summary

No randomized controlled trials have identified the optimal management of patients with asymptomatic ischemia on EST. EST is not generally recommended for asymptomatic persons because of its limited predictive value. EST may sometimes be useful for predicting mortality risk among patients who plan to begin exercise programs, or whose jobs affect public safety, or who have conditions such as diabetes or chronic renal insufficiency.¹

For example, a prospective cohort study of 613 patients with suspected coronary artery disease investigated EST duration, presence of angina, and ST-segment depression as predictors of mortality.² Patients with asymptomatic ischemia (2 mm of ischemic depression) whose EST lasted 15 minutes (DTS=+5, low risk) had a 5-year cardiac mortality of less than 1%, compared with 2% for those whose EST was tolerated for only 7 minutes (DTS=–3, intermediate risk).² (See TABLE for DTS formula.)

Later prospective cohort studies^3,4 confirmed that a low-risk DTS was associated with high 5-year survival—eg, 97% among 2758 patients (median age 49, 70% male, 30% prior myocardial infarction, 49% with angina).³ Those with an intermediate- or high-risk DTS had corresponding survival rates of 90% and 65%, respectively. The DTS was further analyzed in a 5-year follow-up of 9454 patients, 88% of whom were low-risk (75% undergoing screening EST).⁴ Most patients (1406 of 1477) with ST-segment depression ≥1 mm had asymptomatic ischemia, only 71 having EST-induced angina. A low-risk DTS was associated with 98% survival, compared with 92% for patients with an intermediate- or high-risk DTS.⁴

Patients with an intermediate-risk DTS, and normal or near-normal perfusion imaging without cardiomegaly, also comprised a low-risk group with 5-year cardiac survival of 99.5%.⁵ Post-EST heart rate recovery and the Chronotropic Index are enhancements to the DTS.⁶ Used singly or in combination, these tools provided more accurate estimates of 5-year all-cause mortality among 9454 patients referred for EST (TABLE).

Two other prospective cohort studies of middle-aged men with EST showing asymptomatic ischemia did not employ the above enhancements but reported major impact of cardiac risk factors on mortality. Among 25,927 healthy men followed for an average of 8.4 years, the age-adjusted risk of death from all causes of those with asymptomatic ischemia increased from 2-fold (95% confidence interval [CI], 1.1–3.8, P=.03) with no risk factors to 4 (95% CI, 2.7–5.4) with 1 risk factor, 5 (95% CI, 3.3–6.9) with 2 risk factors, and 8 (95% CI, 5.4–12.8) with 3 or more risk factors (P<.0001).⁷ Other investigators found increased mortality from coronary artery disease to be associated with smoking (relative risk [RR]=5.0 [95% CI, 2.1–11.9]), hypercholesterolemia (RR=7.6 [95% CI, 3.0–19.5]) and hypertension (RR=6.7 [95% CI, 2.9–16.0]).⁸

While risk factor reduction seems logical for all patients who have asymptomatic ischemia, actual evidence of benefit is limited. In the MRFIT study,⁹ high-risk men with asymptomatic ischemia were randomized to either usual care or a special intervention to reduce smoking, blood cholesterol, and diastolic blood pressure. The intervention group had lower cardiac mortality than men who received usual care (22 vs 53 per 1000, P<.002).⁹ As observed in 2 large prospective cohort studies, one of which documented abnormal EST in 17%, males who improved their fitness had 23% (95% CI, 4–42) and 44% (95% CI, 5–59) lower mortality over 18 years of mean follow-up, respectively.^10,11 Smoking cessation is also important, associated with 41% lower mortality (95% CI, 20–57).¹¹

Most of the evidence underlying the above recommendations derives from studies of men and hence may not apply directly to women. The American Heart Association’s guidelines¹² for cardiovascular disease prevention in women do not consider EST results in risk assessment. They rely instead on the Framingham Risk Score to stratify women’s 10-year risk of coronary events as low (<10%), intermediate (10%–20%), and high (>20%), and prioritize recommendations for risk factor reduction according to these levels.¹²

TABLE
Duke Treadmill Scores: 5-year all-cause mortality

Recommendations from others

American College of Cardiology/American Heart Association (ACC/AHA) guidelines¹ favor medical treatment for low-risk patients with asymptomatic ischemia (annual cardiac mortality ≤1%—ie, DTS ≥5, or normal HRR or normal CI). The ACC/AHA recommend perfusion imaging (or exercise echocardiography) for patients with asymptomatic ischemia who have intermediate or high-risk DTS.¹ Such imaging can refine prognosis, guide therapy with aspirin, beta blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors, and possibly identify patients who might benefit from coronary angiography and revascularization (AHA/ACC Recommendation Class IIa–IIb, Level of Evidence B–C).