Kristin Hitchcock, MSI

Evidence summary

Radiographic imaging to rule out appendicitis has become more commonplace, but it comes with an increased financial cost and additional delay in surgical intervention. Knowing the accuracy of common diagnostic tests may reduce the need for confirmatory imaging studies that increase both cost and time to surgery.

High levels of 2 or more inflammatory values are helpful

A meta-analysis of patients hospitalized for suspected acute appendicitis analyzed 28 different diagnostic variables in 24 studies.¹ Variables included WBC, granulocyte count, PMN proportion, CRP level, and body temperature; histopathology was the gold standard. In no circumstance did an isolated elevation of any 1 factor result in a significant LR+. In addition, the absence of any 1 variable failed to yield a LR– <0.01 (low enough to exclude appendicitis).

Clinicians inherently combine multiple variables when evaluating patients, and when evaluating patients with abdominal pain, this technique can result in identification of adequate likelihood ratios (TABLE).¹ In general, when 2 or more of the aforementioned inflammatory variables are present, the diagnosis of acute appendicitis is likely. When all markers of inflammation are normal, though acute appendicitis is less likely, the power is insufficient to exclude it as a possible diagnosis.

The value of CRP in the evaluation of suspected appendicitis was confirmed in a retrospective evaluation of 566 patients who underwent appendectomies.² The sensitivity and specificity of the test improved depending on the duration of symptoms for both appendicitis and ruptured appendicitis. For appendicitis, CRP levels >1.4, 4.0, and 10.5 on Days 1, 2, and 3 had sensitivities/specificities of 0.38/0.81, 0.63/0.78, and 0.72/0.83, respectively. For ruptured appendicitis, levels of 3.3, 8.5, and 12.0 on Days 1, 2, and 3 had sensitivities/specificities of 0.77/0.89, 0.70/0.95, and 0.90/0.96, respectively.

Enlarged appendix with inflammatory changes to mesenteric fatIn a series of 439 patients with symptoms suggestive of acute appendicitis, those with confirmed appendicitis (n=101) had a mean WBC count of 14.8 K/μL (95% CI, 13.9–15.8) and a mean neutrophil percentage of 82 (95% CI, 80–84).¹ In contrast, those without appendicitis (n=338) had a mean WBC count of 9.2 K/μL (95% CI, 9.0–9.4) and a mean neutrophil percentage of 68 (95% CI, 66–70).

TABLE
How much do the inflammatory markers tell us? A look at likelihood ratios for appendicitis

Recommendations from others

A review of medical and professional associations revealed no official guidelines regarding the evaluation of suspected acute appendicitis. Surgical textbooks confirm that the diagnosis of acute appendicitis is made primarily by history and examination, with help from laboratory and radiographic studies.³

Evidence summary

Radiographic imaging to rule out appendicitis has become more commonplace, but it comes with an increased financial cost and additional delay in surgical intervention. Knowing the accuracy of common diagnostic tests may reduce the need for confirmatory imaging studies that increase both cost and time to surgery.

High levels of 2 or more inflammatory values are helpful

A meta-analysis of patients hospitalized for suspected acute appendicitis analyzed 28 different diagnostic variables in 24 studies.¹ Variables included WBC, granulocyte count, PMN proportion, CRP level, and body temperature; histopathology was the gold standard. In no circumstance did an isolated elevation of any 1 factor result in a significant LR+. In addition, the absence of any 1 variable failed to yield a LR– <0.01 (low enough to exclude appendicitis).

Clinicians inherently combine multiple variables when evaluating patients, and when evaluating patients with abdominal pain, this technique can result in identification of adequate likelihood ratios (TABLE).¹ In general, when 2 or more of the aforementioned inflammatory variables are present, the diagnosis of acute appendicitis is likely. When all markers of inflammation are normal, though acute appendicitis is less likely, the power is insufficient to exclude it as a possible diagnosis.

The value of CRP in the evaluation of suspected appendicitis was confirmed in a retrospective evaluation of 566 patients who underwent appendectomies.² The sensitivity and specificity of the test improved depending on the duration of symptoms for both appendicitis and ruptured appendicitis. For appendicitis, CRP levels >1.4, 4.0, and 10.5 on Days 1, 2, and 3 had sensitivities/specificities of 0.38/0.81, 0.63/0.78, and 0.72/0.83, respectively. For ruptured appendicitis, levels of 3.3, 8.5, and 12.0 on Days 1, 2, and 3 had sensitivities/specificities of 0.77/0.89, 0.70/0.95, and 0.90/0.96, respectively.

Enlarged appendix with inflammatory changes to mesenteric fatIn a series of 439 patients with symptoms suggestive of acute appendicitis, those with confirmed appendicitis (n=101) had a mean WBC count of 14.8 K/μL (95% CI, 13.9–15.8) and a mean neutrophil percentage of 82 (95% CI, 80–84).¹ In contrast, those without appendicitis (n=338) had a mean WBC count of 9.2 K/μL (95% CI, 9.0–9.4) and a mean neutrophil percentage of 68 (95% CI, 66–70).

TABLE
How much do the inflammatory markers tell us? A look at likelihood ratios for appendicitis

Recommendations from others

A review of medical and professional associations revealed no official guidelines regarding the evaluation of suspected acute appendicitis. Surgical textbooks confirm that the diagnosis of acute appendicitis is made primarily by history and examination, with help from laboratory and radiographic studies.³

Evidence summary

Radiographic imaging to rule out appendicitis has become more commonplace, but it comes with an increased financial cost and additional delay in surgical intervention. Knowing the accuracy of common diagnostic tests may reduce the need for confirmatory imaging studies that increase both cost and time to surgery.

High levels of 2 or more inflammatory values are helpful

A meta-analysis of patients hospitalized for suspected acute appendicitis analyzed 28 different diagnostic variables in 24 studies.¹ Variables included WBC, granulocyte count, PMN proportion, CRP level, and body temperature; histopathology was the gold standard. In no circumstance did an isolated elevation of any 1 factor result in a significant LR+. In addition, the absence of any 1 variable failed to yield a LR– <0.01 (low enough to exclude appendicitis).

Clinicians inherently combine multiple variables when evaluating patients, and when evaluating patients with abdominal pain, this technique can result in identification of adequate likelihood ratios (TABLE).¹ In general, when 2 or more of the aforementioned inflammatory variables are present, the diagnosis of acute appendicitis is likely. When all markers of inflammation are normal, though acute appendicitis is less likely, the power is insufficient to exclude it as a possible diagnosis.

The value of CRP in the evaluation of suspected appendicitis was confirmed in a retrospective evaluation of 566 patients who underwent appendectomies.² The sensitivity and specificity of the test improved depending on the duration of symptoms for both appendicitis and ruptured appendicitis. For appendicitis, CRP levels >1.4, 4.0, and 10.5 on Days 1, 2, and 3 had sensitivities/specificities of 0.38/0.81, 0.63/0.78, and 0.72/0.83, respectively. For ruptured appendicitis, levels of 3.3, 8.5, and 12.0 on Days 1, 2, and 3 had sensitivities/specificities of 0.77/0.89, 0.70/0.95, and 0.90/0.96, respectively.

Enlarged appendix with inflammatory changes to mesenteric fatIn a series of 439 patients with symptoms suggestive of acute appendicitis, those with confirmed appendicitis (n=101) had a mean WBC count of 14.8 K/μL (95% CI, 13.9–15.8) and a mean neutrophil percentage of 82 (95% CI, 80–84).¹ In contrast, those without appendicitis (n=338) had a mean WBC count of 9.2 K/μL (95% CI, 9.0–9.4) and a mean neutrophil percentage of 68 (95% CI, 66–70).

TABLE
How much do the inflammatory markers tell us? A look at likelihood ratios for appendicitis

Recommendations from others

A review of medical and professional associations revealed no official guidelines regarding the evaluation of suspected acute appendicitis. Surgical textbooks confirm that the diagnosis of acute appendicitis is made primarily by history and examination, with help from laboratory and radiographic studies.³

Evidence summary

For acutely febrile patients, the presence of an elevated white blood cell (WBC) count with elevated band forms has dogmatically been thought of as a marker for bacterial infection.¹ Current literature, however, does not support this.²

Neisseria meningitides

A retrospective study of 5353 infants ages 3 to 89 days presenting to the emergency department for evaluation of fever showed that 3 of 4 infants ultimately diagnosed with bacterial meningitis would have been missed if the WBC count alone were used to predict which infants need a lumbar puncture.³ A prospective study of 2492 children ages 3 to 24 months presenting to the emergency department with acute fever and an absolute WBC count >15,000/mm³ revealed that neither a polymorphonuclear count of >10,000/mm³ (>66% segmented forms) nor a band count of >500/mm³ was associated with an increased likelihood of occult bacterial infection.⁴ Other studies show that the WBC alone is poorly discriminatory for identifying either bacteremia or meningitis.^5,6

To improve the diagnostic utility of the CBC, other studies have examined individual components of the white blood cell differential count (TABLE 1). In particular, the use of the absolute neutrophil count (ANC) has been proposed as a superior marker of serious bacterial infection.⁷ A review of 6579 outpatients aged 3 to 36 months presenting to the emergency department with temperatures of 39°C or higher showed an ANC of >10,000/mm³ as more predictive of occult pneumococcal bacteremia than an elevated WBC count (>15,000/mm³) alone.⁸ Another retrospective review of more than 10,000 patients aged 3 to 36 months presenting to the emergency department used logistic regression to identify predictors of bacteremia. In this study, ANC (>9500/mm³) and WBC (>14,300/mm³) were of equal sensitivity (75%) and specificity (75%) in identifying serious bacterial infection.⁹ Finally, the band count alone does not accurately predict serious bacterial infection.¹⁰

In summary, the CBC cannot be used in isolation to differentiate bacterial from viral illness. The CBC can, however, augment clinical data from the history and physical examination to predict the likelihood of serious bacterial illness. As a result, numerous diagnostic criteria, each incorporating elements of the CBC, have been developed in an attempt to accurately differentiate bacterial from viral illness in acutely febrile patients, most typically children (TABLE 2). These criteria differ by age of the patient, clinical testing recommendations, indications for antibiotic therapy, as well as WBC cutoffs.

TABLE 1
WBC markers: How good are they at predicting serious bacterial infection?^9,18,19

TABLE 2
Clinical criteria for predicting serious bacterial infection in febrile children

Recommendations from others

The American College of Emergency Physicians recommends considering antibiotic therapy for previously healthy, well-appearing children ages 3 to 36 months who present with a fever without a clinical source and a WBC count >15,000/mm³.^3,14

The University of Cincinnati Evidence-Based Clinical Practice Guidelines for fever of uncertain source in children ages 2 to 36 months recommends obtaining a CBC for any child who is ill-appearing or at high risk for bacteremia (determined by the clinicians’ judgment). A WBC of ≥15,000/mm³ or ANC >10,000/mm³ provide support for antibiotic therapy.¹⁵ The 1993 American Academy of Pediatrics guidelines for fever ≥39°C without a source in children ages 3 months to 3 years recommends a CBC; if the WBC count ≥15,000/mm³, they recommend a blood culture and treatment with antibiotics pending culture results.^3,16

It is important to note that in the age of Haemophilus influenza and Streptococcus pneumonia vaccination, the rate of occult bacteremia in febrile children presenting without a source has fallen from 3% to 10% to 1% or less.¹⁷ A lower prevalence reduces the utility of routine CBC or blood culture in the evaluation of immunized, febrile children. Parameters such as procalcitonin, interleukin-6, interleukin-8, interleukin-1 receptor antagonist and C-reactive protein show future promise as biochemical markers for identifying serious bacterial infections.¹⁸

Evidence summary

For acutely febrile patients, the presence of an elevated white blood cell (WBC) count with elevated band forms has dogmatically been thought of as a marker for bacterial infection.¹ Current literature, however, does not support this.²

Neisseria meningitides

A retrospective study of 5353 infants ages 3 to 89 days presenting to the emergency department for evaluation of fever showed that 3 of 4 infants ultimately diagnosed with bacterial meningitis would have been missed if the WBC count alone were used to predict which infants need a lumbar puncture.³ A prospective study of 2492 children ages 3 to 24 months presenting to the emergency department with acute fever and an absolute WBC count >15,000/mm³ revealed that neither a polymorphonuclear count of >10,000/mm³ (>66% segmented forms) nor a band count of >500/mm³ was associated with an increased likelihood of occult bacterial infection.⁴ Other studies show that the WBC alone is poorly discriminatory for identifying either bacteremia or meningitis.^5,6

To improve the diagnostic utility of the CBC, other studies have examined individual components of the white blood cell differential count (TABLE 1). In particular, the use of the absolute neutrophil count (ANC) has been proposed as a superior marker of serious bacterial infection.⁷ A review of 6579 outpatients aged 3 to 36 months presenting to the emergency department with temperatures of 39°C or higher showed an ANC of >10,000/mm³ as more predictive of occult pneumococcal bacteremia than an elevated WBC count (>15,000/mm³) alone.⁸ Another retrospective review of more than 10,000 patients aged 3 to 36 months presenting to the emergency department used logistic regression to identify predictors of bacteremia. In this study, ANC (>9500/mm³) and WBC (>14,300/mm³) were of equal sensitivity (75%) and specificity (75%) in identifying serious bacterial infection.⁹ Finally, the band count alone does not accurately predict serious bacterial infection.¹⁰

In summary, the CBC cannot be used in isolation to differentiate bacterial from viral illness. The CBC can, however, augment clinical data from the history and physical examination to predict the likelihood of serious bacterial illness. As a result, numerous diagnostic criteria, each incorporating elements of the CBC, have been developed in an attempt to accurately differentiate bacterial from viral illness in acutely febrile patients, most typically children (TABLE 2). These criteria differ by age of the patient, clinical testing recommendations, indications for antibiotic therapy, as well as WBC cutoffs.

TABLE 1
WBC markers: How good are they at predicting serious bacterial infection?^9,18,19

TABLE 2
Clinical criteria for predicting serious bacterial infection in febrile children

Recommendations from others

The American College of Emergency Physicians recommends considering antibiotic therapy for previously healthy, well-appearing children ages 3 to 36 months who present with a fever without a clinical source and a WBC count >15,000/mm³.^3,14

The University of Cincinnati Evidence-Based Clinical Practice Guidelines for fever of uncertain source in children ages 2 to 36 months recommends obtaining a CBC for any child who is ill-appearing or at high risk for bacteremia (determined by the clinicians’ judgment). A WBC of ≥15,000/mm³ or ANC >10,000/mm³ provide support for antibiotic therapy.¹⁵ The 1993 American Academy of Pediatrics guidelines for fever ≥39°C without a source in children ages 3 months to 3 years recommends a CBC; if the WBC count ≥15,000/mm³, they recommend a blood culture and treatment with antibiotics pending culture results.^3,16

It is important to note that in the age of Haemophilus influenza and Streptococcus pneumonia vaccination, the rate of occult bacteremia in febrile children presenting without a source has fallen from 3% to 10% to 1% or less.¹⁷ A lower prevalence reduces the utility of routine CBC or blood culture in the evaluation of immunized, febrile children. Parameters such as procalcitonin, interleukin-6, interleukin-8, interleukin-1 receptor antagonist and C-reactive protein show future promise as biochemical markers for identifying serious bacterial infections.¹⁸

Evidence summary

For acutely febrile patients, the presence of an elevated white blood cell (WBC) count with elevated band forms has dogmatically been thought of as a marker for bacterial infection.¹ Current literature, however, does not support this.²

Neisseria meningitides

A retrospective study of 5353 infants ages 3 to 89 days presenting to the emergency department for evaluation of fever showed that 3 of 4 infants ultimately diagnosed with bacterial meningitis would have been missed if the WBC count alone were used to predict which infants need a lumbar puncture.³ A prospective study of 2492 children ages 3 to 24 months presenting to the emergency department with acute fever and an absolute WBC count >15,000/mm³ revealed that neither a polymorphonuclear count of >10,000/mm³ (>66% segmented forms) nor a band count of >500/mm³ was associated with an increased likelihood of occult bacterial infection.⁴ Other studies show that the WBC alone is poorly discriminatory for identifying either bacteremia or meningitis.^5,6

To improve the diagnostic utility of the CBC, other studies have examined individual components of the white blood cell differential count (TABLE 1). In particular, the use of the absolute neutrophil count (ANC) has been proposed as a superior marker of serious bacterial infection.⁷ A review of 6579 outpatients aged 3 to 36 months presenting to the emergency department with temperatures of 39°C or higher showed an ANC of >10,000/mm³ as more predictive of occult pneumococcal bacteremia than an elevated WBC count (>15,000/mm³) alone.⁸ Another retrospective review of more than 10,000 patients aged 3 to 36 months presenting to the emergency department used logistic regression to identify predictors of bacteremia. In this study, ANC (>9500/mm³) and WBC (>14,300/mm³) were of equal sensitivity (75%) and specificity (75%) in identifying serious bacterial infection.⁹ Finally, the band count alone does not accurately predict serious bacterial infection.¹⁰

In summary, the CBC cannot be used in isolation to differentiate bacterial from viral illness. The CBC can, however, augment clinical data from the history and physical examination to predict the likelihood of serious bacterial illness. As a result, numerous diagnostic criteria, each incorporating elements of the CBC, have been developed in an attempt to accurately differentiate bacterial from viral illness in acutely febrile patients, most typically children (TABLE 2). These criteria differ by age of the patient, clinical testing recommendations, indications for antibiotic therapy, as well as WBC cutoffs.

TABLE 1
WBC markers: How good are they at predicting serious bacterial infection?^9,18,19

TABLE 2
Clinical criteria for predicting serious bacterial infection in febrile children

Recommendations from others

The American College of Emergency Physicians recommends considering antibiotic therapy for previously healthy, well-appearing children ages 3 to 36 months who present with a fever without a clinical source and a WBC count >15,000/mm³.^3,14

The University of Cincinnati Evidence-Based Clinical Practice Guidelines for fever of uncertain source in children ages 2 to 36 months recommends obtaining a CBC for any child who is ill-appearing or at high risk for bacteremia (determined by the clinicians’ judgment). A WBC of ≥15,000/mm³ or ANC >10,000/mm³ provide support for antibiotic therapy.¹⁵ The 1993 American Academy of Pediatrics guidelines for fever ≥39°C without a source in children ages 3 months to 3 years recommends a CBC; if the WBC count ≥15,000/mm³, they recommend a blood culture and treatment with antibiotics pending culture results.^3,16

It is important to note that in the age of Haemophilus influenza and Streptococcus pneumonia vaccination, the rate of occult bacteremia in febrile children presenting without a source has fallen from 3% to 10% to 1% or less.¹⁷ A lower prevalence reduces the utility of routine CBC or blood culture in the evaluation of immunized, febrile children. Parameters such as procalcitonin, interleukin-6, interleukin-8, interleukin-1 receptor antagonist and C-reactive protein show future promise as biochemical markers for identifying serious bacterial infections.¹⁸

Evidence summary

Numerous trials have shown that beta-blockers lower blood pressure for patients with hypertension. No head-to-head trials of beta-blockers have been conducted that reveal differences in terms of patient-oriented outcomes, such as all-cause mortality, in the treatment of hypertension.

No effect on lung function, but fatigue is a factor

A Cochrane review on the cardioselective beta-blockers atenolol (Tenormin), bisoprolol (Zebeta), and metoprolol (Lopressor) found that single-dose and multiple-treatment studies showed no decline in lung function among patients with mild to moderate reversible airway disease or chronic obstructive pulmonary disease.^3,4 The analysis was not able to identify any differential effect of these beta-blockers with or without intrinsic sympathomimetic activity for patients with lung disease.

That said, beta-blockers do have side effects. One meta-analysis found no difference in the development of depression with beta-blocker therapy; however, first-generation beta-blockers (propranolol and timolol) had higher rates of fatigue than did the later beta-blockers.⁵ They reported that the risk of fatigue was only 18 per 1000 patients (95% confidence interval [CI], 5–30) and the risk for sexual dysfunction was 5 per 1000 patients (95% CI, 2–8) for all beta-blockers as a class. Importantly, they also stratified side-effect findings on the basis of lipophilic vs nonlipophilic and found no difference in side effect frequency.

Adverse outcomes data give reason to pause

Two recent meta-analyses^6,7 on beta-blockers have called into question the effectiveness of these agents in preventing adverse outcomes in treating hypertension.

The first meta-analysis⁶ reviewed 4 studies that compared atenolol with placebo or no treatment, and 5 that compared atenolol with other antihypertensive drugs. They found no outcome differences between atenolol and placebo in the 4 studies, comprising 6825 patients, followed for a mean of 4.6 years. There was no difference in all-cause mortality (relative risk [RR]=1.01; 95% CI, 0.89–1.15), cardiovascular mortality (RR=0.99; 95% CI, 0.83–1.18), or myocardial infarction (RR=0.99; 95% CI, 0.83–1.19). The risk of stroke appeared to be lower in the atenolol than in the placebo group (RR=0.85; 95% CI, 0.72–1.01). When atenolol was compared with other antihypertensives, there were no major differences in blood pressure lowering between the treatment arms.

The authors found a significantly higher mortality (RR=1.13; 95% CI, 1.02–1.25) with atenolol treatment than with other active treatment, in 5 studies comprising 17,671 patients who were followed up for a mean of 4.6 years. Stroke was also more frequent with atenolol in comparison with other agents.

The second meta-analysis⁷ covered 13 randomized controlled trials (n=105,951) comparing treatment with beta-blockers with other antihypertensive drugs. Seven studies (n=27,433) were included in a comparison of beta-blockers and placebo or no treatment. The relative risk of stroke was 16% higher for beta-blockers (95% CI, 4%–30%) than for other drugs. No difference was seen for myocardial infarction. When the effect of beta-blockers was compared with that of placebo or no treatment, the relative risk of stroke was reduced by 19% for all beta-blockers (95% CI, 7%–29%). There was no difference for myocardial infarction or mortality.

An age divide appears with adverse events

A subsequent meta-analysis found that beta-blocker therapy in younger patients (less than 60 years of age) is associated with a significant reduction in cardiovascular morbidity and mortality.⁸ Researchers used data from 145,811 participants in 21 hypertension trials, beta-blockers reduced major cardiovascular outcomes in younger patients (risk ratio=0.86; 95% CI, 0.74–0.99) but not in older patients (risk ratio=0.89; 95% CI, 0.75–1.05).

In active comparator trials, beta-blockers demonstrated similar reductions in morbidity and mortality to other antihypertensive agents in younger patients (risk ratio=0.97; 95% CI, 0.88–1.07) but not in older patients (risk ratio=1.06; 95% CI, 1.01–1.10), with the excess risk being particularly marked for strokes (risk ratio=1.18; 95% CI, 1.07–1.30). The primary outcome researchers evaluated was a composite of stroke, myocardial infarction, and death.

Calcium channel blockers beat beta-blockers in recent review

Finally, a more recent systematic review found beta blockers to be inferior to calcium channel blockers and renin-angiotensin system inhibitors (ACE inhibitors or ARBs) for major endpoints of all-cause mortality, coronary heart disease, stroke, total cardiovascular events, and cardiovascular mortality.⁹ This review found beta-blockers had similar outcomes as diuretics but were less well tolerated than diuretics (RR=1.80; 95% CI, 1.33–2.42) or renin-angiotensin system inhibitors (RR=1.41; 1.29–1.54).

Thirteen trials with 91,561 participants, meeting inclusion criteria, compared beta-blockers with placebo (4 trials; n=23,613), diuretics (5 trials; n=18,241), calcium-channel blockers (4 trials; n=44,825), and renin-angiotensin system inhibitors (3 trials; n=10,828). Compared with placebo, beta-blockers reduced the risk of stroke (RR=0.80; 95% CI, 0.66–0.96) with a marginal fall in total cardiovascular events (RR=0.88; 95% CI, 0.79–0.97), but did not affect all-cause mortality (RR=0.99, 0.88–1.11), coronary heart disease (RR=0.93, 0.81–1.07), or cardiovascular mortality (RR=0.93, 0.80–1.09). The effect on stroke was less than that of calcium-channel blockers (RR=1.24, 1.11–1.40) and renin-angiotensin system inhibitors (RR=1.30, 1.11–1.53). The effect on total cardiovascular events was less than that of calcium-channel blockers (RR=1.18, 1.08–1.29).

Recommendations from others

The Joint National Committee on Hypertension (JNC-7) states that excellent clinical trial data demonstrate that lowering blood pressure with beta-blockers (and several other drug classes) will reduce the complications of hypertension.¹⁰

The European Society of Cardiology recommends beta-blockers as the first choice for antihypertensive therapy, alone or in combination, for patients with previous myocardial infarction, ischemic heart disease, arrhythmias or heart failure, asymptomatic left ventricular dysfunction, diabetes, or high risk of coronary disease, based on the efficacy of these drugs in these patient populations.¹¹

Evidence summary

Numerous trials have shown that beta-blockers lower blood pressure for patients with hypertension. No head-to-head trials of beta-blockers have been conducted that reveal differences in terms of patient-oriented outcomes, such as all-cause mortality, in the treatment of hypertension.

No effect on lung function, but fatigue is a factor

A Cochrane review on the cardioselective beta-blockers atenolol (Tenormin), bisoprolol (Zebeta), and metoprolol (Lopressor) found that single-dose and multiple-treatment studies showed no decline in lung function among patients with mild to moderate reversible airway disease or chronic obstructive pulmonary disease.^3,4 The analysis was not able to identify any differential effect of these beta-blockers with or without intrinsic sympathomimetic activity for patients with lung disease.

That said, beta-blockers do have side effects. One meta-analysis found no difference in the development of depression with beta-blocker therapy; however, first-generation beta-blockers (propranolol and timolol) had higher rates of fatigue than did the later beta-blockers.⁵ They reported that the risk of fatigue was only 18 per 1000 patients (95% confidence interval [CI], 5–30) and the risk for sexual dysfunction was 5 per 1000 patients (95% CI, 2–8) for all beta-blockers as a class. Importantly, they also stratified side-effect findings on the basis of lipophilic vs nonlipophilic and found no difference in side effect frequency.

Adverse outcomes data give reason to pause

Two recent meta-analyses^6,7 on beta-blockers have called into question the effectiveness of these agents in preventing adverse outcomes in treating hypertension.

The first meta-analysis⁶ reviewed 4 studies that compared atenolol with placebo or no treatment, and 5 that compared atenolol with other antihypertensive drugs. They found no outcome differences between atenolol and placebo in the 4 studies, comprising 6825 patients, followed for a mean of 4.6 years. There was no difference in all-cause mortality (relative risk [RR]=1.01; 95% CI, 0.89–1.15), cardiovascular mortality (RR=0.99; 95% CI, 0.83–1.18), or myocardial infarction (RR=0.99; 95% CI, 0.83–1.19). The risk of stroke appeared to be lower in the atenolol than in the placebo group (RR=0.85; 95% CI, 0.72–1.01). When atenolol was compared with other antihypertensives, there were no major differences in blood pressure lowering between the treatment arms.

The authors found a significantly higher mortality (RR=1.13; 95% CI, 1.02–1.25) with atenolol treatment than with other active treatment, in 5 studies comprising 17,671 patients who were followed up for a mean of 4.6 years. Stroke was also more frequent with atenolol in comparison with other agents.

The second meta-analysis⁷ covered 13 randomized controlled trials (n=105,951) comparing treatment with beta-blockers with other antihypertensive drugs. Seven studies (n=27,433) were included in a comparison of beta-blockers and placebo or no treatment. The relative risk of stroke was 16% higher for beta-blockers (95% CI, 4%–30%) than for other drugs. No difference was seen for myocardial infarction. When the effect of beta-blockers was compared with that of placebo or no treatment, the relative risk of stroke was reduced by 19% for all beta-blockers (95% CI, 7%–29%). There was no difference for myocardial infarction or mortality.

An age divide appears with adverse events

A subsequent meta-analysis found that beta-blocker therapy in younger patients (less than 60 years of age) is associated with a significant reduction in cardiovascular morbidity and mortality.⁸ Researchers used data from 145,811 participants in 21 hypertension trials, beta-blockers reduced major cardiovascular outcomes in younger patients (risk ratio=0.86; 95% CI, 0.74–0.99) but not in older patients (risk ratio=0.89; 95% CI, 0.75–1.05).

In active comparator trials, beta-blockers demonstrated similar reductions in morbidity and mortality to other antihypertensive agents in younger patients (risk ratio=0.97; 95% CI, 0.88–1.07) but not in older patients (risk ratio=1.06; 95% CI, 1.01–1.10), with the excess risk being particularly marked for strokes (risk ratio=1.18; 95% CI, 1.07–1.30). The primary outcome researchers evaluated was a composite of stroke, myocardial infarction, and death.

Calcium channel blockers beat beta-blockers in recent review

Finally, a more recent systematic review found beta blockers to be inferior to calcium channel blockers and renin-angiotensin system inhibitors (ACE inhibitors or ARBs) for major endpoints of all-cause mortality, coronary heart disease, stroke, total cardiovascular events, and cardiovascular mortality.⁹ This review found beta-blockers had similar outcomes as diuretics but were less well tolerated than diuretics (RR=1.80; 95% CI, 1.33–2.42) or renin-angiotensin system inhibitors (RR=1.41; 1.29–1.54).

Thirteen trials with 91,561 participants, meeting inclusion criteria, compared beta-blockers with placebo (4 trials; n=23,613), diuretics (5 trials; n=18,241), calcium-channel blockers (4 trials; n=44,825), and renin-angiotensin system inhibitors (3 trials; n=10,828). Compared with placebo, beta-blockers reduced the risk of stroke (RR=0.80; 95% CI, 0.66–0.96) with a marginal fall in total cardiovascular events (RR=0.88; 95% CI, 0.79–0.97), but did not affect all-cause mortality (RR=0.99, 0.88–1.11), coronary heart disease (RR=0.93, 0.81–1.07), or cardiovascular mortality (RR=0.93, 0.80–1.09). The effect on stroke was less than that of calcium-channel blockers (RR=1.24, 1.11–1.40) and renin-angiotensin system inhibitors (RR=1.30, 1.11–1.53). The effect on total cardiovascular events was less than that of calcium-channel blockers (RR=1.18, 1.08–1.29).

Recommendations from others

The Joint National Committee on Hypertension (JNC-7) states that excellent clinical trial data demonstrate that lowering blood pressure with beta-blockers (and several other drug classes) will reduce the complications of hypertension.¹⁰

The European Society of Cardiology recommends beta-blockers as the first choice for antihypertensive therapy, alone or in combination, for patients with previous myocardial infarction, ischemic heart disease, arrhythmias or heart failure, asymptomatic left ventricular dysfunction, diabetes, or high risk of coronary disease, based on the efficacy of these drugs in these patient populations.¹¹

Evidence summary

Numerous trials have shown that beta-blockers lower blood pressure for patients with hypertension. No head-to-head trials of beta-blockers have been conducted that reveal differences in terms of patient-oriented outcomes, such as all-cause mortality, in the treatment of hypertension.

No effect on lung function, but fatigue is a factor

A Cochrane review on the cardioselective beta-blockers atenolol (Tenormin), bisoprolol (Zebeta), and metoprolol (Lopressor) found that single-dose and multiple-treatment studies showed no decline in lung function among patients with mild to moderate reversible airway disease or chronic obstructive pulmonary disease.^3,4 The analysis was not able to identify any differential effect of these beta-blockers with or without intrinsic sympathomimetic activity for patients with lung disease.

That said, beta-blockers do have side effects. One meta-analysis found no difference in the development of depression with beta-blocker therapy; however, first-generation beta-blockers (propranolol and timolol) had higher rates of fatigue than did the later beta-blockers.⁵ They reported that the risk of fatigue was only 18 per 1000 patients (95% confidence interval [CI], 5–30) and the risk for sexual dysfunction was 5 per 1000 patients (95% CI, 2–8) for all beta-blockers as a class. Importantly, they also stratified side-effect findings on the basis of lipophilic vs nonlipophilic and found no difference in side effect frequency.

Adverse outcomes data give reason to pause

Two recent meta-analyses^6,7 on beta-blockers have called into question the effectiveness of these agents in preventing adverse outcomes in treating hypertension.

The first meta-analysis⁶ reviewed 4 studies that compared atenolol with placebo or no treatment, and 5 that compared atenolol with other antihypertensive drugs. They found no outcome differences between atenolol and placebo in the 4 studies, comprising 6825 patients, followed for a mean of 4.6 years. There was no difference in all-cause mortality (relative risk [RR]=1.01; 95% CI, 0.89–1.15), cardiovascular mortality (RR=0.99; 95% CI, 0.83–1.18), or myocardial infarction (RR=0.99; 95% CI, 0.83–1.19). The risk of stroke appeared to be lower in the atenolol than in the placebo group (RR=0.85; 95% CI, 0.72–1.01). When atenolol was compared with other antihypertensives, there were no major differences in blood pressure lowering between the treatment arms.

The authors found a significantly higher mortality (RR=1.13; 95% CI, 1.02–1.25) with atenolol treatment than with other active treatment, in 5 studies comprising 17,671 patients who were followed up for a mean of 4.6 years. Stroke was also more frequent with atenolol in comparison with other agents.

The second meta-analysis⁷ covered 13 randomized controlled trials (n=105,951) comparing treatment with beta-blockers with other antihypertensive drugs. Seven studies (n=27,433) were included in a comparison of beta-blockers and placebo or no treatment. The relative risk of stroke was 16% higher for beta-blockers (95% CI, 4%–30%) than for other drugs. No difference was seen for myocardial infarction. When the effect of beta-blockers was compared with that of placebo or no treatment, the relative risk of stroke was reduced by 19% for all beta-blockers (95% CI, 7%–29%). There was no difference for myocardial infarction or mortality.

An age divide appears with adverse events

A subsequent meta-analysis found that beta-blocker therapy in younger patients (less than 60 years of age) is associated with a significant reduction in cardiovascular morbidity and mortality.⁸ Researchers used data from 145,811 participants in 21 hypertension trials, beta-blockers reduced major cardiovascular outcomes in younger patients (risk ratio=0.86; 95% CI, 0.74–0.99) but not in older patients (risk ratio=0.89; 95% CI, 0.75–1.05).

In active comparator trials, beta-blockers demonstrated similar reductions in morbidity and mortality to other antihypertensive agents in younger patients (risk ratio=0.97; 95% CI, 0.88–1.07) but not in older patients (risk ratio=1.06; 95% CI, 1.01–1.10), with the excess risk being particularly marked for strokes (risk ratio=1.18; 95% CI, 1.07–1.30). The primary outcome researchers evaluated was a composite of stroke, myocardial infarction, and death.

Calcium channel blockers beat beta-blockers in recent review

Finally, a more recent systematic review found beta blockers to be inferior to calcium channel blockers and renin-angiotensin system inhibitors (ACE inhibitors or ARBs) for major endpoints of all-cause mortality, coronary heart disease, stroke, total cardiovascular events, and cardiovascular mortality.⁹ This review found beta-blockers had similar outcomes as diuretics but were less well tolerated than diuretics (RR=1.80; 95% CI, 1.33–2.42) or renin-angiotensin system inhibitors (RR=1.41; 1.29–1.54).

Thirteen trials with 91,561 participants, meeting inclusion criteria, compared beta-blockers with placebo (4 trials; n=23,613), diuretics (5 trials; n=18,241), calcium-channel blockers (4 trials; n=44,825), and renin-angiotensin system inhibitors (3 trials; n=10,828). Compared with placebo, beta-blockers reduced the risk of stroke (RR=0.80; 95% CI, 0.66–0.96) with a marginal fall in total cardiovascular events (RR=0.88; 95% CI, 0.79–0.97), but did not affect all-cause mortality (RR=0.99, 0.88–1.11), coronary heart disease (RR=0.93, 0.81–1.07), or cardiovascular mortality (RR=0.93, 0.80–1.09). The effect on stroke was less than that of calcium-channel blockers (RR=1.24, 1.11–1.40) and renin-angiotensin system inhibitors (RR=1.30, 1.11–1.53). The effect on total cardiovascular events was less than that of calcium-channel blockers (RR=1.18, 1.08–1.29).

Recommendations from others

The Joint National Committee on Hypertension (JNC-7) states that excellent clinical trial data demonstrate that lowering blood pressure with beta-blockers (and several other drug classes) will reduce the complications of hypertension.¹⁰

The European Society of Cardiology recommends beta-blockers as the first choice for antihypertensive therapy, alone or in combination, for patients with previous myocardial infarction, ischemic heart disease, arrhythmias or heart failure, asymptomatic left ventricular dysfunction, diabetes, or high risk of coronary disease, based on the efficacy of these drugs in these patient populations.¹¹

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 systematic review evaluated beginning combination therapy (adding insulin to oral medication) compared with switching to insulin alone in patients with type 2 diabetes mellitus with inadequate glycemic control on oral medication.¹ Twenty RCTs studied a total of 1811 patients; glycemic control was the primary outcome measure. Oral medication comprised either sulfonylureas (75%), metformin (4%), or both (21%). Individual studies used different insulin dosing schedules and statistical measures. However, overall, combination therapy provided glucose control comparable with insulin alone. In only 1 small, low-quality study did insulin plus metformin reduce HbA_1c more than other combination therapy regimens or insulin alone. Ten studies reported a trend toward less weight gain with combination therapy that included metformin. Fourteen studies found the same incidence of hypoglycemic episodes in combination therapy and insulin alone.

Three later RCTs of overweight patients with inadequate control on oral agents (HbA_1c >7% on a sulfonylurea, metformin, or both) also compared beginning combination therapy with switching to insulin alone (with 70/30 or NPH insulin twice daily). In one study with 64 patients followed for 12 months, HbA_1c fell by 0.14% less (nonsignificant) in the combination therapy group (bedtime NPH plus sulfonylurea and metformin) than in the insulin alone group (70/30 twice daily).² The combination therapy group gained significantly less weight than the insulin-alone group (1.3 kg vs 4.2 kg; P=.01).

In the second study of 261 patients, the combination therapy group (glimepiride [Amaryl] plus bedtime NPH) had a significantly higher HbA_1c after 9 months than 2 groups using insulin alone (twice daily 70/30, and twice daily NPH insulin) (8.9% vs 8.3% and 8.4%).³ Mean weight gain was similar in all 3 groups but only a minority of patients reached a target HbA_1c of 6.5%. In the final study of only 16 patients, HbA1c after 6 months improved significantly and equally in both groups (baseline: 8.3%, combination therapy final: 6.8%; insulin alone final: 7.0%). However, the combination therapy group gained significantly less weight.⁴

An open-label RCT with 341 patients who were inadequately controlled on metformin compared beginning combination therapy (biphasic insulin aspart 30/70 [Novolog Mix 70/30] and metformin) with switching to insulin alone (biphasic insulin aspart 30/70).⁵ A third group added a second oral medication (sulfonylurea and metformin). After 16 weeks, patients taking combination therapy had a significantly lower HbA_1c than those on insulin alone (treatment difference 0.39%, P=.007).

Overall, combination therapy and 2 oral medications reduced HbA_1c by the same amount, but combination therapy reduced HbA_1c more in a subpopulation of patients with HbA_1c >9.0% at baseline (treatment difference 0.46%, P=.027). The group on insulin alone weighed significantly more (4.6 kg, P<.001) at the end of the trial than the group taking 2 oral medications.

An open-label RCT of 756 patients with inadequate glycemic control (HbA_1c >7.5%, mean 8.6%) on either 1 or 2 oral agents (70% taking both metformin and a sulfonylurea) compared combination therapy using bedtime insulin glargine with combination therapy using morning NPH.⁶ Each group titrated insulin doses to achieve a target fasting glucose ≤100. By 24 weeks, both groups had equivalently reduced HbA_1c (mean HbA_1c=6.96% with glargine, and 6.97% with NPH; P=NS), but fewer patients experienced nocturnal hypoglycemia with glargine than with NPH (33.2% vs 26.7%, P<.05).

Another open-label RCT evaluated 281 patients with at least 3 months of inadequate glycemic control (HbA_1c=7.4%–14.7%) on a sulfonylurea.⁷ Patients were randomized to a) switching to a combination of biphasic insulin aspart 30/70 plus pioglitazone, b) adding pioglitazone to the sulfonylurea, or c) switching to insulin alone (biphasic insulin aspart 30/70). After 18 weeks, insulin plus pioglitazone reduced HbA_1c significantly more than either glyburide plus pioglitazone (P=.005) or insulin alone (P=.005). However, the insulin plus pioglitazone group had the most weight gain (mean 4 kg, similar to other pioglitazone trials). There were no major hypoglycemic events.

Another open-label RCT evaluated 217 patients inadequately controlled (HbA_1c=7.5%–11%) on a 2-drug oral regimen (metformin and a sulfonylurea, each drug dosed at ≥50% of the recommended maximum), randomized to add either insulin glargine or rosiglitazone (Avandia).⁸ Both groups reduced HbA_1c equivalently after 24 weeks (–1.7% for glargine vs –1.5% for rosiglitazone). However, in patients with a baseline HbA_1c >9.5%, adding insulin glargine reduced HbA_1c significantly more than rosiglitazone.

Recommendations from others

A comparative analysis of guidelines on diabetes from 13 different countries (including the US) found general agreement in the recommendation to add a second oral agent to maximum doses of an initial agent in patients with poor glycemic control.⁹ However, no consensus was reached on the value or indications of combination therapy with oral agents and insulin.

The European Diabetes Policy Group recommends adding a second oral agent when the maximum dose of a single agent is reached, and using triple therapy when targets are not reached on maximum tolerated doses of 2 agents. Continued therapy with oral agents is advised when initiating insulin.¹⁰

Evidence summary

A systematic review evaluated beginning combination therapy (adding insulin to oral medication) compared with switching to insulin alone in patients with type 2 diabetes mellitus with inadequate glycemic control on oral medication.¹ Twenty RCTs studied a total of 1811 patients; glycemic control was the primary outcome measure. Oral medication comprised either sulfonylureas (75%), metformin (4%), or both (21%). Individual studies used different insulin dosing schedules and statistical measures. However, overall, combination therapy provided glucose control comparable with insulin alone. In only 1 small, low-quality study did insulin plus metformin reduce HbA_1c more than other combination therapy regimens or insulin alone. Ten studies reported a trend toward less weight gain with combination therapy that included metformin. Fourteen studies found the same incidence of hypoglycemic episodes in combination therapy and insulin alone.

Three later RCTs of overweight patients with inadequate control on oral agents (HbA_1c >7% on a sulfonylurea, metformin, or both) also compared beginning combination therapy with switching to insulin alone (with 70/30 or NPH insulin twice daily). In one study with 64 patients followed for 12 months, HbA_1c fell by 0.14% less (nonsignificant) in the combination therapy group (bedtime NPH plus sulfonylurea and metformin) than in the insulin alone group (70/30 twice daily).² The combination therapy group gained significantly less weight than the insulin-alone group (1.3 kg vs 4.2 kg; P=.01).

In the second study of 261 patients, the combination therapy group (glimepiride [Amaryl] plus bedtime NPH) had a significantly higher HbA_1c after 9 months than 2 groups using insulin alone (twice daily 70/30, and twice daily NPH insulin) (8.9% vs 8.3% and 8.4%).³ Mean weight gain was similar in all 3 groups but only a minority of patients reached a target HbA_1c of 6.5%. In the final study of only 16 patients, HbA1c after 6 months improved significantly and equally in both groups (baseline: 8.3%, combination therapy final: 6.8%; insulin alone final: 7.0%). However, the combination therapy group gained significantly less weight.⁴

An open-label RCT with 341 patients who were inadequately controlled on metformin compared beginning combination therapy (biphasic insulin aspart 30/70 [Novolog Mix 70/30] and metformin) with switching to insulin alone (biphasic insulin aspart 30/70).⁵ A third group added a second oral medication (sulfonylurea and metformin). After 16 weeks, patients taking combination therapy had a significantly lower HbA_1c than those on insulin alone (treatment difference 0.39%, P=.007).

Overall, combination therapy and 2 oral medications reduced HbA_1c by the same amount, but combination therapy reduced HbA_1c more in a subpopulation of patients with HbA_1c >9.0% at baseline (treatment difference 0.46%, P=.027). The group on insulin alone weighed significantly more (4.6 kg, P<.001) at the end of the trial than the group taking 2 oral medications.

An open-label RCT of 756 patients with inadequate glycemic control (HbA_1c >7.5%, mean 8.6%) on either 1 or 2 oral agents (70% taking both metformin and a sulfonylurea) compared combination therapy using bedtime insulin glargine with combination therapy using morning NPH.⁶ Each group titrated insulin doses to achieve a target fasting glucose ≤100. By 24 weeks, both groups had equivalently reduced HbA_1c (mean HbA_1c=6.96% with glargine, and 6.97% with NPH; P=NS), but fewer patients experienced nocturnal hypoglycemia with glargine than with NPH (33.2% vs 26.7%, P<.05).

Another open-label RCT evaluated 281 patients with at least 3 months of inadequate glycemic control (HbA_1c=7.4%–14.7%) on a sulfonylurea.⁷ Patients were randomized to a) switching to a combination of biphasic insulin aspart 30/70 plus pioglitazone, b) adding pioglitazone to the sulfonylurea, or c) switching to insulin alone (biphasic insulin aspart 30/70). After 18 weeks, insulin plus pioglitazone reduced HbA_1c significantly more than either glyburide plus pioglitazone (P=.005) or insulin alone (P=.005). However, the insulin plus pioglitazone group had the most weight gain (mean 4 kg, similar to other pioglitazone trials). There were no major hypoglycemic events.

Another open-label RCT evaluated 217 patients inadequately controlled (HbA_1c=7.5%–11%) on a 2-drug oral regimen (metformin and a sulfonylurea, each drug dosed at ≥50% of the recommended maximum), randomized to add either insulin glargine or rosiglitazone (Avandia).⁸ Both groups reduced HbA_1c equivalently after 24 weeks (–1.7% for glargine vs –1.5% for rosiglitazone). However, in patients with a baseline HbA_1c >9.5%, adding insulin glargine reduced HbA_1c significantly more than rosiglitazone.

Recommendations from others

A comparative analysis of guidelines on diabetes from 13 different countries (including the US) found general agreement in the recommendation to add a second oral agent to maximum doses of an initial agent in patients with poor glycemic control.⁹ However, no consensus was reached on the value or indications of combination therapy with oral agents and insulin.

The European Diabetes Policy Group recommends adding a second oral agent when the maximum dose of a single agent is reached, and using triple therapy when targets are not reached on maximum tolerated doses of 2 agents. Continued therapy with oral agents is advised when initiating insulin.¹⁰

Evidence summary

A systematic review evaluated beginning combination therapy (adding insulin to oral medication) compared with switching to insulin alone in patients with type 2 diabetes mellitus with inadequate glycemic control on oral medication.¹ Twenty RCTs studied a total of 1811 patients; glycemic control was the primary outcome measure. Oral medication comprised either sulfonylureas (75%), metformin (4%), or both (21%). Individual studies used different insulin dosing schedules and statistical measures. However, overall, combination therapy provided glucose control comparable with insulin alone. In only 1 small, low-quality study did insulin plus metformin reduce HbA_1c more than other combination therapy regimens or insulin alone. Ten studies reported a trend toward less weight gain with combination therapy that included metformin. Fourteen studies found the same incidence of hypoglycemic episodes in combination therapy and insulin alone.

Three later RCTs of overweight patients with inadequate control on oral agents (HbA_1c >7% on a sulfonylurea, metformin, or both) also compared beginning combination therapy with switching to insulin alone (with 70/30 or NPH insulin twice daily). In one study with 64 patients followed for 12 months, HbA_1c fell by 0.14% less (nonsignificant) in the combination therapy group (bedtime NPH plus sulfonylurea and metformin) than in the insulin alone group (70/30 twice daily).² The combination therapy group gained significantly less weight than the insulin-alone group (1.3 kg vs 4.2 kg; P=.01).

In the second study of 261 patients, the combination therapy group (glimepiride [Amaryl] plus bedtime NPH) had a significantly higher HbA_1c after 9 months than 2 groups using insulin alone (twice daily 70/30, and twice daily NPH insulin) (8.9% vs 8.3% and 8.4%).³ Mean weight gain was similar in all 3 groups but only a minority of patients reached a target HbA_1c of 6.5%. In the final study of only 16 patients, HbA1c after 6 months improved significantly and equally in both groups (baseline: 8.3%, combination therapy final: 6.8%; insulin alone final: 7.0%). However, the combination therapy group gained significantly less weight.⁴

An open-label RCT with 341 patients who were inadequately controlled on metformin compared beginning combination therapy (biphasic insulin aspart 30/70 [Novolog Mix 70/30] and metformin) with switching to insulin alone (biphasic insulin aspart 30/70).⁵ A third group added a second oral medication (sulfonylurea and metformin). After 16 weeks, patients taking combination therapy had a significantly lower HbA_1c than those on insulin alone (treatment difference 0.39%, P=.007).

Overall, combination therapy and 2 oral medications reduced HbA_1c by the same amount, but combination therapy reduced HbA_1c more in a subpopulation of patients with HbA_1c >9.0% at baseline (treatment difference 0.46%, P=.027). The group on insulin alone weighed significantly more (4.6 kg, P<.001) at the end of the trial than the group taking 2 oral medications.

An open-label RCT of 756 patients with inadequate glycemic control (HbA_1c >7.5%, mean 8.6%) on either 1 or 2 oral agents (70% taking both metformin and a sulfonylurea) compared combination therapy using bedtime insulin glargine with combination therapy using morning NPH.⁶ Each group titrated insulin doses to achieve a target fasting glucose ≤100. By 24 weeks, both groups had equivalently reduced HbA_1c (mean HbA_1c=6.96% with glargine, and 6.97% with NPH; P=NS), but fewer patients experienced nocturnal hypoglycemia with glargine than with NPH (33.2% vs 26.7%, P<.05).

Another open-label RCT evaluated 281 patients with at least 3 months of inadequate glycemic control (HbA_1c=7.4%–14.7%) on a sulfonylurea.⁷ Patients were randomized to a) switching to a combination of biphasic insulin aspart 30/70 plus pioglitazone, b) adding pioglitazone to the sulfonylurea, or c) switching to insulin alone (biphasic insulin aspart 30/70). After 18 weeks, insulin plus pioglitazone reduced HbA_1c significantly more than either glyburide plus pioglitazone (P=.005) or insulin alone (P=.005). However, the insulin plus pioglitazone group had the most weight gain (mean 4 kg, similar to other pioglitazone trials). There were no major hypoglycemic events.

Another open-label RCT evaluated 217 patients inadequately controlled (HbA_1c=7.5%–11%) on a 2-drug oral regimen (metformin and a sulfonylurea, each drug dosed at ≥50% of the recommended maximum), randomized to add either insulin glargine or rosiglitazone (Avandia).⁸ Both groups reduced HbA_1c equivalently after 24 weeks (–1.7% for glargine vs –1.5% for rosiglitazone). However, in patients with a baseline HbA_1c >9.5%, adding insulin glargine reduced HbA_1c significantly more than rosiglitazone.

Recommendations from others

A comparative analysis of guidelines on diabetes from 13 different countries (including the US) found general agreement in the recommendation to add a second oral agent to maximum doses of an initial agent in patients with poor glycemic control.⁹ However, no consensus was reached on the value or indications of combination therapy with oral agents and insulin.

The European Diabetes Policy Group recommends adding a second oral agent when the maximum dose of a single agent is reached, and using triple therapy when targets are not reached on maximum tolerated doses of 2 agents. Continued therapy with oral agents is advised when initiating insulin.¹⁰

Evidence summary

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia and the second most common cause of bacterial meningitis in the United States.¹ An estimated 40,000 people die annually in the US from pneumococcal infections.¹ Even with antibiotic treatment and intensive care unit support, the mortality of patients with pneumococcal bacteremia approaches 25% to 30%.¹

Because of the importance of this pathogen, it has been the focus of several trials to demonstrate the efficacy of the primary vaccination. To date, 7 meta-analyses have been completed to assess the efficacy of pneumococcal vaccine in adults, with varying results.^2-7 Most recently, a Cochrane Review (updated in 2005)⁸ concluded that “the combined results from randomized studies fail to show that the polysaccharide vaccine is effective in preventing either pneumonia or death.” However, they did recognize that the nonrandomized studies have consistently shown that the polysaccharide vaccine is effective in reducing the more specific outcome of invasive pneumococcal disease (bacteremia and meningitis).

Multiple studies have used measurement of antibody levels to assess the response of patients to the vaccine and for justification of the need for revaccination. However, measurement of antibody levels to pneumococcal serotypes is difficult, inexact, and is only a surrogate marker for the immune status of a patient, which also relies on the overall function of their immune system. Although pneumococcal vaccine is most highly recommended in patients with chronic disease or immunodeficiency, these patients have a poorer initial response rate and a faster decline in antibody levels than younger, immunocompetent recipients of the vaccine.^1,9

A study of pneumococcal strains cultured from hospitalized patients demonstrated a duration of protection against pneumococcal infection that was much longer than that predicted by the shorter duration of antibody levels. The vaccine’s ability to reduce infection (due to serotypes included in the vaccine) lasted for at least 9 years and overall efficacy for preventing infection caused by the serotypes included in the vaccine was 57%.¹

Revaccination is safe; particularly when performed more than 5 years after the initial vaccination. Injection site reactions are more common and more severe in revaccinated persons (rising from 3% to 15% in the immunocompetent patient).¹⁰ Revaccination, however, does not result in increased rates of hospitalization, and few severe reactions have been reported.¹¹

No randomized or prospective trials regarding the clinical efficacy of revaccination have been completed. However, when reviewing the studies of antibody response, several summary conclusions can be made. Among those who were nonresponders to the initial vaccination, revaccination (even repeated revaccination) is not effective in stimulating any significant antibody response.^12-14 Among those who responded to the primary vaccination, revaccination can stimulate a second antibody response—albeit to lower levels and with less duration than after the initial vaccination.^13,15-17 Among those who do respond to revaccination, antibody levels can rapidly decline to undetectable levels in a matter of months, and they may or may not retain protection against disease over time.^14,15 It appears that revaccination recommendations have been based on the safety of the vaccination, concern for patients at risk and reduced antibody levels, rather than on proven clinical utility.

Recommendations from others

The Advisory Committee on Immunization Practices (ACIP) advises that the vaccine be used in “persons with diseases and other conditions predisposing to the development of bacteremic pneumococcal pneumonia” and that “revaccination should not be done at intervals less than five years.” They state "the value of vaccination on the basis of advanced age is not clear at this time.” (Further details may be found at: www.aafp.org/PreBuilt/agecharts_adultimmunization.pdf.)

The American Academy of Family Physicians, American College of Physicians, the American College of Obstetricians and Gynecologists and the American Diabetes Association follow the ACIP recommendations.

Evidence summary

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia and the second most common cause of bacterial meningitis in the United States.¹ An estimated 40,000 people die annually in the US from pneumococcal infections.¹ Even with antibiotic treatment and intensive care unit support, the mortality of patients with pneumococcal bacteremia approaches 25% to 30%.¹

Because of the importance of this pathogen, it has been the focus of several trials to demonstrate the efficacy of the primary vaccination. To date, 7 meta-analyses have been completed to assess the efficacy of pneumococcal vaccine in adults, with varying results.^2-7 Most recently, a Cochrane Review (updated in 2005)⁸ concluded that “the combined results from randomized studies fail to show that the polysaccharide vaccine is effective in preventing either pneumonia or death.” However, they did recognize that the nonrandomized studies have consistently shown that the polysaccharide vaccine is effective in reducing the more specific outcome of invasive pneumococcal disease (bacteremia and meningitis).

Multiple studies have used measurement of antibody levels to assess the response of patients to the vaccine and for justification of the need for revaccination. However, measurement of antibody levels to pneumococcal serotypes is difficult, inexact, and is only a surrogate marker for the immune status of a patient, which also relies on the overall function of their immune system. Although pneumococcal vaccine is most highly recommended in patients with chronic disease or immunodeficiency, these patients have a poorer initial response rate and a faster decline in antibody levels than younger, immunocompetent recipients of the vaccine.^1,9

A study of pneumococcal strains cultured from hospitalized patients demonstrated a duration of protection against pneumococcal infection that was much longer than that predicted by the shorter duration of antibody levels. The vaccine’s ability to reduce infection (due to serotypes included in the vaccine) lasted for at least 9 years and overall efficacy for preventing infection caused by the serotypes included in the vaccine was 57%.¹

Revaccination is safe; particularly when performed more than 5 years after the initial vaccination. Injection site reactions are more common and more severe in revaccinated persons (rising from 3% to 15% in the immunocompetent patient).¹⁰ Revaccination, however, does not result in increased rates of hospitalization, and few severe reactions have been reported.¹¹

No randomized or prospective trials regarding the clinical efficacy of revaccination have been completed. However, when reviewing the studies of antibody response, several summary conclusions can be made. Among those who were nonresponders to the initial vaccination, revaccination (even repeated revaccination) is not effective in stimulating any significant antibody response.^12-14 Among those who responded to the primary vaccination, revaccination can stimulate a second antibody response—albeit to lower levels and with less duration than after the initial vaccination.^13,15-17 Among those who do respond to revaccination, antibody levels can rapidly decline to undetectable levels in a matter of months, and they may or may not retain protection against disease over time.^14,15 It appears that revaccination recommendations have been based on the safety of the vaccination, concern for patients at risk and reduced antibody levels, rather than on proven clinical utility.

Recommendations from others

The Advisory Committee on Immunization Practices (ACIP) advises that the vaccine be used in “persons with diseases and other conditions predisposing to the development of bacteremic pneumococcal pneumonia” and that “revaccination should not be done at intervals less than five years.” They state "the value of vaccination on the basis of advanced age is not clear at this time.” (Further details may be found at: www.aafp.org/PreBuilt/agecharts_adultimmunization.pdf.)

The American Academy of Family Physicians, American College of Physicians, the American College of Obstetricians and Gynecologists and the American Diabetes Association follow the ACIP recommendations.

Evidence summary

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia and the second most common cause of bacterial meningitis in the United States.¹ An estimated 40,000 people die annually in the US from pneumococcal infections.¹ Even with antibiotic treatment and intensive care unit support, the mortality of patients with pneumococcal bacteremia approaches 25% to 30%.¹

Because of the importance of this pathogen, it has been the focus of several trials to demonstrate the efficacy of the primary vaccination. To date, 7 meta-analyses have been completed to assess the efficacy of pneumococcal vaccine in adults, with varying results.^2-7 Most recently, a Cochrane Review (updated in 2005)⁸ concluded that “the combined results from randomized studies fail to show that the polysaccharide vaccine is effective in preventing either pneumonia or death.” However, they did recognize that the nonrandomized studies have consistently shown that the polysaccharide vaccine is effective in reducing the more specific outcome of invasive pneumococcal disease (bacteremia and meningitis).

Multiple studies have used measurement of antibody levels to assess the response of patients to the vaccine and for justification of the need for revaccination. However, measurement of antibody levels to pneumococcal serotypes is difficult, inexact, and is only a surrogate marker for the immune status of a patient, which also relies on the overall function of their immune system. Although pneumococcal vaccine is most highly recommended in patients with chronic disease or immunodeficiency, these patients have a poorer initial response rate and a faster decline in antibody levels than younger, immunocompetent recipients of the vaccine.^1,9

A study of pneumococcal strains cultured from hospitalized patients demonstrated a duration of protection against pneumococcal infection that was much longer than that predicted by the shorter duration of antibody levels. The vaccine’s ability to reduce infection (due to serotypes included in the vaccine) lasted for at least 9 years and overall efficacy for preventing infection caused by the serotypes included in the vaccine was 57%.¹

Revaccination is safe; particularly when performed more than 5 years after the initial vaccination. Injection site reactions are more common and more severe in revaccinated persons (rising from 3% to 15% in the immunocompetent patient).¹⁰ Revaccination, however, does not result in increased rates of hospitalization, and few severe reactions have been reported.¹¹

No randomized or prospective trials regarding the clinical efficacy of revaccination have been completed. However, when reviewing the studies of antibody response, several summary conclusions can be made. Among those who were nonresponders to the initial vaccination, revaccination (even repeated revaccination) is not effective in stimulating any significant antibody response.^12-14 Among those who responded to the primary vaccination, revaccination can stimulate a second antibody response—albeit to lower levels and with less duration than after the initial vaccination.^13,15-17 Among those who do respond to revaccination, antibody levels can rapidly decline to undetectable levels in a matter of months, and they may or may not retain protection against disease over time.^14,15 It appears that revaccination recommendations have been based on the safety of the vaccination, concern for patients at risk and reduced antibody levels, rather than on proven clinical utility.

Recommendations from others

The Advisory Committee on Immunization Practices (ACIP) advises that the vaccine be used in “persons with diseases and other conditions predisposing to the development of bacteremic pneumococcal pneumonia” and that “revaccination should not be done at intervals less than five years.” They state "the value of vaccination on the basis of advanced age is not clear at this time.” (Further details may be found at: www.aafp.org/PreBuilt/agecharts_adultimmunization.pdf.)

The American Academy of Family Physicians, American College of Physicians, the American College of Obstetricians and Gynecologists and the American Diabetes Association follow the ACIP recommendations.

Evidence summary

The benefits of statin therapy appear to extend beyond the realm of their cholesterol-lowering properties.⁴ These benefits, such as reduction in post—myocardial infarction (MI) deaths and reinfarctions, are seen quickly after initiation of therapy. Other drugs, such as aspirin and beta-blockers, have also been shown to improve early outcomes when started after cardiovascular events, although waiting until the patient is hemodynamically stable to initiate beta-blockade reduces the risk of cardiogenic shock.⁵ If standard agents are either not started or withdrawn after a cardiovascular event, patients are at increased risk of harm.^6,7

Physiological research. Studies of patients with stroke and those with only risk factors for cardiovascular disease show that platelet activity is increased when statins are discontinued.^8,9 Additionally, tissue plasminogen activator levels are decreased after discontinuation of statins, resulting in a relatively hypercoagulable state.¹⁰ Animal studies of stroke in mice showed mice whose statin was abruptly stopped had more damage from stroke than those whose statin was continued.¹¹

High-risk cardiovascular patients. Preliminary human data suggested that stopping statins increased risk of recurrent events for patients who recently had a primary cardiovascular event. One retrospective case-control study evaluated 4870 patients who had statin therapy withdrawn on admission to the hospital for non-ST segment elevation MI (NSTEMI). Patients who had their statins withheld had increased rates of heart failure, arrhythmia, shock, and death (hazard ratio=2.32; 95% confidence interval [CI], 2.02–2.67).¹² A post-hoc analysis of data from the PRISM trial found that among the 86 patients who were admitted for chest pain and had their statin withdrawn, a higher rate of death and nonfatal MI was observed, compared with the 379 patients whose statins were continued (hazard ratio=2.93; 95% CI, 1.64–6.27). This effect was seen in the first week and was independent of cholesterol levels and measures of severity of illness.¹³

Low-risk cardiovascular patients. A post-hoc analysis of the washout period of a prospective study of 9473 asymptomatic outpatients who were previously taking statins showed that for these lower-risk patients, similar rates of cardiovascular events could be expected during withdrawal (any statin) or initiation of atorvastatin therapy. The monthly event rate during the discontinuation phase was 0.20% and during initiation was 0.26% (P=NS).¹⁴

Recommendations from others

Currently, no expert panels or specialty bodies make recommendations regarding how or when to discontinue statins. The Institute for Clinical Systems Improvement recommends that all patients with chronic stable coronary artery disease should be considered for statin use regardless of their lipid levels; however, no mention of discontinuing statins is made.¹⁵

Evidence summary

The benefits of statin therapy appear to extend beyond the realm of their cholesterol-lowering properties.⁴ These benefits, such as reduction in post—myocardial infarction (MI) deaths and reinfarctions, are seen quickly after initiation of therapy. Other drugs, such as aspirin and beta-blockers, have also been shown to improve early outcomes when started after cardiovascular events, although waiting until the patient is hemodynamically stable to initiate beta-blockade reduces the risk of cardiogenic shock.⁵ If standard agents are either not started or withdrawn after a cardiovascular event, patients are at increased risk of harm.^6,7

Physiological research. Studies of patients with stroke and those with only risk factors for cardiovascular disease show that platelet activity is increased when statins are discontinued.^8,9 Additionally, tissue plasminogen activator levels are decreased after discontinuation of statins, resulting in a relatively hypercoagulable state.¹⁰ Animal studies of stroke in mice showed mice whose statin was abruptly stopped had more damage from stroke than those whose statin was continued.¹¹

High-risk cardiovascular patients. Preliminary human data suggested that stopping statins increased risk of recurrent events for patients who recently had a primary cardiovascular event. One retrospective case-control study evaluated 4870 patients who had statin therapy withdrawn on admission to the hospital for non-ST segment elevation MI (NSTEMI). Patients who had their statins withheld had increased rates of heart failure, arrhythmia, shock, and death (hazard ratio=2.32; 95% confidence interval [CI], 2.02–2.67).¹² A post-hoc analysis of data from the PRISM trial found that among the 86 patients who were admitted for chest pain and had their statin withdrawn, a higher rate of death and nonfatal MI was observed, compared with the 379 patients whose statins were continued (hazard ratio=2.93; 95% CI, 1.64–6.27). This effect was seen in the first week and was independent of cholesterol levels and measures of severity of illness.¹³

Low-risk cardiovascular patients. A post-hoc analysis of the washout period of a prospective study of 9473 asymptomatic outpatients who were previously taking statins showed that for these lower-risk patients, similar rates of cardiovascular events could be expected during withdrawal (any statin) or initiation of atorvastatin therapy. The monthly event rate during the discontinuation phase was 0.20% and during initiation was 0.26% (P=NS).¹⁴

Recommendations from others

Currently, no expert panels or specialty bodies make recommendations regarding how or when to discontinue statins. The Institute for Clinical Systems Improvement recommends that all patients with chronic stable coronary artery disease should be considered for statin use regardless of their lipid levels; however, no mention of discontinuing statins is made.¹⁵

Evidence summary

The benefits of statin therapy appear to extend beyond the realm of their cholesterol-lowering properties.⁴ These benefits, such as reduction in post—myocardial infarction (MI) deaths and reinfarctions, are seen quickly after initiation of therapy. Other drugs, such as aspirin and beta-blockers, have also been shown to improve early outcomes when started after cardiovascular events, although waiting until the patient is hemodynamically stable to initiate beta-blockade reduces the risk of cardiogenic shock.⁵ If standard agents are either not started or withdrawn after a cardiovascular event, patients are at increased risk of harm.^6,7

Physiological research. Studies of patients with stroke and those with only risk factors for cardiovascular disease show that platelet activity is increased when statins are discontinued.^8,9 Additionally, tissue plasminogen activator levels are decreased after discontinuation of statins, resulting in a relatively hypercoagulable state.¹⁰ Animal studies of stroke in mice showed mice whose statin was abruptly stopped had more damage from stroke than those whose statin was continued.¹¹

High-risk cardiovascular patients. Preliminary human data suggested that stopping statins increased risk of recurrent events for patients who recently had a primary cardiovascular event. One retrospective case-control study evaluated 4870 patients who had statin therapy withdrawn on admission to the hospital for non-ST segment elevation MI (NSTEMI). Patients who had their statins withheld had increased rates of heart failure, arrhythmia, shock, and death (hazard ratio=2.32; 95% confidence interval [CI], 2.02–2.67).¹² A post-hoc analysis of data from the PRISM trial found that among the 86 patients who were admitted for chest pain and had their statin withdrawn, a higher rate of death and nonfatal MI was observed, compared with the 379 patients whose statins were continued (hazard ratio=2.93; 95% CI, 1.64–6.27). This effect was seen in the first week and was independent of cholesterol levels and measures of severity of illness.¹³

Low-risk cardiovascular patients. A post-hoc analysis of the washout period of a prospective study of 9473 asymptomatic outpatients who were previously taking statins showed that for these lower-risk patients, similar rates of cardiovascular events could be expected during withdrawal (any statin) or initiation of atorvastatin therapy. The monthly event rate during the discontinuation phase was 0.20% and during initiation was 0.26% (P=NS).¹⁴

Recommendations from others

Currently, no expert panels or specialty bodies make recommendations regarding how or when to discontinue statins. The Institute for Clinical Systems Improvement recommends that all patients with chronic stable coronary artery disease should be considered for statin use regardless of their lipid levels; however, no mention of discontinuing statins is made.¹⁵