PURLs

ILLUSTRATIVE CASE

A healthy 31-year-old woman schedules a visit because of congestion and rhinorrhea. She tells you that her cold symptoms developed in the last day or 2 and asks for something to speed her recovery. What can you suggest?

Americans experience roughly 500 million episodes of noninfluenza-related viral respiratory tract infections annually (ie, common colds), or roughly 2.5 episodes per person each year. The total economic burden of the common cold is nearly $40 billion annually.²

Most cold remedies offer little relief
We’ve all cared for patients with cold symptoms. And despite the desire to help, many of us have been frustrated by the fact that there is no cure for the common cold, and most over-the-counter therapies offer little or no relief.

What about zinc? Zinc has been in and out of favor as a treatment for the common cold, based on contradictory findings, since the first randomized trial was published in 1984.³

A 1998 systematic review (which did not include a quantitative synthesis of data) suggested that zinc was beneficial in reducing the duration and severity of cold symptoms.⁴ A meta-analysis published in 2000 found that zinc was ineffective compared with placebo in reducing the likelihood that cold symptoms were present after 7 days.⁵ A meta-analysis published in June 2011 concluded that zinc lozenges reduce the duration of cold symptoms by 12% to 48%, but only at daily doses >75 mg.⁶

These conflicting results have made it difficult to recommend zinc to patients—until now.

STUDY SUMMARY: Zinc for colds? Cochrane review provides convincing evidence

The 2011 Cochrane review that’s the focus of this PURL¹ addressed the question: Does zinc reduce the duration and severity of the common cold? The review also assessed zinc’s ability to prevent colds, although only 2 studies focused on prevention.

The researchers included only randomized, double-blind, placebo-controlled trials in which oral zinc supplementation was used for ≥5 consecutive days for treatment or ≥5 months for prevention. Studies included patients of any age, taking any dosage and any formulation of zinc.

Primary outcomes included the duration of symptoms, the severity of symptoms, and the incidence of the common cold in prevention studies. Secondary outcomes included the proportion of patients symptomatic after 3, 5, and 7 days of treatment, the time to resolution of individual symptoms (eg, cough), change in individual symptom scores, school absences, antibiotic use, and adverse effects.

Thirteen therapeutic trials and 2 prevention trials met the inclusion criteria. These studies, all of which were judged to be of high quality with a low risk of bias, had a total of 996 patients in the therapeutic trials and 394 patients in the prevention trials. Participants ranged in age from 1 to 65 years.

Therapeutic trials. In general, therapeutic studies included lozenges containing 10 to 24 mg zinc gluconate, with one lozenge taken every 1 to 4 hours during the day for 3 to 7 days. In one therapeutic trial that enrolled only children ages 1 to 10, the intervention group took zinc sulfate syrup (15 mg bid) for 10 days. In 11 of the 13 therapeutic studies, treatment began in the first 24 hours of symptoms; in the remaining 2, it began within 48 hours of symptoms.

Ten studies reported on duration of symptoms; 6 of them were similar enough to allow for pooling of results. The pooled results showed that patients who took zinc had a shorter duration of cold symptoms (0.97 days; 95% confidence interval [CI], -1.56 to -0.38), compared with those on placebo. Pooled results from 5 trials revealed that zinc significantly reduced the severity of symptoms by a standard effect size of 0.39 (95% CI, -0.77 to -0.02), which is considered a small to moderate effect.

Prevention trials. In one prevention trial, which included only children ages 6½ to 10 years, those in the intervention group took one 10-mg zinc sulfate tablet 6 days a week for 5 months. In the other trial, children in the intervention group took 15 mg zinc sulfate syrup daily for 7 months.

Pooled results from these 2 studies revealed that daily zinc supplementation substantially reduced the incidence of colds. The incident rate ratio (the number of children who developed colds while taking zinc compared with the number who developed colds while on placebo) was 0.64 (95% CI, 0.47-0.88). In the original trials, one study found a difference of 0.5 colds (1.7 in the control group vs 1.2 in the intervention group) per season, and the other found a difference of 1.8 colds per season (3.15 in the control group vs 1.37 in the intervention group).

WHAT’s NEW: Evidence of zinc’s cold relief properties is conclusive

This Cochrane review provides convincing evidence from 13 randomized placebo-controlled trials that taking zinc soon after the onset of symptoms of the common cold significantly reduces both the duration and severity of symptoms. Zinc supplements are widely available over the counter, so you can recommend that patients take zinc the next time they develop a cold.

In addition, 2 prevention trials found that zinc can reduce the incidence of colds in children, whether it is taken as a syrup or in tablet form. There have been few trials of zinc for prophylaxis of the common cold, and no previous meta-analyses included preventive studies.⁷ This Cochrane review substantiates the effectiveness of zinc for prophylaxis of the common cold in young children.

However, children need to take zinc daily for prophylaxis, which may be inconvenient. Long-term safety information is not yet available. Given these considerations, parents may choose to wait for additional evidence about safety before considering daily prophylaxis.

CAVEATS: Adverse effects, long-term use may create problems

In this meta-analysis, side effects from zinc were common. The 2 most frequently reported were bad taste (pooled odds ratio [OR], 2.64; 95% CI, 1.91-3.64) and nausea (pooled OR, 2.15; 95% CI, 1.44-3.23). When you recommend zinc, warn your patients about these adverse effects. The side effects are not severe, so patients can decide for themselves whether the benefit of a reduction in cold duration is worth the downside of nausea and a bad taste in the mouth.

It is also important to note that the trials included in the meta-analysis enrolled healthy children and adults ≤65 years old. Whether zinc benefits people with chronic illnesses (eg, chronic obstructive pulmonary disease) who develop colds is unknown.

Prolonged elevated serum zinc levels can interfere with copper metabolism, and the adverse effects of long-term use of zinc as prophylaxis are unknown. The trials included in the meta-analysis took place in relatively affluent countries in which zinc deficiency is uncommon. It is not known what impact zinc supplementation would have on people in poor countries.

Of the 15 studies included in the meta-analysis, 10 received support from pharmaceutical companies, 4 received support from foundations, and one received support from both.

CHALLENGES TO IMPLEMENTATION: When to talk to patients about zinc

Most patients do not seek medical care for colds. Those who do typically present only after having symptoms for several days, and it is not clear whether zinc supplementation has the same beneficial effects when started after the first 24 hours.²

Thus, you may have few opportunities in the office to recommend zinc for patients with colds, for whom there is evidence of immediate benefit. More likely, you’ll need to incorporate a zinc recommendation into your overall advice about colds.

Zinc is available over the counter in various forms and dosage. After recommending zinc, you may be confronted with the question of which dose, brand, and formulation is best—a question which, unfortunately, remains unanswered.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A healthy 31-year-old woman schedules a visit because of congestion and rhinorrhea. She tells you that her cold symptoms developed in the last day or 2 and asks for something to speed her recovery. What can you suggest?

Americans experience roughly 500 million episodes of noninfluenza-related viral respiratory tract infections annually (ie, common colds), or roughly 2.5 episodes per person each year. The total economic burden of the common cold is nearly $40 billion annually.²

Most cold remedies offer little relief
We’ve all cared for patients with cold symptoms. And despite the desire to help, many of us have been frustrated by the fact that there is no cure for the common cold, and most over-the-counter therapies offer little or no relief.

What about zinc? Zinc has been in and out of favor as a treatment for the common cold, based on contradictory findings, since the first randomized trial was published in 1984.³

A 1998 systematic review (which did not include a quantitative synthesis of data) suggested that zinc was beneficial in reducing the duration and severity of cold symptoms.⁴ A meta-analysis published in 2000 found that zinc was ineffective compared with placebo in reducing the likelihood that cold symptoms were present after 7 days.⁵ A meta-analysis published in June 2011 concluded that zinc lozenges reduce the duration of cold symptoms by 12% to 48%, but only at daily doses >75 mg.⁶

These conflicting results have made it difficult to recommend zinc to patients—until now.

STUDY SUMMARY: Zinc for colds? Cochrane review provides convincing evidence

The 2011 Cochrane review that’s the focus of this PURL¹ addressed the question: Does zinc reduce the duration and severity of the common cold? The review also assessed zinc’s ability to prevent colds, although only 2 studies focused on prevention.

The researchers included only randomized, double-blind, placebo-controlled trials in which oral zinc supplementation was used for ≥5 consecutive days for treatment or ≥5 months for prevention. Studies included patients of any age, taking any dosage and any formulation of zinc.

Primary outcomes included the duration of symptoms, the severity of symptoms, and the incidence of the common cold in prevention studies. Secondary outcomes included the proportion of patients symptomatic after 3, 5, and 7 days of treatment, the time to resolution of individual symptoms (eg, cough), change in individual symptom scores, school absences, antibiotic use, and adverse effects.

Thirteen therapeutic trials and 2 prevention trials met the inclusion criteria. These studies, all of which were judged to be of high quality with a low risk of bias, had a total of 996 patients in the therapeutic trials and 394 patients in the prevention trials. Participants ranged in age from 1 to 65 years.

Therapeutic trials. In general, therapeutic studies included lozenges containing 10 to 24 mg zinc gluconate, with one lozenge taken every 1 to 4 hours during the day for 3 to 7 days. In one therapeutic trial that enrolled only children ages 1 to 10, the intervention group took zinc sulfate syrup (15 mg bid) for 10 days. In 11 of the 13 therapeutic studies, treatment began in the first 24 hours of symptoms; in the remaining 2, it began within 48 hours of symptoms.

Ten studies reported on duration of symptoms; 6 of them were similar enough to allow for pooling of results. The pooled results showed that patients who took zinc had a shorter duration of cold symptoms (0.97 days; 95% confidence interval [CI], -1.56 to -0.38), compared with those on placebo. Pooled results from 5 trials revealed that zinc significantly reduced the severity of symptoms by a standard effect size of 0.39 (95% CI, -0.77 to -0.02), which is considered a small to moderate effect.

Prevention trials. In one prevention trial, which included only children ages 6½ to 10 years, those in the intervention group took one 10-mg zinc sulfate tablet 6 days a week for 5 months. In the other trial, children in the intervention group took 15 mg zinc sulfate syrup daily for 7 months.

Pooled results from these 2 studies revealed that daily zinc supplementation substantially reduced the incidence of colds. The incident rate ratio (the number of children who developed colds while taking zinc compared with the number who developed colds while on placebo) was 0.64 (95% CI, 0.47-0.88). In the original trials, one study found a difference of 0.5 colds (1.7 in the control group vs 1.2 in the intervention group) per season, and the other found a difference of 1.8 colds per season (3.15 in the control group vs 1.37 in the intervention group).

WHAT’s NEW: Evidence of zinc’s cold relief properties is conclusive

This Cochrane review provides convincing evidence from 13 randomized placebo-controlled trials that taking zinc soon after the onset of symptoms of the common cold significantly reduces both the duration and severity of symptoms. Zinc supplements are widely available over the counter, so you can recommend that patients take zinc the next time they develop a cold.

In addition, 2 prevention trials found that zinc can reduce the incidence of colds in children, whether it is taken as a syrup or in tablet form. There have been few trials of zinc for prophylaxis of the common cold, and no previous meta-analyses included preventive studies.⁷ This Cochrane review substantiates the effectiveness of zinc for prophylaxis of the common cold in young children.

However, children need to take zinc daily for prophylaxis, which may be inconvenient. Long-term safety information is not yet available. Given these considerations, parents may choose to wait for additional evidence about safety before considering daily prophylaxis.

CAVEATS: Adverse effects, long-term use may create problems

In this meta-analysis, side effects from zinc were common. The 2 most frequently reported were bad taste (pooled odds ratio [OR], 2.64; 95% CI, 1.91-3.64) and nausea (pooled OR, 2.15; 95% CI, 1.44-3.23). When you recommend zinc, warn your patients about these adverse effects. The side effects are not severe, so patients can decide for themselves whether the benefit of a reduction in cold duration is worth the downside of nausea and a bad taste in the mouth.

It is also important to note that the trials included in the meta-analysis enrolled healthy children and adults ≤65 years old. Whether zinc benefits people with chronic illnesses (eg, chronic obstructive pulmonary disease) who develop colds is unknown.

Prolonged elevated serum zinc levels can interfere with copper metabolism, and the adverse effects of long-term use of zinc as prophylaxis are unknown. The trials included in the meta-analysis took place in relatively affluent countries in which zinc deficiency is uncommon. It is not known what impact zinc supplementation would have on people in poor countries.

Of the 15 studies included in the meta-analysis, 10 received support from pharmaceutical companies, 4 received support from foundations, and one received support from both.

CHALLENGES TO IMPLEMENTATION: When to talk to patients about zinc

Most patients do not seek medical care for colds. Those who do typically present only after having symptoms for several days, and it is not clear whether zinc supplementation has the same beneficial effects when started after the first 24 hours.²

Thus, you may have few opportunities in the office to recommend zinc for patients with colds, for whom there is evidence of immediate benefit. More likely, you’ll need to incorporate a zinc recommendation into your overall advice about colds.

Zinc is available over the counter in various forms and dosage. After recommending zinc, you may be confronted with the question of which dose, brand, and formulation is best—a question which, unfortunately, remains unanswered.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A healthy 31-year-old woman schedules a visit because of congestion and rhinorrhea. She tells you that her cold symptoms developed in the last day or 2 and asks for something to speed her recovery. What can you suggest?

Americans experience roughly 500 million episodes of noninfluenza-related viral respiratory tract infections annually (ie, common colds), or roughly 2.5 episodes per person each year. The total economic burden of the common cold is nearly $40 billion annually.²

Most cold remedies offer little relief
We’ve all cared for patients with cold symptoms. And despite the desire to help, many of us have been frustrated by the fact that there is no cure for the common cold, and most over-the-counter therapies offer little or no relief.

What about zinc? Zinc has been in and out of favor as a treatment for the common cold, based on contradictory findings, since the first randomized trial was published in 1984.³

A 1998 systematic review (which did not include a quantitative synthesis of data) suggested that zinc was beneficial in reducing the duration and severity of cold symptoms.⁴ A meta-analysis published in 2000 found that zinc was ineffective compared with placebo in reducing the likelihood that cold symptoms were present after 7 days.⁵ A meta-analysis published in June 2011 concluded that zinc lozenges reduce the duration of cold symptoms by 12% to 48%, but only at daily doses >75 mg.⁶

These conflicting results have made it difficult to recommend zinc to patients—until now.

STUDY SUMMARY: Zinc for colds? Cochrane review provides convincing evidence

The 2011 Cochrane review that’s the focus of this PURL¹ addressed the question: Does zinc reduce the duration and severity of the common cold? The review also assessed zinc’s ability to prevent colds, although only 2 studies focused on prevention.

The researchers included only randomized, double-blind, placebo-controlled trials in which oral zinc supplementation was used for ≥5 consecutive days for treatment or ≥5 months for prevention. Studies included patients of any age, taking any dosage and any formulation of zinc.

Primary outcomes included the duration of symptoms, the severity of symptoms, and the incidence of the common cold in prevention studies. Secondary outcomes included the proportion of patients symptomatic after 3, 5, and 7 days of treatment, the time to resolution of individual symptoms (eg, cough), change in individual symptom scores, school absences, antibiotic use, and adverse effects.

Thirteen therapeutic trials and 2 prevention trials met the inclusion criteria. These studies, all of which were judged to be of high quality with a low risk of bias, had a total of 996 patients in the therapeutic trials and 394 patients in the prevention trials. Participants ranged in age from 1 to 65 years.

Therapeutic trials. In general, therapeutic studies included lozenges containing 10 to 24 mg zinc gluconate, with one lozenge taken every 1 to 4 hours during the day for 3 to 7 days. In one therapeutic trial that enrolled only children ages 1 to 10, the intervention group took zinc sulfate syrup (15 mg bid) for 10 days. In 11 of the 13 therapeutic studies, treatment began in the first 24 hours of symptoms; in the remaining 2, it began within 48 hours of symptoms.

Ten studies reported on duration of symptoms; 6 of them were similar enough to allow for pooling of results. The pooled results showed that patients who took zinc had a shorter duration of cold symptoms (0.97 days; 95% confidence interval [CI], -1.56 to -0.38), compared with those on placebo. Pooled results from 5 trials revealed that zinc significantly reduced the severity of symptoms by a standard effect size of 0.39 (95% CI, -0.77 to -0.02), which is considered a small to moderate effect.

Prevention trials. In one prevention trial, which included only children ages 6½ to 10 years, those in the intervention group took one 10-mg zinc sulfate tablet 6 days a week for 5 months. In the other trial, children in the intervention group took 15 mg zinc sulfate syrup daily for 7 months.

Pooled results from these 2 studies revealed that daily zinc supplementation substantially reduced the incidence of colds. The incident rate ratio (the number of children who developed colds while taking zinc compared with the number who developed colds while on placebo) was 0.64 (95% CI, 0.47-0.88). In the original trials, one study found a difference of 0.5 colds (1.7 in the control group vs 1.2 in the intervention group) per season, and the other found a difference of 1.8 colds per season (3.15 in the control group vs 1.37 in the intervention group).

WHAT’s NEW: Evidence of zinc’s cold relief properties is conclusive

This Cochrane review provides convincing evidence from 13 randomized placebo-controlled trials that taking zinc soon after the onset of symptoms of the common cold significantly reduces both the duration and severity of symptoms. Zinc supplements are widely available over the counter, so you can recommend that patients take zinc the next time they develop a cold.

In addition, 2 prevention trials found that zinc can reduce the incidence of colds in children, whether it is taken as a syrup or in tablet form. There have been few trials of zinc for prophylaxis of the common cold, and no previous meta-analyses included preventive studies.⁷ This Cochrane review substantiates the effectiveness of zinc for prophylaxis of the common cold in young children.

However, children need to take zinc daily for prophylaxis, which may be inconvenient. Long-term safety information is not yet available. Given these considerations, parents may choose to wait for additional evidence about safety before considering daily prophylaxis.

CAVEATS: Adverse effects, long-term use may create problems

In this meta-analysis, side effects from zinc were common. The 2 most frequently reported were bad taste (pooled odds ratio [OR], 2.64; 95% CI, 1.91-3.64) and nausea (pooled OR, 2.15; 95% CI, 1.44-3.23). When you recommend zinc, warn your patients about these adverse effects. The side effects are not severe, so patients can decide for themselves whether the benefit of a reduction in cold duration is worth the downside of nausea and a bad taste in the mouth.

It is also important to note that the trials included in the meta-analysis enrolled healthy children and adults ≤65 years old. Whether zinc benefits people with chronic illnesses (eg, chronic obstructive pulmonary disease) who develop colds is unknown.

Prolonged elevated serum zinc levels can interfere with copper metabolism, and the adverse effects of long-term use of zinc as prophylaxis are unknown. The trials included in the meta-analysis took place in relatively affluent countries in which zinc deficiency is uncommon. It is not known what impact zinc supplementation would have on people in poor countries.

Of the 15 studies included in the meta-analysis, 10 received support from pharmaceutical companies, 4 received support from foundations, and one received support from both.

CHALLENGES TO IMPLEMENTATION: When to talk to patients about zinc

Most patients do not seek medical care for colds. Those who do typically present only after having symptoms for several days, and it is not clear whether zinc supplementation has the same beneficial effects when started after the first 24 hours.²

Thus, you may have few opportunities in the office to recommend zinc for patients with colds, for whom there is evidence of immediate benefit. More likely, you’ll need to incorporate a zinc recommendation into your overall advice about colds.

Zinc is available over the counter in various forms and dosage. After recommending zinc, you may be confronted with the question of which dose, brand, and formulation is best—a question which, unfortunately, remains unanswered.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 56-year-old man with a history of systolic heart failure and an EF of 30% returns to your clinic for routine follow-up. He reports that he gets mildly short of breath while mowing the lawn, but his condition is stable. He’s already taking an angiotensin-converting enzyme inhibitor (ACEI) and a beta-blocker, and his potassium level is 4.8 mmol/L. Should he also be taking eplerenone?

Heart failure has reached epidemic proportions in the United States.^2-4 Each year, heart failure accounts for more than 1 million hospitalizations,^3,5 and millions more are living with the disease.² ACEIs and beta-blockers are known to decrease hospitalization and mortality for these patients. Recent evidence suggests that mineralocorticoid-receptor antagonists have additional benefits.^2,4,6

Benefits for Class III and IV heart failure are well established
The Randomized Aldactone Evaluation Study (RALES) showed that spironolactone decreased all-cause mortality and hospitalization for cardiovascular causes in patients with Class III and IV heart failure.⁷ In the Ephesus study, the addition of eplerenone to optimal therapy reduced morbidity and mortality in patients with a myocardial infarction (MI) complicated by systolic heart failure.⁸ These studies led to the current guidelines, which recommend using a mineralocorticoid-receptor antagonist for patients with NYHA Class III and IV heart failure, as well as patients with acute MI and either left ventricular dysfunction or heart failure.^2,4,6 Until recently, however, there was no reason to think about using this class of medications for patients with less severe disease.

STUDY SUMMARY: Eplerenone improves outcomes for patients with mild symptoms

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)¹ was a randomized, double-blinded trial designed to evaluate the effect of eplerenone on patients with less severe disease. Eligible patients were older than 55 years, with Class II heart failure and an EF ≤30% (or >30%-35% with a QRS interval >130 ms). Their existing drug regimen had to include an ACEI, angiotensin receptor blocker, or both, as well as a beta-blocker. Patients with a potassium level >5.0 mmol/L, acute MI, or a low glomerular filtration rate (GFR <30 mL/min) were excluded.

Randomization occurred within 6 months of hospitalization for a cardiovascular disorder; study participants without a recent hospitalization were included if they had either a plasma level of B-type natriuretic peptide (BNP) >250 pg/mL or a pro-BNP >500 pg/mL for men or >750 pg/mL for women. A total of 2737 patients were randomized to receive either eplerenone 25 mg/d (the daily dosage was increased to 50 mg after 4 weeks if the potassium level remained <5 mmol/L) or placebo. Patients with an estimated GFR of 30 to 49 mL/min were started on 25 mg eplerenone every other day; if that dose was tolerated, it was increased to 25 mg/d after 4 weeks.

The primary outcome was a composite of death from cardiovascular causes or a first hospitalization for heart failure. Secondary outcomes included any hospitalization for heart failure, all-cause mortality, and cardiovascular death.

Patients were evaluated every 4 months. The dose of the eplerenone was decreased if the potassium level was 5.5 to 5.9 mmol/L, and stopped altogether if potassium was >6 mmol/L. Potassium levels were measured within 72 hours of a dosage change, and the drug restarted if potassium levels returned to <5.0 mmol/L.

After 5 months of data collection, 60% of patients in the eplerenone group were on the higher dosage (50 mg/d), as were 65% of the patients receiving placebo. At the conclusion of the trial, the study drug had been discontinued in 16% of patients in the eplerenone group and 17% of the controls.

The primary outcome (death from a cardiovascular cause or hospitalization for heart failure) occurred in 18% of patients in the eplerenone group vs 26% of those on placebo. The number needed to treat to prevent one primary outcome was estimated to be 19 per year of follow-up, and 51 per year of follow-up to postpone one death. The study was terminated early (after a median follow-up of 21 months) due to the clear benefits that were evident in the eplerenone group.

WHAT’S NEW?: We have another way to help Class II patients

Previously, mineralocorticoid-receptor antagonists were recommended only for carefully selected patients—those with a history of MI and heart failure, diabetes and heart failure, or more severe (Class III or IV) heart failure.^4,7 This study shows that heart failure patients with milder symptoms can benefit from eplerenone, as well.

CAVEATS: Cost differential means it pays to try spironolactone first

Eplerenone is expensive (approximately $100 for 30 25-mg tablets at Drugstore.com compared with $4 for the same quantity of spironolactone at Walmart.com). Because eplerenone’s beneficial effects are likely due to its action as a mineralocorticoid-receptor antagonist, it makes sense to use spironolactone as a first-line agent and reserve eplerenone for patients who cannot tolerate it.

Risk of hyperkalemia
Both spironolactone and eplerenone can cause hyperkalemia and should not be used in patients with a baseline potassium level >5.0 mmol/L. Patients who are started on either of these medications should have their potassium levels checked after 3 days, 7 days, and 1 month, then periodically, whenever the dosage is changed.⁴ If the potassium level is >5.0 mmol/L, the dose should be decreased by 50%—and the drug should be stopped if the potassium level is >5.5 mmol/L.¹

In this study, serum potassium levels were >5.5 mmol/L in 12% of patients in the eplerenone group and 7% of those on placebo—a statistically significant difference. Eplerenone therapy was reduced or discontinued in hyperkalemic patients. No one suffered from the significant, but rare, sequelae associated with hyperkalemia, including arrhythmias and sudden death.

Only 2.4% of the patients included in this study were African American (the majority were white, but there was a significant number [11.5%] of Asians). We cannot be sure that African Americans with less severe heart failure would reap the same benefits from treatment with a mineralocorticoid-receptor antagonist.

This was a well-done RCT, which found a significant benefit of eplerenone over placebo. It was a relatively small study, however, and it would help if the findings were replicated in larger studies. It is noteworthy, too, that this study was supported by Pfizer, which manufactures eplerenone, and 2 of the authors were employed by the pharmaceutical company.

CHALLENGES TO IMPLEMENTATION: Close follow-up, lab work is crucial

Hyperkalemia can be a significant side effect of both spironolactone and eplerenone. Patients started on either medication will need close follow-up and frequent lab monitoring of potassium levels. Patients who are unable or unwilling to comply with this strict follow-up are not good candidates for either drug.

Overall, this is a straightforward change to implement. In many cases, convincing patients of the benefits of taking yet another pill will be the greatest challenge. For the right patient population, however, both eplerenone and spironolactone appear to be medications we should encourage more often.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 56-year-old man with a history of systolic heart failure and an EF of 30% returns to your clinic for routine follow-up. He reports that he gets mildly short of breath while mowing the lawn, but his condition is stable. He’s already taking an angiotensin-converting enzyme inhibitor (ACEI) and a beta-blocker, and his potassium level is 4.8 mmol/L. Should he also be taking eplerenone?

Heart failure has reached epidemic proportions in the United States.^2-4 Each year, heart failure accounts for more than 1 million hospitalizations,^3,5 and millions more are living with the disease.² ACEIs and beta-blockers are known to decrease hospitalization and mortality for these patients. Recent evidence suggests that mineralocorticoid-receptor antagonists have additional benefits.^2,4,6

Benefits for Class III and IV heart failure are well established
The Randomized Aldactone Evaluation Study (RALES) showed that spironolactone decreased all-cause mortality and hospitalization for cardiovascular causes in patients with Class III and IV heart failure.⁷ In the Ephesus study, the addition of eplerenone to optimal therapy reduced morbidity and mortality in patients with a myocardial infarction (MI) complicated by systolic heart failure.⁸ These studies led to the current guidelines, which recommend using a mineralocorticoid-receptor antagonist for patients with NYHA Class III and IV heart failure, as well as patients with acute MI and either left ventricular dysfunction or heart failure.^2,4,6 Until recently, however, there was no reason to think about using this class of medications for patients with less severe disease.

STUDY SUMMARY: Eplerenone improves outcomes for patients with mild symptoms

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)¹ was a randomized, double-blinded trial designed to evaluate the effect of eplerenone on patients with less severe disease. Eligible patients were older than 55 years, with Class II heart failure and an EF ≤30% (or >30%-35% with a QRS interval >130 ms). Their existing drug regimen had to include an ACEI, angiotensin receptor blocker, or both, as well as a beta-blocker. Patients with a potassium level >5.0 mmol/L, acute MI, or a low glomerular filtration rate (GFR <30 mL/min) were excluded.

Randomization occurred within 6 months of hospitalization for a cardiovascular disorder; study participants without a recent hospitalization were included if they had either a plasma level of B-type natriuretic peptide (BNP) >250 pg/mL or a pro-BNP >500 pg/mL for men or >750 pg/mL for women. A total of 2737 patients were randomized to receive either eplerenone 25 mg/d (the daily dosage was increased to 50 mg after 4 weeks if the potassium level remained <5 mmol/L) or placebo. Patients with an estimated GFR of 30 to 49 mL/min were started on 25 mg eplerenone every other day; if that dose was tolerated, it was increased to 25 mg/d after 4 weeks.

The primary outcome was a composite of death from cardiovascular causes or a first hospitalization for heart failure. Secondary outcomes included any hospitalization for heart failure, all-cause mortality, and cardiovascular death.

Patients were evaluated every 4 months. The dose of the eplerenone was decreased if the potassium level was 5.5 to 5.9 mmol/L, and stopped altogether if potassium was >6 mmol/L. Potassium levels were measured within 72 hours of a dosage change, and the drug restarted if potassium levels returned to <5.0 mmol/L.

After 5 months of data collection, 60% of patients in the eplerenone group were on the higher dosage (50 mg/d), as were 65% of the patients receiving placebo. At the conclusion of the trial, the study drug had been discontinued in 16% of patients in the eplerenone group and 17% of the controls.

The primary outcome (death from a cardiovascular cause or hospitalization for heart failure) occurred in 18% of patients in the eplerenone group vs 26% of those on placebo. The number needed to treat to prevent one primary outcome was estimated to be 19 per year of follow-up, and 51 per year of follow-up to postpone one death. The study was terminated early (after a median follow-up of 21 months) due to the clear benefits that were evident in the eplerenone group.

WHAT’S NEW?: We have another way to help Class II patients

Previously, mineralocorticoid-receptor antagonists were recommended only for carefully selected patients—those with a history of MI and heart failure, diabetes and heart failure, or more severe (Class III or IV) heart failure.^4,7 This study shows that heart failure patients with milder symptoms can benefit from eplerenone, as well.

CAVEATS: Cost differential means it pays to try spironolactone first

Eplerenone is expensive (approximately $100 for 30 25-mg tablets at Drugstore.com compared with $4 for the same quantity of spironolactone at Walmart.com). Because eplerenone’s beneficial effects are likely due to its action as a mineralocorticoid-receptor antagonist, it makes sense to use spironolactone as a first-line agent and reserve eplerenone for patients who cannot tolerate it.

Risk of hyperkalemia
Both spironolactone and eplerenone can cause hyperkalemia and should not be used in patients with a baseline potassium level >5.0 mmol/L. Patients who are started on either of these medications should have their potassium levels checked after 3 days, 7 days, and 1 month, then periodically, whenever the dosage is changed.⁴ If the potassium level is >5.0 mmol/L, the dose should be decreased by 50%—and the drug should be stopped if the potassium level is >5.5 mmol/L.¹

In this study, serum potassium levels were >5.5 mmol/L in 12% of patients in the eplerenone group and 7% of those on placebo—a statistically significant difference. Eplerenone therapy was reduced or discontinued in hyperkalemic patients. No one suffered from the significant, but rare, sequelae associated with hyperkalemia, including arrhythmias and sudden death.

Only 2.4% of the patients included in this study were African American (the majority were white, but there was a significant number [11.5%] of Asians). We cannot be sure that African Americans with less severe heart failure would reap the same benefits from treatment with a mineralocorticoid-receptor antagonist.

This was a well-done RCT, which found a significant benefit of eplerenone over placebo. It was a relatively small study, however, and it would help if the findings were replicated in larger studies. It is noteworthy, too, that this study was supported by Pfizer, which manufactures eplerenone, and 2 of the authors were employed by the pharmaceutical company.

CHALLENGES TO IMPLEMENTATION: Close follow-up, lab work is crucial

Hyperkalemia can be a significant side effect of both spironolactone and eplerenone. Patients started on either medication will need close follow-up and frequent lab monitoring of potassium levels. Patients who are unable or unwilling to comply with this strict follow-up are not good candidates for either drug.

Overall, this is a straightforward change to implement. In many cases, convincing patients of the benefits of taking yet another pill will be the greatest challenge. For the right patient population, however, both eplerenone and spironolactone appear to be medications we should encourage more often.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 56-year-old man with a history of systolic heart failure and an EF of 30% returns to your clinic for routine follow-up. He reports that he gets mildly short of breath while mowing the lawn, but his condition is stable. He’s already taking an angiotensin-converting enzyme inhibitor (ACEI) and a beta-blocker, and his potassium level is 4.8 mmol/L. Should he also be taking eplerenone?

Heart failure has reached epidemic proportions in the United States.^2-4 Each year, heart failure accounts for more than 1 million hospitalizations,^3,5 and millions more are living with the disease.² ACEIs and beta-blockers are known to decrease hospitalization and mortality for these patients. Recent evidence suggests that mineralocorticoid-receptor antagonists have additional benefits.^2,4,6

Benefits for Class III and IV heart failure are well established
The Randomized Aldactone Evaluation Study (RALES) showed that spironolactone decreased all-cause mortality and hospitalization for cardiovascular causes in patients with Class III and IV heart failure.⁷ In the Ephesus study, the addition of eplerenone to optimal therapy reduced morbidity and mortality in patients with a myocardial infarction (MI) complicated by systolic heart failure.⁸ These studies led to the current guidelines, which recommend using a mineralocorticoid-receptor antagonist for patients with NYHA Class III and IV heart failure, as well as patients with acute MI and either left ventricular dysfunction or heart failure.^2,4,6 Until recently, however, there was no reason to think about using this class of medications for patients with less severe disease.

STUDY SUMMARY: Eplerenone improves outcomes for patients with mild symptoms

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)¹ was a randomized, double-blinded trial designed to evaluate the effect of eplerenone on patients with less severe disease. Eligible patients were older than 55 years, with Class II heart failure and an EF ≤30% (or >30%-35% with a QRS interval >130 ms). Their existing drug regimen had to include an ACEI, angiotensin receptor blocker, or both, as well as a beta-blocker. Patients with a potassium level >5.0 mmol/L, acute MI, or a low glomerular filtration rate (GFR <30 mL/min) were excluded.

Randomization occurred within 6 months of hospitalization for a cardiovascular disorder; study participants without a recent hospitalization were included if they had either a plasma level of B-type natriuretic peptide (BNP) >250 pg/mL or a pro-BNP >500 pg/mL for men or >750 pg/mL for women. A total of 2737 patients were randomized to receive either eplerenone 25 mg/d (the daily dosage was increased to 50 mg after 4 weeks if the potassium level remained <5 mmol/L) or placebo. Patients with an estimated GFR of 30 to 49 mL/min were started on 25 mg eplerenone every other day; if that dose was tolerated, it was increased to 25 mg/d after 4 weeks.

The primary outcome was a composite of death from cardiovascular causes or a first hospitalization for heart failure. Secondary outcomes included any hospitalization for heart failure, all-cause mortality, and cardiovascular death.

Patients were evaluated every 4 months. The dose of the eplerenone was decreased if the potassium level was 5.5 to 5.9 mmol/L, and stopped altogether if potassium was >6 mmol/L. Potassium levels were measured within 72 hours of a dosage change, and the drug restarted if potassium levels returned to <5.0 mmol/L.

After 5 months of data collection, 60% of patients in the eplerenone group were on the higher dosage (50 mg/d), as were 65% of the patients receiving placebo. At the conclusion of the trial, the study drug had been discontinued in 16% of patients in the eplerenone group and 17% of the controls.

The primary outcome (death from a cardiovascular cause or hospitalization for heart failure) occurred in 18% of patients in the eplerenone group vs 26% of those on placebo. The number needed to treat to prevent one primary outcome was estimated to be 19 per year of follow-up, and 51 per year of follow-up to postpone one death. The study was terminated early (after a median follow-up of 21 months) due to the clear benefits that were evident in the eplerenone group.

WHAT’S NEW?: We have another way to help Class II patients

Previously, mineralocorticoid-receptor antagonists were recommended only for carefully selected patients—those with a history of MI and heart failure, diabetes and heart failure, or more severe (Class III or IV) heart failure.^4,7 This study shows that heart failure patients with milder symptoms can benefit from eplerenone, as well.

CAVEATS: Cost differential means it pays to try spironolactone first

Eplerenone is expensive (approximately $100 for 30 25-mg tablets at Drugstore.com compared with $4 for the same quantity of spironolactone at Walmart.com). Because eplerenone’s beneficial effects are likely due to its action as a mineralocorticoid-receptor antagonist, it makes sense to use spironolactone as a first-line agent and reserve eplerenone for patients who cannot tolerate it.

Risk of hyperkalemia
Both spironolactone and eplerenone can cause hyperkalemia and should not be used in patients with a baseline potassium level >5.0 mmol/L. Patients who are started on either of these medications should have their potassium levels checked after 3 days, 7 days, and 1 month, then periodically, whenever the dosage is changed.⁴ If the potassium level is >5.0 mmol/L, the dose should be decreased by 50%—and the drug should be stopped if the potassium level is >5.5 mmol/L.¹

In this study, serum potassium levels were >5.5 mmol/L in 12% of patients in the eplerenone group and 7% of those on placebo—a statistically significant difference. Eplerenone therapy was reduced or discontinued in hyperkalemic patients. No one suffered from the significant, but rare, sequelae associated with hyperkalemia, including arrhythmias and sudden death.

Only 2.4% of the patients included in this study were African American (the majority were white, but there was a significant number [11.5%] of Asians). We cannot be sure that African Americans with less severe heart failure would reap the same benefits from treatment with a mineralocorticoid-receptor antagonist.

This was a well-done RCT, which found a significant benefit of eplerenone over placebo. It was a relatively small study, however, and it would help if the findings were replicated in larger studies. It is noteworthy, too, that this study was supported by Pfizer, which manufactures eplerenone, and 2 of the authors were employed by the pharmaceutical company.

CHALLENGES TO IMPLEMENTATION: Close follow-up, lab work is crucial

Hyperkalemia can be a significant side effect of both spironolactone and eplerenone. Patients started on either medication will need close follow-up and frequent lab monitoring of potassium levels. Patients who are unable or unwilling to comply with this strict follow-up are not good candidates for either drug.

Overall, this is a straightforward change to implement. In many cases, convincing patients of the benefits of taking yet another pill will be the greatest challenge. For the right patient population, however, both eplerenone and spironolactone appear to be medications we should encourage more often.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 32-year-old woman comes to your office complaining of heavy, but regular, menstrual bleeding, accompanied by clots and heavy cramping that often leave her drained and unable to work. She has taken oral contraceptives in the past, but they caused nausea, and nonsteroidal anti-inflammatory drugs (NSAIDs) did not provide adequate symptom relief.

A pelvic ultrasound shows that the patient has normal endometrial thickness and no fibroids. Aside from surgical intervention or the placement of a hormonal intrauterine device (IUD), what can you offer her?

Heavy menstrual bleeding is a frequent problem, common enough to cause an estimated 10% to 30% of women of reproductive age to seek treatment.^2-4 Often the bleeding is severe enough to adversely affect the patient’s social, physical, and emotional well-being.

Adverse effects, variable efficacy limit use of other treatments
Quantitatively defined as blood loss ≥80 mL per cycle, heavy menstrual bleeding can also be diagnosed based on a patient’s perception of menstrual blood loss and its effect on her daily life.^5,6 NSAIDs, hormonal medications, the placement of a hormonal IUD, and surgical procedures are all treatment options, but potential adverse effects, contraindications, personal preference, and variable efficacy can limit their use.⁷

The fibrinolysis-blood loss link
Fibrinolytic activity in menstrual blood, leading to increasing blood loss, has prompted the evaluation of hemostatic agents as potential therapeutic options.⁸ Oral tranexamic acid decreases fibrinolysis, thereby reducing menstrual blood loss;⁹ however, gastrointestinal (GI) side effects limit the usefulness of immediate-release tranexamic acid.^9,10

This formulation of tranexamic acid has been used in Europe for heavy menstrual bleeding. A Cochrane review published in 2000 included 4 studies that compared immediate-release tranexamic acid therapy with placebo. The meta-analysis found a significant reduction in mean blood loss compared with placebo (weighted mean difference [WMD]=-94.0 mL; 95% confidence interval [CI], -151.4 to -36.5) and a significant change in mean reduction of blood loss (WMD=-110.2 mL; 95% CI, -146.5 to -73.8) compared with baseline in the treatment group. However, only one of the studies measured perceived improvement in monthly menstrual blood loss, and its sample size was inadequate to provide a precise estimate of the effect (relative risk [RR] 2.5; 95% CI, 0.9-7.3).¹¹

An extended-release option. Oral extended-release (ER) tranexamic acid (Lysteda), approved by the US Food and Drug Administration in 2009,¹² reduces blood loss with fewer GI effects than immediate-release tranexamic acid. In the RCT detailed below, Lukes et al assessed the efficacy and safety of this new formulation.

STUDY SUMMARY: ER formulation reduces blood loss, boosts quality of life

The researchers conducted a multicenter, randomized, double-blind placebo-controlled study comparing the effect of ER tranexamic acid on reduction of menstrual blood flow compared with placebo.¹ Reduction in menstrual blood loss >50 mL and a reduction in menstrual blood loss ≥36 mL (an amount previously established to be perceived as meaningful to women) were related primary outcomes. Improvements in limitations in social or leisure and physical activities and in self-perceived menstrual blood loss were secondary outcomes.

Study participants were women ages 18 to 49 years who had heavy menstrual bleeding, a normal pelvic exam, and a normal transvaginal ultrasound; current use of a nonhormonal birth control method was also required. Women with fibroids were not excluded unless surgery was planned. Exclusion criteria included significant coagulation issues, endocrinopathy, ocular disease, pregnancy or lactation, endometrial abnormalities, cervical cancer, anovulatory dysfunctional uterine bleeding, metrorrhagia, menometrorrhagia, and polymenorrhea.

Participants were randomized to receive either tranexamic acid 1.3 g by mouth 3 times a day for 5 days per menstrual cycle, beginning with the onset of heavy bleeding, or a matched placebo. The use of anticoagulants or NSAIDs during the menstrual period was not permitted.

Heavy bleeding was defined as ≥60 mL of blood loss in one measured cycle and an average ≥80 mL of blood loss over 2 measured cycles.

Mean reduction in blood loss per cycle over 6 cycles was 70 mL (a 40.4% reduction) in the active treatment group vs 13 mL (an 8.2% reduction) in the placebo group (P<.001). The proportion of women with a ≥50% reduction from baseline in blood loss was greater in the tranexamic acid group compared with the placebo group (35% vs 7%; P<.001), yielding a number needed to treat of 4. The mean reduction in perceived blood loss was also greater in the treatment group, but the difference was not statistically significant.

The researchers used a validated menstrual quality-of-life scale that measured social and physical quality of life using a 5-point Likert scale. Women treated with tranexamic acid had a mean reduction of 0.89 points from baseline on the social and leisure activity question, compared with a mean reduction of 0.38 points for those in the placebo group. On the physical activity question, those in the tranexamic acid group had a mean reduction of 0.90 points from baseline, vs a mean decline of 0.35 points in the placebo group.

These findings indicate that the women who received tranexamic acid experienced significantly fewer limitations in social and physical activities. Responses to a question about limitations in work activities showed that the treatment group had significant improvements there, as well. The ER form of tranexamic acid used in the study was well tolerated, with no significant differences in adverse effects between the intervention and control groups.

WHAT’S NEW: Women with heavy menstrual bleeding have a new option

The ER formulation of tranexamic acid used in the study does not appear to have the GI side effects associated with the immediate-release formula.

Tranexamic acid is taken only during the menstrual cycle and does not interfere with ovulation. Thus, it can be used by women who desire fertility but are troubled by heavy bleeding.

CAVEATS: Questions about related conditions, use with hormones remain

The study included women with regular heavy menstrual periods (menorrhagia) and therefore may not be applicable to those with irregular heavy periods or anovulatory, dysfunctional uterine bleeding. In clinical practice, these conditions may overlap, but the safety and efficacy of tranexamic acid in such cases is unclear.

Another caveat, at least theoretically, is that research to date has neither identified nor excluded the possibility that tranexamic acid with concomitant use of hormonal agents might increase the risk of thrombotic events.¹³ This risk is low based on evidence to date, but the theoretical uncertainty leads us to be cautious about the combination of tranexamic acid and hormonal therapy for long-term use.

Xanodyne Pharmaceuticals (which manufactured Lysteda) and Ferring Pharmaceuticals (its current owner) were major sponsors of this study. While we cannot recognize any source of bias as a result of sponsorship, the independence of the investigators in publishing the findings was not clearly stated, so it is possible that future independent studies would contradict these findings.

CHALLENGES TO IMPLEMENTATION: The treatment is costly

Lysteda is expensive, costing about $170 for 30 tablets of 650 mg each.¹⁴ Cost aside, ER tranexamic acid appears to be safe, with no major barriers to its use.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 32-year-old woman comes to your office complaining of heavy, but regular, menstrual bleeding, accompanied by clots and heavy cramping that often leave her drained and unable to work. She has taken oral contraceptives in the past, but they caused nausea, and nonsteroidal anti-inflammatory drugs (NSAIDs) did not provide adequate symptom relief.

A pelvic ultrasound shows that the patient has normal endometrial thickness and no fibroids. Aside from surgical intervention or the placement of a hormonal intrauterine device (IUD), what can you offer her?

Heavy menstrual bleeding is a frequent problem, common enough to cause an estimated 10% to 30% of women of reproductive age to seek treatment.^2-4 Often the bleeding is severe enough to adversely affect the patient’s social, physical, and emotional well-being.

Adverse effects, variable efficacy limit use of other treatments
Quantitatively defined as blood loss ≥80 mL per cycle, heavy menstrual bleeding can also be diagnosed based on a patient’s perception of menstrual blood loss and its effect on her daily life.^5,6 NSAIDs, hormonal medications, the placement of a hormonal IUD, and surgical procedures are all treatment options, but potential adverse effects, contraindications, personal preference, and variable efficacy can limit their use.⁷

The fibrinolysis-blood loss link
Fibrinolytic activity in menstrual blood, leading to increasing blood loss, has prompted the evaluation of hemostatic agents as potential therapeutic options.⁸ Oral tranexamic acid decreases fibrinolysis, thereby reducing menstrual blood loss;⁹ however, gastrointestinal (GI) side effects limit the usefulness of immediate-release tranexamic acid.^9,10

This formulation of tranexamic acid has been used in Europe for heavy menstrual bleeding. A Cochrane review published in 2000 included 4 studies that compared immediate-release tranexamic acid therapy with placebo. The meta-analysis found a significant reduction in mean blood loss compared with placebo (weighted mean difference [WMD]=-94.0 mL; 95% confidence interval [CI], -151.4 to -36.5) and a significant change in mean reduction of blood loss (WMD=-110.2 mL; 95% CI, -146.5 to -73.8) compared with baseline in the treatment group. However, only one of the studies measured perceived improvement in monthly menstrual blood loss, and its sample size was inadequate to provide a precise estimate of the effect (relative risk [RR] 2.5; 95% CI, 0.9-7.3).¹¹

An extended-release option. Oral extended-release (ER) tranexamic acid (Lysteda), approved by the US Food and Drug Administration in 2009,¹² reduces blood loss with fewer GI effects than immediate-release tranexamic acid. In the RCT detailed below, Lukes et al assessed the efficacy and safety of this new formulation.

STUDY SUMMARY: ER formulation reduces blood loss, boosts quality of life

The researchers conducted a multicenter, randomized, double-blind placebo-controlled study comparing the effect of ER tranexamic acid on reduction of menstrual blood flow compared with placebo.¹ Reduction in menstrual blood loss >50 mL and a reduction in menstrual blood loss ≥36 mL (an amount previously established to be perceived as meaningful to women) were related primary outcomes. Improvements in limitations in social or leisure and physical activities and in self-perceived menstrual blood loss were secondary outcomes.

Study participants were women ages 18 to 49 years who had heavy menstrual bleeding, a normal pelvic exam, and a normal transvaginal ultrasound; current use of a nonhormonal birth control method was also required. Women with fibroids were not excluded unless surgery was planned. Exclusion criteria included significant coagulation issues, endocrinopathy, ocular disease, pregnancy or lactation, endometrial abnormalities, cervical cancer, anovulatory dysfunctional uterine bleeding, metrorrhagia, menometrorrhagia, and polymenorrhea.

Participants were randomized to receive either tranexamic acid 1.3 g by mouth 3 times a day for 5 days per menstrual cycle, beginning with the onset of heavy bleeding, or a matched placebo. The use of anticoagulants or NSAIDs during the menstrual period was not permitted.

Heavy bleeding was defined as ≥60 mL of blood loss in one measured cycle and an average ≥80 mL of blood loss over 2 measured cycles.

Mean reduction in blood loss per cycle over 6 cycles was 70 mL (a 40.4% reduction) in the active treatment group vs 13 mL (an 8.2% reduction) in the placebo group (P<.001). The proportion of women with a ≥50% reduction from baseline in blood loss was greater in the tranexamic acid group compared with the placebo group (35% vs 7%; P<.001), yielding a number needed to treat of 4. The mean reduction in perceived blood loss was also greater in the treatment group, but the difference was not statistically significant.

The researchers used a validated menstrual quality-of-life scale that measured social and physical quality of life using a 5-point Likert scale. Women treated with tranexamic acid had a mean reduction of 0.89 points from baseline on the social and leisure activity question, compared with a mean reduction of 0.38 points for those in the placebo group. On the physical activity question, those in the tranexamic acid group had a mean reduction of 0.90 points from baseline, vs a mean decline of 0.35 points in the placebo group.

These findings indicate that the women who received tranexamic acid experienced significantly fewer limitations in social and physical activities. Responses to a question about limitations in work activities showed that the treatment group had significant improvements there, as well. The ER form of tranexamic acid used in the study was well tolerated, with no significant differences in adverse effects between the intervention and control groups.

WHAT’S NEW: Women with heavy menstrual bleeding have a new option

The ER formulation of tranexamic acid used in the study does not appear to have the GI side effects associated with the immediate-release formula.

Tranexamic acid is taken only during the menstrual cycle and does not interfere with ovulation. Thus, it can be used by women who desire fertility but are troubled by heavy bleeding.

CAVEATS: Questions about related conditions, use with hormones remain

The study included women with regular heavy menstrual periods (menorrhagia) and therefore may not be applicable to those with irregular heavy periods or anovulatory, dysfunctional uterine bleeding. In clinical practice, these conditions may overlap, but the safety and efficacy of tranexamic acid in such cases is unclear.

Another caveat, at least theoretically, is that research to date has neither identified nor excluded the possibility that tranexamic acid with concomitant use of hormonal agents might increase the risk of thrombotic events.¹³ This risk is low based on evidence to date, but the theoretical uncertainty leads us to be cautious about the combination of tranexamic acid and hormonal therapy for long-term use.

Xanodyne Pharmaceuticals (which manufactured Lysteda) and Ferring Pharmaceuticals (its current owner) were major sponsors of this study. While we cannot recognize any source of bias as a result of sponsorship, the independence of the investigators in publishing the findings was not clearly stated, so it is possible that future independent studies would contradict these findings.

CHALLENGES TO IMPLEMENTATION: The treatment is costly

Lysteda is expensive, costing about $170 for 30 tablets of 650 mg each.¹⁴ Cost aside, ER tranexamic acid appears to be safe, with no major barriers to its use.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 32-year-old woman comes to your office complaining of heavy, but regular, menstrual bleeding, accompanied by clots and heavy cramping that often leave her drained and unable to work. She has taken oral contraceptives in the past, but they caused nausea, and nonsteroidal anti-inflammatory drugs (NSAIDs) did not provide adequate symptom relief.

A pelvic ultrasound shows that the patient has normal endometrial thickness and no fibroids. Aside from surgical intervention or the placement of a hormonal intrauterine device (IUD), what can you offer her?

Heavy menstrual bleeding is a frequent problem, common enough to cause an estimated 10% to 30% of women of reproductive age to seek treatment.^2-4 Often the bleeding is severe enough to adversely affect the patient’s social, physical, and emotional well-being.

Adverse effects, variable efficacy limit use of other treatments
Quantitatively defined as blood loss ≥80 mL per cycle, heavy menstrual bleeding can also be diagnosed based on a patient’s perception of menstrual blood loss and its effect on her daily life.^5,6 NSAIDs, hormonal medications, the placement of a hormonal IUD, and surgical procedures are all treatment options, but potential adverse effects, contraindications, personal preference, and variable efficacy can limit their use.⁷

The fibrinolysis-blood loss link
Fibrinolytic activity in menstrual blood, leading to increasing blood loss, has prompted the evaluation of hemostatic agents as potential therapeutic options.⁸ Oral tranexamic acid decreases fibrinolysis, thereby reducing menstrual blood loss;⁹ however, gastrointestinal (GI) side effects limit the usefulness of immediate-release tranexamic acid.^9,10

This formulation of tranexamic acid has been used in Europe for heavy menstrual bleeding. A Cochrane review published in 2000 included 4 studies that compared immediate-release tranexamic acid therapy with placebo. The meta-analysis found a significant reduction in mean blood loss compared with placebo (weighted mean difference [WMD]=-94.0 mL; 95% confidence interval [CI], -151.4 to -36.5) and a significant change in mean reduction of blood loss (WMD=-110.2 mL; 95% CI, -146.5 to -73.8) compared with baseline in the treatment group. However, only one of the studies measured perceived improvement in monthly menstrual blood loss, and its sample size was inadequate to provide a precise estimate of the effect (relative risk [RR] 2.5; 95% CI, 0.9-7.3).¹¹

An extended-release option. Oral extended-release (ER) tranexamic acid (Lysteda), approved by the US Food and Drug Administration in 2009,¹² reduces blood loss with fewer GI effects than immediate-release tranexamic acid. In the RCT detailed below, Lukes et al assessed the efficacy and safety of this new formulation.

STUDY SUMMARY: ER formulation reduces blood loss, boosts quality of life

The researchers conducted a multicenter, randomized, double-blind placebo-controlled study comparing the effect of ER tranexamic acid on reduction of menstrual blood flow compared with placebo.¹ Reduction in menstrual blood loss >50 mL and a reduction in menstrual blood loss ≥36 mL (an amount previously established to be perceived as meaningful to women) were related primary outcomes. Improvements in limitations in social or leisure and physical activities and in self-perceived menstrual blood loss were secondary outcomes.

Study participants were women ages 18 to 49 years who had heavy menstrual bleeding, a normal pelvic exam, and a normal transvaginal ultrasound; current use of a nonhormonal birth control method was also required. Women with fibroids were not excluded unless surgery was planned. Exclusion criteria included significant coagulation issues, endocrinopathy, ocular disease, pregnancy or lactation, endometrial abnormalities, cervical cancer, anovulatory dysfunctional uterine bleeding, metrorrhagia, menometrorrhagia, and polymenorrhea.

Participants were randomized to receive either tranexamic acid 1.3 g by mouth 3 times a day for 5 days per menstrual cycle, beginning with the onset of heavy bleeding, or a matched placebo. The use of anticoagulants or NSAIDs during the menstrual period was not permitted.

Heavy bleeding was defined as ≥60 mL of blood loss in one measured cycle and an average ≥80 mL of blood loss over 2 measured cycles.

Mean reduction in blood loss per cycle over 6 cycles was 70 mL (a 40.4% reduction) in the active treatment group vs 13 mL (an 8.2% reduction) in the placebo group (P<.001). The proportion of women with a ≥50% reduction from baseline in blood loss was greater in the tranexamic acid group compared with the placebo group (35% vs 7%; P<.001), yielding a number needed to treat of 4. The mean reduction in perceived blood loss was also greater in the treatment group, but the difference was not statistically significant.

The researchers used a validated menstrual quality-of-life scale that measured social and physical quality of life using a 5-point Likert scale. Women treated with tranexamic acid had a mean reduction of 0.89 points from baseline on the social and leisure activity question, compared with a mean reduction of 0.38 points for those in the placebo group. On the physical activity question, those in the tranexamic acid group had a mean reduction of 0.90 points from baseline, vs a mean decline of 0.35 points in the placebo group.

These findings indicate that the women who received tranexamic acid experienced significantly fewer limitations in social and physical activities. Responses to a question about limitations in work activities showed that the treatment group had significant improvements there, as well. The ER form of tranexamic acid used in the study was well tolerated, with no significant differences in adverse effects between the intervention and control groups.

WHAT’S NEW: Women with heavy menstrual bleeding have a new option

The ER formulation of tranexamic acid used in the study does not appear to have the GI side effects associated with the immediate-release formula.

Tranexamic acid is taken only during the menstrual cycle and does not interfere with ovulation. Thus, it can be used by women who desire fertility but are troubled by heavy bleeding.

CAVEATS: Questions about related conditions, use with hormones remain

The study included women with regular heavy menstrual periods (menorrhagia) and therefore may not be applicable to those with irregular heavy periods or anovulatory, dysfunctional uterine bleeding. In clinical practice, these conditions may overlap, but the safety and efficacy of tranexamic acid in such cases is unclear.

Another caveat, at least theoretically, is that research to date has neither identified nor excluded the possibility that tranexamic acid with concomitant use of hormonal agents might increase the risk of thrombotic events.¹³ This risk is low based on evidence to date, but the theoretical uncertainty leads us to be cautious about the combination of tranexamic acid and hormonal therapy for long-term use.

Xanodyne Pharmaceuticals (which manufactured Lysteda) and Ferring Pharmaceuticals (its current owner) were major sponsors of this study. While we cannot recognize any source of bias as a result of sponsorship, the independence of the investigators in publishing the findings was not clearly stated, so it is possible that future independent studies would contradict these findings.

CHALLENGES TO IMPLEMENTATION: The treatment is costly

Lysteda is expensive, costing about $170 for 30 tablets of 650 mg each.¹⁴ Cost aside, ER tranexamic acid appears to be safe, with no major barriers to its use.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 60-year-old African American man with type 2 diabetes comes in for a follow-up visit. He is currently taking metformin 1000 mg BID, glipizide 10 mg BID, and rosiglitazone 8 mg daily. His glucose levels are well controlled and his last hemoglobin A1c was 6.8%.

Should you discontinue the rosiglitazone?

We have been reluctant to use rosiglitazone for the treatment of type 2 diabetes since 2007, when a meta-analysis found the drug to be associated with a significant elevation in risk for myocardial infarction (MI) and a borderline significant increase in risk for cardiovascular mortality.² A US Food and Drug Administration (FDA) advisory committee reviewed the evidence in 2007, but did not recommend removing rosiglitazone (Avandia, manufactured by GlaxoSmithKline [GSK]) from the market.³ Annual US sales of the drug, which fell by more than 60% over the next 2 years, totaled $408 million in 2009.⁴

Body of evidence grows
Since then, additional evidence of the risk associated with rosiglitazone has come to light. The latest study, reviewed here, is an update of the 2007 meta-analysis.² The authors used standard methodology like that of their original study, and added an alternative methodology that enabled them to include more trials.

Two FDA safety advisories have also been issued. The first, in September 2010, notified providers and patients of plans to restrict access to rosiglitazone because of its elevated risk of cardiovascular events. An update followed in February 2011, indicating that the drug label now includes a black box warning of that risk.⁵

STUDY SUMMARY: Expanded meta-analysis highlights MI risk

The new meta-analysis included 56 trials and a total of 35,531 patients. Of these, 19,509 (55%) were randomized to receive rosiglitazone, and 16,022 (45%) were assigned to a comparator group, which could be either placebo or active treatment.

To be included in the meta-analysis, a trial had to have a randomized comparator group, the duration of treatment had to be similar for all study groups, and participants had to have >24 weeks of drug exposure.¹ Outcomes of interest were MI and cardiovascular mortality. The earlier meta-analysis included 42 studies, all of which had at least one of these outcomes.² The alternative methodology used in this study—in which smaller studies were grouped by randomization ratios and larger trials were reviewed individually—made it possible to include studies without any MIs or cardiovascular deaths.

The researchers identified 3 groups of trials for inclusion:

• The first group consisted of 5 studies that GSK submitted to the FDA in 1999 for presentation to the advisory committee, which recommended approval of rosiglitazone. In these 5 trials, 1967 patients were randomly assigned to receive rosiglitazone and 793 patients received either a comparator drug or placebo.
• The second group included 48 trials, which were primarily identified from the GSK clinical trial registry. These trials were not originally published, but a legal court settlement mandated their eventual publication,⁶ providing new data not available for the previous meta-analysis. In these 48 trials, a total of 11,231 patients were randomly assigned to receive rosiglitazone and 7473 received either a comparator drug or placebo.
• The third—and smallest—group featured 3 large prospective randomized trials that had been published in major medical journals.^7-9 A total of 6311 patients were randomly assigned to receive rosiglitazone and 7756 patients received comparator drugs.

Fifteen of the 56 trials did not report any MIs, and 30 trials did not report any cardiovascular mortality. The trials without either outcome were not part of the primary analysis, but were included in the alternative analysis.

For the 41 trials with ≥1 MI, rosiglitazone therapy significantly increased the risk of MI (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.02-1.63; P=.04), but did not affect cardiovascular mortality (OR, 1.03; 95% CI, 0.78-1.36; P=.04).

The results of the alternative analysis were very similar to the primary results, showing an increased risk for MI (OR, 1.28; 95% CI, 1.01-1.62), but no change in cardiovascular mortality (OR, 0.99; 95% CI, 0.75-1.32).

WHAT’S NEW: A stronger case for a safer alternative

We believe that this meta-analysis strengthens the case against the use of rosiglitazone for the treatment of type 2 diabetes. The number of trials and patients studied is substantial, and the alternative analytic approach allowed the researchers to include all 56 available trials, whether or not any MIs or cardiovascular deaths were reported.

At an FDA advisory committee meeting in July 2010, the recommendation to remove rosiglitazone from the market received a plurality of votes. That recommendation was not carried out, however because 4 other options—all of which involved leaving rosiglitazone on the market—taken together, received more votes.¹⁰

We think this meta-analysis provides substantial doubt about the safety of rosiglitazone. If there is a safer alternative, the decision not to use rosiglitazone becomes even easier. An important question, then, is whether the other thiazolidinedione on the market, pioglitazone (Actos), carries similar risks.

The PROACTIVE trial, a large cardiovascular outcomes study published in 2005,¹¹ and a patient-level meta-analysis of cardiovascular outcomes published in 2007,¹² assessed the risk of death, MI, and stroke in a diverse population of patients taking pioglitazone. Compared with studies of cardiovascular events associated with rosiglitazone, the PROACTIVE trial and the meta-analysis showed that pioglitazone has a significantly lower risk of death, MI, or stroke.

For patients who are doing well on rosiglitazone, a within-class switch to pioglitazone would appear to decrease coronary artery events. However, it must be noted that both drugs have a black box warning regarding congestive heart failure. (The black box warning for rosiglitazone now identifies the increased risk of MI, as well).⁵

CAVEATS: Missing data weaken analysis

The authors of the meta-analysis reported here were unable to obtain individual patient outcomes, which would have allowed them to do a more powerful analysis. However, other meta-analyses, including one from the FDA,¹³ found similar results.

CHALLENGES TO IMPLEMENTATION: Patients and physicians may be reluctant to switch

Theoretically, a switch to pioglitazone is an easy choice, as it is the same class of medication as rosiglitazone but has a lower risk of MI. The use of rosiglitazone caused about 83,000 excess MIs between 1999 and 2007, the FDA estimated.¹⁴ That number has since been downgraded to up to 6000 excess MIs annually to reflect the reduced usage of the drug.^1,14 But when patients are doing well on a particular medication, neither they nor their doctor may want to change to another drug, especially when the adverse effects of the current medication are uncommon. Nonetheless, reevaluation of their diabetic medication regimen often gives patients an opportunity to ensure that they are taking the best first-line agent—which in many cases is metformin, and not a thiazolidinedione at all.¹⁵

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 60-year-old African American man with type 2 diabetes comes in for a follow-up visit. He is currently taking metformin 1000 mg BID, glipizide 10 mg BID, and rosiglitazone 8 mg daily. His glucose levels are well controlled and his last hemoglobin A1c was 6.8%.

Should you discontinue the rosiglitazone?

We have been reluctant to use rosiglitazone for the treatment of type 2 diabetes since 2007, when a meta-analysis found the drug to be associated with a significant elevation in risk for myocardial infarction (MI) and a borderline significant increase in risk for cardiovascular mortality.² A US Food and Drug Administration (FDA) advisory committee reviewed the evidence in 2007, but did not recommend removing rosiglitazone (Avandia, manufactured by GlaxoSmithKline [GSK]) from the market.³ Annual US sales of the drug, which fell by more than 60% over the next 2 years, totaled $408 million in 2009.⁴

Body of evidence grows
Since then, additional evidence of the risk associated with rosiglitazone has come to light. The latest study, reviewed here, is an update of the 2007 meta-analysis.² The authors used standard methodology like that of their original study, and added an alternative methodology that enabled them to include more trials.

Two FDA safety advisories have also been issued. The first, in September 2010, notified providers and patients of plans to restrict access to rosiglitazone because of its elevated risk of cardiovascular events. An update followed in February 2011, indicating that the drug label now includes a black box warning of that risk.⁵

STUDY SUMMARY: Expanded meta-analysis highlights MI risk

The new meta-analysis included 56 trials and a total of 35,531 patients. Of these, 19,509 (55%) were randomized to receive rosiglitazone, and 16,022 (45%) were assigned to a comparator group, which could be either placebo or active treatment.

To be included in the meta-analysis, a trial had to have a randomized comparator group, the duration of treatment had to be similar for all study groups, and participants had to have >24 weeks of drug exposure.¹ Outcomes of interest were MI and cardiovascular mortality. The earlier meta-analysis included 42 studies, all of which had at least one of these outcomes.² The alternative methodology used in this study—in which smaller studies were grouped by randomization ratios and larger trials were reviewed individually—made it possible to include studies without any MIs or cardiovascular deaths.

The researchers identified 3 groups of trials for inclusion:

• The first group consisted of 5 studies that GSK submitted to the FDA in 1999 for presentation to the advisory committee, which recommended approval of rosiglitazone. In these 5 trials, 1967 patients were randomly assigned to receive rosiglitazone and 793 patients received either a comparator drug or placebo.
• The second group included 48 trials, which were primarily identified from the GSK clinical trial registry. These trials were not originally published, but a legal court settlement mandated their eventual publication,⁶ providing new data not available for the previous meta-analysis. In these 48 trials, a total of 11,231 patients were randomly assigned to receive rosiglitazone and 7473 received either a comparator drug or placebo.
• The third—and smallest—group featured 3 large prospective randomized trials that had been published in major medical journals.^7-9 A total of 6311 patients were randomly assigned to receive rosiglitazone and 7756 patients received comparator drugs.

Fifteen of the 56 trials did not report any MIs, and 30 trials did not report any cardiovascular mortality. The trials without either outcome were not part of the primary analysis, but were included in the alternative analysis.

For the 41 trials with ≥1 MI, rosiglitazone therapy significantly increased the risk of MI (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.02-1.63; P=.04), but did not affect cardiovascular mortality (OR, 1.03; 95% CI, 0.78-1.36; P=.04).

The results of the alternative analysis were very similar to the primary results, showing an increased risk for MI (OR, 1.28; 95% CI, 1.01-1.62), but no change in cardiovascular mortality (OR, 0.99; 95% CI, 0.75-1.32).

WHAT’S NEW: A stronger case for a safer alternative

We believe that this meta-analysis strengthens the case against the use of rosiglitazone for the treatment of type 2 diabetes. The number of trials and patients studied is substantial, and the alternative analytic approach allowed the researchers to include all 56 available trials, whether or not any MIs or cardiovascular deaths were reported.

At an FDA advisory committee meeting in July 2010, the recommendation to remove rosiglitazone from the market received a plurality of votes. That recommendation was not carried out, however because 4 other options—all of which involved leaving rosiglitazone on the market—taken together, received more votes.¹⁰

We think this meta-analysis provides substantial doubt about the safety of rosiglitazone. If there is a safer alternative, the decision not to use rosiglitazone becomes even easier. An important question, then, is whether the other thiazolidinedione on the market, pioglitazone (Actos), carries similar risks.

The PROACTIVE trial, a large cardiovascular outcomes study published in 2005,¹¹ and a patient-level meta-analysis of cardiovascular outcomes published in 2007,¹² assessed the risk of death, MI, and stroke in a diverse population of patients taking pioglitazone. Compared with studies of cardiovascular events associated with rosiglitazone, the PROACTIVE trial and the meta-analysis showed that pioglitazone has a significantly lower risk of death, MI, or stroke.

For patients who are doing well on rosiglitazone, a within-class switch to pioglitazone would appear to decrease coronary artery events. However, it must be noted that both drugs have a black box warning regarding congestive heart failure. (The black box warning for rosiglitazone now identifies the increased risk of MI, as well).⁵

CAVEATS: Missing data weaken analysis

The authors of the meta-analysis reported here were unable to obtain individual patient outcomes, which would have allowed them to do a more powerful analysis. However, other meta-analyses, including one from the FDA,¹³ found similar results.

CHALLENGES TO IMPLEMENTATION: Patients and physicians may be reluctant to switch

Theoretically, a switch to pioglitazone is an easy choice, as it is the same class of medication as rosiglitazone but has a lower risk of MI. The use of rosiglitazone caused about 83,000 excess MIs between 1999 and 2007, the FDA estimated.¹⁴ That number has since been downgraded to up to 6000 excess MIs annually to reflect the reduced usage of the drug.^1,14 But when patients are doing well on a particular medication, neither they nor their doctor may want to change to another drug, especially when the adverse effects of the current medication are uncommon. Nonetheless, reevaluation of their diabetic medication regimen often gives patients an opportunity to ensure that they are taking the best first-line agent—which in many cases is metformin, and not a thiazolidinedione at all.¹⁵

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 60-year-old African American man with type 2 diabetes comes in for a follow-up visit. He is currently taking metformin 1000 mg BID, glipizide 10 mg BID, and rosiglitazone 8 mg daily. His glucose levels are well controlled and his last hemoglobin A1c was 6.8%.

Should you discontinue the rosiglitazone?

We have been reluctant to use rosiglitazone for the treatment of type 2 diabetes since 2007, when a meta-analysis found the drug to be associated with a significant elevation in risk for myocardial infarction (MI) and a borderline significant increase in risk for cardiovascular mortality.² A US Food and Drug Administration (FDA) advisory committee reviewed the evidence in 2007, but did not recommend removing rosiglitazone (Avandia, manufactured by GlaxoSmithKline [GSK]) from the market.³ Annual US sales of the drug, which fell by more than 60% over the next 2 years, totaled $408 million in 2009.⁴

Body of evidence grows
Since then, additional evidence of the risk associated with rosiglitazone has come to light. The latest study, reviewed here, is an update of the 2007 meta-analysis.² The authors used standard methodology like that of their original study, and added an alternative methodology that enabled them to include more trials.

Two FDA safety advisories have also been issued. The first, in September 2010, notified providers and patients of plans to restrict access to rosiglitazone because of its elevated risk of cardiovascular events. An update followed in February 2011, indicating that the drug label now includes a black box warning of that risk.⁵

STUDY SUMMARY: Expanded meta-analysis highlights MI risk

The new meta-analysis included 56 trials and a total of 35,531 patients. Of these, 19,509 (55%) were randomized to receive rosiglitazone, and 16,022 (45%) were assigned to a comparator group, which could be either placebo or active treatment.

To be included in the meta-analysis, a trial had to have a randomized comparator group, the duration of treatment had to be similar for all study groups, and participants had to have >24 weeks of drug exposure.¹ Outcomes of interest were MI and cardiovascular mortality. The earlier meta-analysis included 42 studies, all of which had at least one of these outcomes.² The alternative methodology used in this study—in which smaller studies were grouped by randomization ratios and larger trials were reviewed individually—made it possible to include studies without any MIs or cardiovascular deaths.

The researchers identified 3 groups of trials for inclusion:

• The first group consisted of 5 studies that GSK submitted to the FDA in 1999 for presentation to the advisory committee, which recommended approval of rosiglitazone. In these 5 trials, 1967 patients were randomly assigned to receive rosiglitazone and 793 patients received either a comparator drug or placebo.
• The second group included 48 trials, which were primarily identified from the GSK clinical trial registry. These trials were not originally published, but a legal court settlement mandated their eventual publication,⁶ providing new data not available for the previous meta-analysis. In these 48 trials, a total of 11,231 patients were randomly assigned to receive rosiglitazone and 7473 received either a comparator drug or placebo.
• The third—and smallest—group featured 3 large prospective randomized trials that had been published in major medical journals.^7-9 A total of 6311 patients were randomly assigned to receive rosiglitazone and 7756 patients received comparator drugs.

Fifteen of the 56 trials did not report any MIs, and 30 trials did not report any cardiovascular mortality. The trials without either outcome were not part of the primary analysis, but were included in the alternative analysis.

For the 41 trials with ≥1 MI, rosiglitazone therapy significantly increased the risk of MI (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.02-1.63; P=.04), but did not affect cardiovascular mortality (OR, 1.03; 95% CI, 0.78-1.36; P=.04).

The results of the alternative analysis were very similar to the primary results, showing an increased risk for MI (OR, 1.28; 95% CI, 1.01-1.62), but no change in cardiovascular mortality (OR, 0.99; 95% CI, 0.75-1.32).

WHAT’S NEW: A stronger case for a safer alternative

We believe that this meta-analysis strengthens the case against the use of rosiglitazone for the treatment of type 2 diabetes. The number of trials and patients studied is substantial, and the alternative analytic approach allowed the researchers to include all 56 available trials, whether or not any MIs or cardiovascular deaths were reported.

At an FDA advisory committee meeting in July 2010, the recommendation to remove rosiglitazone from the market received a plurality of votes. That recommendation was not carried out, however because 4 other options—all of which involved leaving rosiglitazone on the market—taken together, received more votes.¹⁰

We think this meta-analysis provides substantial doubt about the safety of rosiglitazone. If there is a safer alternative, the decision not to use rosiglitazone becomes even easier. An important question, then, is whether the other thiazolidinedione on the market, pioglitazone (Actos), carries similar risks.

The PROACTIVE trial, a large cardiovascular outcomes study published in 2005,¹¹ and a patient-level meta-analysis of cardiovascular outcomes published in 2007,¹² assessed the risk of death, MI, and stroke in a diverse population of patients taking pioglitazone. Compared with studies of cardiovascular events associated with rosiglitazone, the PROACTIVE trial and the meta-analysis showed that pioglitazone has a significantly lower risk of death, MI, or stroke.

For patients who are doing well on rosiglitazone, a within-class switch to pioglitazone would appear to decrease coronary artery events. However, it must be noted that both drugs have a black box warning regarding congestive heart failure. (The black box warning for rosiglitazone now identifies the increased risk of MI, as well).⁵

CAVEATS: Missing data weaken analysis

The authors of the meta-analysis reported here were unable to obtain individual patient outcomes, which would have allowed them to do a more powerful analysis. However, other meta-analyses, including one from the FDA,¹³ found similar results.

CHALLENGES TO IMPLEMENTATION: Patients and physicians may be reluctant to switch

Theoretically, a switch to pioglitazone is an easy choice, as it is the same class of medication as rosiglitazone but has a lower risk of MI. The use of rosiglitazone caused about 83,000 excess MIs between 1999 and 2007, the FDA estimated.¹⁴ That number has since been downgraded to up to 6000 excess MIs annually to reflect the reduced usage of the drug.^1,14 But when patients are doing well on a particular medication, neither they nor their doctor may want to change to another drug, especially when the adverse effects of the current medication are uncommon. Nonetheless, reevaluation of their diabetic medication regimen often gives patients an opportunity to ensure that they are taking the best first-line agent—which in many cases is metformin, and not a thiazolidinedione at all.¹⁵

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 75-year-old man with persistent atrial fibrillation and diabetes comes to your office for a check of his international normalized ratio (INR). It has been hard to keep his INR within the normal range of 2 to 3 in recent months, and today is no different: The patient’s INR is 1.7, although he insists he has been compliant with his warfarin regimen and has had no change in diet or other medications. What other anticoagulation options can you offer him?

Patients with atrial fibrillation have a 3% to 8% annual risk of stroke.² Both adjusted-dose warfarin and antiplatelet agents such as aspirin have been shown to be effective at reducing this risk, although warfarin is significantly more effective.³

Those who have atrial fibrillation and a previous history of thromboembolism or rheumatic mitral stenosis or more than one moderate risk factor (age ≥75 years, hypertension, heart failure, impaired left ventricular systolic function, or diabetes) have the highest stroke risk. The American College of Cardiology/American Heart Association Task Force/ European Society of Cardiology (ACC/AHA/ ESC) 2006 guidelines for the management of atrial fibrillation recommend chronic anticoagulation with an oral vitamin K antagonist, such as warfarin, for these high-risk patients.⁴

Warfarin therapy is challenging
We have all experienced the frustrations of maintaining our patients on warfarin at a therapeutic INR; the average patient is within this range only about 67% of the time, although this varies dramatically from patient to patient.⁵

Many of our patients have experienced the inconvenience and cost of repeated monitoring, as well as the morbidity associated with both major and minor bleeding related to warfarin use. And there are many potential interactions between warfarin and foods or other drugs.

Is the new oral anticoagulant a better bet?
There are anticoagulants that do not require monitoring (eg, enoxaparin), but few patients are willing to undergo daily subcutaneous injections, and the cost is often prohibitive. Now there is another alternative.

Dabigatran (Pradaxa), an oral direct thrombin inhibitor, was approved by the US Food and Drug Administration in October 2010 for the prevention of stroke and systemic embolism in patients with atrial fibrillation.⁶ Dabigatran is administered twice daily in a fixed dose. Because it has a relatively short half-life (12-17 hours), it does not require INR monitoring. Dabigatran has no known interactions with foods and minimal interactions with other medications. Its value as a warfarin alternative for patients with atrial fibrillation was addressed in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study detailed below.

STUDY SUMMARY: At higher dose, dabigatran prevents more strokes than warfarin

RE-LY included 18,113 patients from 951 facilities in 44 countries. To be eligible for the study, patients had to have atrial fibrillation documented on an electrocardiogram and at least one additional risk factor for stroke.

Participants were randomized into one of 3 groups: dabigatran 110 mg twice daily, dabigatran 150 mg twice daily (both administered in a blinded fashion), or warfarin (administered in an unblinded fashion and dosed to maintain an INR between 2 and 3). Baseline characteristics, such as age, sex, and CHADS₂ (congestive heart failure, hypertension, age, diabetes, prior stroke) score, were similar across all 3 groups. The median duration of follow-up was 2 years, and complete follow-up occurred in 99.9% of participants.

The primary outcome of the study was stroke or systemic embolism. The primary safety outcome was major hemorrhage, defined as a reduction in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of blood, or symptomatic bleeding in a critical area/organ. Other outcomes were death, myocardial infarction (MI), pulmonary embolism, transient ischemic attack, and hospitalization.

For the primary outcome of prevention of stroke or systemic embolism, the 150-mg dose of dabigatran was superior to warfarin (1.11% vs 1.69% per year, relative risk [RR], 0.66; 95% confidence interval [CI], 0.53-0.82; P<.001 for superiority). The major bleeding rates were similar for dabigatran 150 mg and warfarin, although major gastrointestinal bleeding rates were significantly higher with this dose of dabigatran compared with warfarin (TABLE). Minor bleeding was more common in the warfarin group (16.37% vs 14.84%; RR, 0.91; 95% CI, 0.85-0.97; P=.005).

The 110-mg dose of dabigatran (which is not available in the United States) was neither inferior nor superior to warfarin for the prevention of stroke or systemic embolism. This dose of dabigatran had a lower risk of major bleeding compared with warfarin.

TABLE
Dabigatran vs warfarin: A look at the evidence¹

Mortality rates are similar
Rates of death from any cause were similar among the 3 treatment groups. The rates of hemorrhagic stroke were lower in both dabigatran groups compared with the warfarin group, while rates of MI were lower in the warfarin group than in either of the dabigatran groups.

Dyspepsia was the only other adverse effect that was significantly more common among dabigatran users vs warfarin users. Rates of hepatotoxicity, which was a problem wiThearlier oral direct thrombin inhibitors, were similar for both drugs. Multiple subgroup analyses revealed no significant interaction between the treatment effect of dabigatran and variables such as sex, body mass index, creatinine clearance, CHADS₂ score, aspirin use, or previous long-term use of a vitamin K antagonist.

WHAT’S NEW: This easier-to-use oral anticoagulant is a viable option

Dabigatran gives physicians and patients with atrial fibrillation an option that is more convenient than warfarin for stroke prevention. Its 150-mg dose is more effective in preventing stroke compared with warfarin, and comparable in terms of bleeding risk.

CAVEATS: Unknown long-term effects, potential for bias

The median follow-up in the RE-LY study was 2 years. Longer-term efficacy and safety data may differ from the initial results.

The trial was funded by Boehringer Ingelheim, the manufacturer of dabigatran (Pradaxa). However, study coordination, data management, and analysis were performed independently by the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.

Patients taking dabigatran received the medication in a blinded fashion, but the warfarin group could not be blinded because of the need for INR monitoring and dosage adjustments. To decrease potential bias, the outcome events were assessed by 2 independent investigators who were blinded to the treatment assignments.

CHALLENGES TO IMPLEMENTATION: Cost of dabigatran may be a barrier

The wholesale price of dabigatran, as quoted by Boehringer Ingelheim, is $6.75 per day; the retail price for a 30-day supply is approximately $235, according to drugstore.com, Walgreens, and Walmart). In comparison, a one-month supply of warfarin is about $15. Out-of-pocket costs for many patients will likely be high until dabigatran is added to insurers’ formularies. When costs for monitoring and hospitalizations or treatment for complications associated with warfarin are factored in, however, dabigatran is cost effective, a recent study indicates.⁷

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 75-year-old man with persistent atrial fibrillation and diabetes comes to your office for a check of his international normalized ratio (INR). It has been hard to keep his INR within the normal range of 2 to 3 in recent months, and today is no different: The patient’s INR is 1.7, although he insists he has been compliant with his warfarin regimen and has had no change in diet or other medications. What other anticoagulation options can you offer him?

Patients with atrial fibrillation have a 3% to 8% annual risk of stroke.² Both adjusted-dose warfarin and antiplatelet agents such as aspirin have been shown to be effective at reducing this risk, although warfarin is significantly more effective.³

Those who have atrial fibrillation and a previous history of thromboembolism or rheumatic mitral stenosis or more than one moderate risk factor (age ≥75 years, hypertension, heart failure, impaired left ventricular systolic function, or diabetes) have the highest stroke risk. The American College of Cardiology/American Heart Association Task Force/ European Society of Cardiology (ACC/AHA/ ESC) 2006 guidelines for the management of atrial fibrillation recommend chronic anticoagulation with an oral vitamin K antagonist, such as warfarin, for these high-risk patients.⁴

Warfarin therapy is challenging
We have all experienced the frustrations of maintaining our patients on warfarin at a therapeutic INR; the average patient is within this range only about 67% of the time, although this varies dramatically from patient to patient.⁵

Many of our patients have experienced the inconvenience and cost of repeated monitoring, as well as the morbidity associated with both major and minor bleeding related to warfarin use. And there are many potential interactions between warfarin and foods or other drugs.

Is the new oral anticoagulant a better bet?
There are anticoagulants that do not require monitoring (eg, enoxaparin), but few patients are willing to undergo daily subcutaneous injections, and the cost is often prohibitive. Now there is another alternative.

Dabigatran (Pradaxa), an oral direct thrombin inhibitor, was approved by the US Food and Drug Administration in October 2010 for the prevention of stroke and systemic embolism in patients with atrial fibrillation.⁶ Dabigatran is administered twice daily in a fixed dose. Because it has a relatively short half-life (12-17 hours), it does not require INR monitoring. Dabigatran has no known interactions with foods and minimal interactions with other medications. Its value as a warfarin alternative for patients with atrial fibrillation was addressed in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study detailed below.

STUDY SUMMARY: At higher dose, dabigatran prevents more strokes than warfarin

RE-LY included 18,113 patients from 951 facilities in 44 countries. To be eligible for the study, patients had to have atrial fibrillation documented on an electrocardiogram and at least one additional risk factor for stroke.

Participants were randomized into one of 3 groups: dabigatran 110 mg twice daily, dabigatran 150 mg twice daily (both administered in a blinded fashion), or warfarin (administered in an unblinded fashion and dosed to maintain an INR between 2 and 3). Baseline characteristics, such as age, sex, and CHADS₂ (congestive heart failure, hypertension, age, diabetes, prior stroke) score, were similar across all 3 groups. The median duration of follow-up was 2 years, and complete follow-up occurred in 99.9% of participants.

The primary outcome of the study was stroke or systemic embolism. The primary safety outcome was major hemorrhage, defined as a reduction in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of blood, or symptomatic bleeding in a critical area/organ. Other outcomes were death, myocardial infarction (MI), pulmonary embolism, transient ischemic attack, and hospitalization.

For the primary outcome of prevention of stroke or systemic embolism, the 150-mg dose of dabigatran was superior to warfarin (1.11% vs 1.69% per year, relative risk [RR], 0.66; 95% confidence interval [CI], 0.53-0.82; P<.001 for superiority). The major bleeding rates were similar for dabigatran 150 mg and warfarin, although major gastrointestinal bleeding rates were significantly higher with this dose of dabigatran compared with warfarin (TABLE). Minor bleeding was more common in the warfarin group (16.37% vs 14.84%; RR, 0.91; 95% CI, 0.85-0.97; P=.005).

The 110-mg dose of dabigatran (which is not available in the United States) was neither inferior nor superior to warfarin for the prevention of stroke or systemic embolism. This dose of dabigatran had a lower risk of major bleeding compared with warfarin.

TABLE
Dabigatran vs warfarin: A look at the evidence¹

Mortality rates are similar
Rates of death from any cause were similar among the 3 treatment groups. The rates of hemorrhagic stroke were lower in both dabigatran groups compared with the warfarin group, while rates of MI were lower in the warfarin group than in either of the dabigatran groups.

Dyspepsia was the only other adverse effect that was significantly more common among dabigatran users vs warfarin users. Rates of hepatotoxicity, which was a problem wiThearlier oral direct thrombin inhibitors, were similar for both drugs. Multiple subgroup analyses revealed no significant interaction between the treatment effect of dabigatran and variables such as sex, body mass index, creatinine clearance, CHADS₂ score, aspirin use, or previous long-term use of a vitamin K antagonist.

WHAT’S NEW: This easier-to-use oral anticoagulant is a viable option

Dabigatran gives physicians and patients with atrial fibrillation an option that is more convenient than warfarin for stroke prevention. Its 150-mg dose is more effective in preventing stroke compared with warfarin, and comparable in terms of bleeding risk.

CAVEATS: Unknown long-term effects, potential for bias

The median follow-up in the RE-LY study was 2 years. Longer-term efficacy and safety data may differ from the initial results.

The trial was funded by Boehringer Ingelheim, the manufacturer of dabigatran (Pradaxa). However, study coordination, data management, and analysis were performed independently by the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.

Patients taking dabigatran received the medication in a blinded fashion, but the warfarin group could not be blinded because of the need for INR monitoring and dosage adjustments. To decrease potential bias, the outcome events were assessed by 2 independent investigators who were blinded to the treatment assignments.

CHALLENGES TO IMPLEMENTATION: Cost of dabigatran may be a barrier

The wholesale price of dabigatran, as quoted by Boehringer Ingelheim, is $6.75 per day; the retail price for a 30-day supply is approximately $235, according to drugstore.com, Walgreens, and Walmart). In comparison, a one-month supply of warfarin is about $15. Out-of-pocket costs for many patients will likely be high until dabigatran is added to insurers’ formularies. When costs for monitoring and hospitalizations or treatment for complications associated with warfarin are factored in, however, dabigatran is cost effective, a recent study indicates.⁷

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 75-year-old man with persistent atrial fibrillation and diabetes comes to your office for a check of his international normalized ratio (INR). It has been hard to keep his INR within the normal range of 2 to 3 in recent months, and today is no different: The patient’s INR is 1.7, although he insists he has been compliant with his warfarin regimen and has had no change in diet or other medications. What other anticoagulation options can you offer him?

Patients with atrial fibrillation have a 3% to 8% annual risk of stroke.² Both adjusted-dose warfarin and antiplatelet agents such as aspirin have been shown to be effective at reducing this risk, although warfarin is significantly more effective.³

Those who have atrial fibrillation and a previous history of thromboembolism or rheumatic mitral stenosis or more than one moderate risk factor (age ≥75 years, hypertension, heart failure, impaired left ventricular systolic function, or diabetes) have the highest stroke risk. The American College of Cardiology/American Heart Association Task Force/ European Society of Cardiology (ACC/AHA/ ESC) 2006 guidelines for the management of atrial fibrillation recommend chronic anticoagulation with an oral vitamin K antagonist, such as warfarin, for these high-risk patients.⁴

Warfarin therapy is challenging
We have all experienced the frustrations of maintaining our patients on warfarin at a therapeutic INR; the average patient is within this range only about 67% of the time, although this varies dramatically from patient to patient.⁵

Many of our patients have experienced the inconvenience and cost of repeated monitoring, as well as the morbidity associated with both major and minor bleeding related to warfarin use. And there are many potential interactions between warfarin and foods or other drugs.

Is the new oral anticoagulant a better bet?
There are anticoagulants that do not require monitoring (eg, enoxaparin), but few patients are willing to undergo daily subcutaneous injections, and the cost is often prohibitive. Now there is another alternative.

Dabigatran (Pradaxa), an oral direct thrombin inhibitor, was approved by the US Food and Drug Administration in October 2010 for the prevention of stroke and systemic embolism in patients with atrial fibrillation.⁶ Dabigatran is administered twice daily in a fixed dose. Because it has a relatively short half-life (12-17 hours), it does not require INR monitoring. Dabigatran has no known interactions with foods and minimal interactions with other medications. Its value as a warfarin alternative for patients with atrial fibrillation was addressed in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study detailed below.

STUDY SUMMARY: At higher dose, dabigatran prevents more strokes than warfarin

RE-LY included 18,113 patients from 951 facilities in 44 countries. To be eligible for the study, patients had to have atrial fibrillation documented on an electrocardiogram and at least one additional risk factor for stroke.

Participants were randomized into one of 3 groups: dabigatran 110 mg twice daily, dabigatran 150 mg twice daily (both administered in a blinded fashion), or warfarin (administered in an unblinded fashion and dosed to maintain an INR between 2 and 3). Baseline characteristics, such as age, sex, and CHADS₂ (congestive heart failure, hypertension, age, diabetes, prior stroke) score, were similar across all 3 groups. The median duration of follow-up was 2 years, and complete follow-up occurred in 99.9% of participants.

The primary outcome of the study was stroke or systemic embolism. The primary safety outcome was major hemorrhage, defined as a reduction in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of blood, or symptomatic bleeding in a critical area/organ. Other outcomes were death, myocardial infarction (MI), pulmonary embolism, transient ischemic attack, and hospitalization.

For the primary outcome of prevention of stroke or systemic embolism, the 150-mg dose of dabigatran was superior to warfarin (1.11% vs 1.69% per year, relative risk [RR], 0.66; 95% confidence interval [CI], 0.53-0.82; P<.001 for superiority). The major bleeding rates were similar for dabigatran 150 mg and warfarin, although major gastrointestinal bleeding rates were significantly higher with this dose of dabigatran compared with warfarin (TABLE). Minor bleeding was more common in the warfarin group (16.37% vs 14.84%; RR, 0.91; 95% CI, 0.85-0.97; P=.005).

The 110-mg dose of dabigatran (which is not available in the United States) was neither inferior nor superior to warfarin for the prevention of stroke or systemic embolism. This dose of dabigatran had a lower risk of major bleeding compared with warfarin.

TABLE
Dabigatran vs warfarin: A look at the evidence¹

Mortality rates are similar
Rates of death from any cause were similar among the 3 treatment groups. The rates of hemorrhagic stroke were lower in both dabigatran groups compared with the warfarin group, while rates of MI were lower in the warfarin group than in either of the dabigatran groups.

Dyspepsia was the only other adverse effect that was significantly more common among dabigatran users vs warfarin users. Rates of hepatotoxicity, which was a problem wiThearlier oral direct thrombin inhibitors, were similar for both drugs. Multiple subgroup analyses revealed no significant interaction between the treatment effect of dabigatran and variables such as sex, body mass index, creatinine clearance, CHADS₂ score, aspirin use, or previous long-term use of a vitamin K antagonist.

WHAT’S NEW: This easier-to-use oral anticoagulant is a viable option

Dabigatran gives physicians and patients with atrial fibrillation an option that is more convenient than warfarin for stroke prevention. Its 150-mg dose is more effective in preventing stroke compared with warfarin, and comparable in terms of bleeding risk.

CAVEATS: Unknown long-term effects, potential for bias

The median follow-up in the RE-LY study was 2 years. Longer-term efficacy and safety data may differ from the initial results.

The trial was funded by Boehringer Ingelheim, the manufacturer of dabigatran (Pradaxa). However, study coordination, data management, and analysis were performed independently by the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.

Patients taking dabigatran received the medication in a blinded fashion, but the warfarin group could not be blinded because of the need for INR monitoring and dosage adjustments. To decrease potential bias, the outcome events were assessed by 2 independent investigators who were blinded to the treatment assignments.

CHALLENGES TO IMPLEMENTATION: Cost of dabigatran may be a barrier

The wholesale price of dabigatran, as quoted by Boehringer Ingelheim, is $6.75 per day; the retail price for a 30-day supply is approximately $235, according to drugstore.com, Walgreens, and Walmart). In comparison, a one-month supply of warfarin is about $15. Out-of-pocket costs for many patients will likely be high until dabigatran is added to insurers’ formularies. When costs for monitoring and hospitalizations or treatment for complications associated with warfarin are factored in, however, dabigatran is cost effective, a recent study indicates.⁷

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 47-year-old man limps into your office complaining of ankle pain. The patient is well known to you and has a long history of dyspepsia, which is aggravated when he takes any oral nonsteroidal anti-inflammatory drug (NSAID). He injured his ankle while playing basketball. You diagnose acute ankle sprain. Would a topical NSAID be a safe option for pain relief for this patient?

Patients with tendon and ligament injuries often see their family physician for care. Rest, ice, compression, elevation (RICE) therapy is first-line treatment for these injuries.² Oral NSAIDs, such as diclofenac, piroxicam, and ibuprofen reduce swelling and lead to a more rapid return to activity than RICE alone in patients with ankle sprains,³ and relieve pain associated with muscle strains, too. Acetaminophen provides comparable pain relief and resumption of normal activities.⁴

Help for those who can’t take oral NSAIDs
Oral NSAIDs, however, are contraindicated for patients with a history of gastrointestinal bleeding and must be used cautiously in those with chronic kidney disease. Some patients can’t tolerate the adverse effects, which may include stomach upset, vomiting, and abdominal pain. Others may have medication interactions that prohibit use of oral NSAIDs.

Numerous high-quality, randomized, double-blinded placebo-controlled trials of topical NSAIDs have been conducted in recent years, involving diclofenac—the only topical NSAID available in the United States— as well as other topical agents on the market outside of this country. A recent Cochrane review, detailed below, assessed the efficacy of topical NSAIDs for patients with acute musculoskeletal injuries.

STUDY SUMMARY: Topical NSAIDs provided significant relief

This meta-analysis of 47 high-quality, randomized, double-blinded, placebo-controlled trials included 3455 patients with acute strain, sprain, sport, or overuse injuries.¹ Four of the 47 trials, with a total of 746 participants, studied topical diclofenac.

There was significant heterogeneity in the studies included in the review, but each arm of every trial had at least 10 participants >16 years of age with a painful musculoskeletal injury sustained within the previous 48 hours. To be included in the Cochrane meta-analysis, participants had to have used a topical NSAID at least once a day for ≥3 days.

The primary outcome measure was a reduction in pain ≥50% from baseline. Post-treatment data were obtained approximately 7 days after the injury. Of the patients receiving any topical NSAID, 65% (1181/1822) had successful treatment, compared with 43% (695/1633) receiving a placebo. The number needed to treat (NNT) with a topical NSAID instead of placebo was 4.5 (95% confidence interval, 3.9-5.3) to reduce pain ≥50%.

For patients using topical diclofenac, 52% (166/319) had a 50% reduction in pain, vs 25% (77/307) using a topical placebo. The NNT for topical diclofenac was 3.7, about the same as for oral NSAIDs.⁵

Adverse events were rare in the topical NSAID group: 6.3% had a local adverse event such as a skin reaction vs 5.9% in the topical placebo group. There were no systemic adverse events with topical diclofenac. While all topical NSAIDs combined showed a few minor adverse events compared with placebo, no serious systemic events were reported.

WHAT’S NEW: Topical NSAIDs are a useful alternative

Patients now have another option when seeking treatment for acute musculoskeletal pain. In addition to those who are unable to take oral NSAIDs, some patients may prefer a topical preparation because of perceived or actual side effects and safety profiles.

CAVEATS: Dosing intervals were not established

This meta-analysis included studies that examined a variety of dosing strategies and conditions, so an optimal dosing interval is not clear. However, the studies generally found evidence of benefit regardless of the acute condition and the amount and type of topical NSAID used. Diclofenac had the best results compared with other topical NSAIDs. Benzydamine, which is not sold in the United States, was the only topical NSAID not found to be statistically beneficial compared with placebo, based on 3 studies.

Topical NSAIDs have a small amount of systemic absorption, with blood concentrations about 5% of those from oral NSAIDs. However, patients with a strict contraindication to oral NSAIDs (for example, severe allergy) may also have a contraindication to topical NSAIDs. Also, all patients should be cautioned to avoid oral NSAIDs while using a topical preparation.⁶

CHALLENGES TO IMPLEMENTATION: Topical NSAIDs are costly

In the United States, topical diclofenac is available only by prescription. This may create accessibility and cost differences between oral and topical NSAIDs. The average cost of a typical 10-day acute injury treatment of an adult with oral ibuprofen would be about $3 for plain tablets ($10 for extended release and enteric coated), vs about $65 for diclofenac gel, $113 for a diclofenac patch, and $66 for a diclofenac topical solution (www.drugstore.com, accessed December 2, 2010).

Physician inertia may also interfere with implementation. Physicians may not add a new medication to current prescribing options, although there appear to be no medical barriers to topical NSAIDs. This meta-analysis shows that topical NSAIDs are safe and effective for pain relief from acute injuries.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 47-year-old man limps into your office complaining of ankle pain. The patient is well known to you and has a long history of dyspepsia, which is aggravated when he takes any oral nonsteroidal anti-inflammatory drug (NSAID). He injured his ankle while playing basketball. You diagnose acute ankle sprain. Would a topical NSAID be a safe option for pain relief for this patient?

Patients with tendon and ligament injuries often see their family physician for care. Rest, ice, compression, elevation (RICE) therapy is first-line treatment for these injuries.² Oral NSAIDs, such as diclofenac, piroxicam, and ibuprofen reduce swelling and lead to a more rapid return to activity than RICE alone in patients with ankle sprains,³ and relieve pain associated with muscle strains, too. Acetaminophen provides comparable pain relief and resumption of normal activities.⁴

Help for those who can’t take oral NSAIDs
Oral NSAIDs, however, are contraindicated for patients with a history of gastrointestinal bleeding and must be used cautiously in those with chronic kidney disease. Some patients can’t tolerate the adverse effects, which may include stomach upset, vomiting, and abdominal pain. Others may have medication interactions that prohibit use of oral NSAIDs.

Numerous high-quality, randomized, double-blinded placebo-controlled trials of topical NSAIDs have been conducted in recent years, involving diclofenac—the only topical NSAID available in the United States— as well as other topical agents on the market outside of this country. A recent Cochrane review, detailed below, assessed the efficacy of topical NSAIDs for patients with acute musculoskeletal injuries.

STUDY SUMMARY: Topical NSAIDs provided significant relief

This meta-analysis of 47 high-quality, randomized, double-blinded, placebo-controlled trials included 3455 patients with acute strain, sprain, sport, or overuse injuries.¹ Four of the 47 trials, with a total of 746 participants, studied topical diclofenac.

There was significant heterogeneity in the studies included in the review, but each arm of every trial had at least 10 participants >16 years of age with a painful musculoskeletal injury sustained within the previous 48 hours. To be included in the Cochrane meta-analysis, participants had to have used a topical NSAID at least once a day for ≥3 days.

The primary outcome measure was a reduction in pain ≥50% from baseline. Post-treatment data were obtained approximately 7 days after the injury. Of the patients receiving any topical NSAID, 65% (1181/1822) had successful treatment, compared with 43% (695/1633) receiving a placebo. The number needed to treat (NNT) with a topical NSAID instead of placebo was 4.5 (95% confidence interval, 3.9-5.3) to reduce pain ≥50%.

For patients using topical diclofenac, 52% (166/319) had a 50% reduction in pain, vs 25% (77/307) using a topical placebo. The NNT for topical diclofenac was 3.7, about the same as for oral NSAIDs.⁵

Adverse events were rare in the topical NSAID group: 6.3% had a local adverse event such as a skin reaction vs 5.9% in the topical placebo group. There were no systemic adverse events with topical diclofenac. While all topical NSAIDs combined showed a few minor adverse events compared with placebo, no serious systemic events were reported.

WHAT’S NEW: Topical NSAIDs are a useful alternative

Patients now have another option when seeking treatment for acute musculoskeletal pain. In addition to those who are unable to take oral NSAIDs, some patients may prefer a topical preparation because of perceived or actual side effects and safety profiles.

CAVEATS: Dosing intervals were not established

This meta-analysis included studies that examined a variety of dosing strategies and conditions, so an optimal dosing interval is not clear. However, the studies generally found evidence of benefit regardless of the acute condition and the amount and type of topical NSAID used. Diclofenac had the best results compared with other topical NSAIDs. Benzydamine, which is not sold in the United States, was the only topical NSAID not found to be statistically beneficial compared with placebo, based on 3 studies.

Topical NSAIDs have a small amount of systemic absorption, with blood concentrations about 5% of those from oral NSAIDs. However, patients with a strict contraindication to oral NSAIDs (for example, severe allergy) may also have a contraindication to topical NSAIDs. Also, all patients should be cautioned to avoid oral NSAIDs while using a topical preparation.⁶

CHALLENGES TO IMPLEMENTATION: Topical NSAIDs are costly

In the United States, topical diclofenac is available only by prescription. This may create accessibility and cost differences between oral and topical NSAIDs. The average cost of a typical 10-day acute injury treatment of an adult with oral ibuprofen would be about $3 for plain tablets ($10 for extended release and enteric coated), vs about $65 for diclofenac gel, $113 for a diclofenac patch, and $66 for a diclofenac topical solution (www.drugstore.com, accessed December 2, 2010).

Physician inertia may also interfere with implementation. Physicians may not add a new medication to current prescribing options, although there appear to be no medical barriers to topical NSAIDs. This meta-analysis shows that topical NSAIDs are safe and effective for pain relief from acute injuries.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 47-year-old man limps into your office complaining of ankle pain. The patient is well known to you and has a long history of dyspepsia, which is aggravated when he takes any oral nonsteroidal anti-inflammatory drug (NSAID). He injured his ankle while playing basketball. You diagnose acute ankle sprain. Would a topical NSAID be a safe option for pain relief for this patient?

Patients with tendon and ligament injuries often see their family physician for care. Rest, ice, compression, elevation (RICE) therapy is first-line treatment for these injuries.² Oral NSAIDs, such as diclofenac, piroxicam, and ibuprofen reduce swelling and lead to a more rapid return to activity than RICE alone in patients with ankle sprains,³ and relieve pain associated with muscle strains, too. Acetaminophen provides comparable pain relief and resumption of normal activities.⁴

Help for those who can’t take oral NSAIDs
Oral NSAIDs, however, are contraindicated for patients with a history of gastrointestinal bleeding and must be used cautiously in those with chronic kidney disease. Some patients can’t tolerate the adverse effects, which may include stomach upset, vomiting, and abdominal pain. Others may have medication interactions that prohibit use of oral NSAIDs.

Numerous high-quality, randomized, double-blinded placebo-controlled trials of topical NSAIDs have been conducted in recent years, involving diclofenac—the only topical NSAID available in the United States— as well as other topical agents on the market outside of this country. A recent Cochrane review, detailed below, assessed the efficacy of topical NSAIDs for patients with acute musculoskeletal injuries.

STUDY SUMMARY: Topical NSAIDs provided significant relief

This meta-analysis of 47 high-quality, randomized, double-blinded, placebo-controlled trials included 3455 patients with acute strain, sprain, sport, or overuse injuries.¹ Four of the 47 trials, with a total of 746 participants, studied topical diclofenac.

There was significant heterogeneity in the studies included in the review, but each arm of every trial had at least 10 participants >16 years of age with a painful musculoskeletal injury sustained within the previous 48 hours. To be included in the Cochrane meta-analysis, participants had to have used a topical NSAID at least once a day for ≥3 days.

The primary outcome measure was a reduction in pain ≥50% from baseline. Post-treatment data were obtained approximately 7 days after the injury. Of the patients receiving any topical NSAID, 65% (1181/1822) had successful treatment, compared with 43% (695/1633) receiving a placebo. The number needed to treat (NNT) with a topical NSAID instead of placebo was 4.5 (95% confidence interval, 3.9-5.3) to reduce pain ≥50%.

For patients using topical diclofenac, 52% (166/319) had a 50% reduction in pain, vs 25% (77/307) using a topical placebo. The NNT for topical diclofenac was 3.7, about the same as for oral NSAIDs.⁵

Adverse events were rare in the topical NSAID group: 6.3% had a local adverse event such as a skin reaction vs 5.9% in the topical placebo group. There were no systemic adverse events with topical diclofenac. While all topical NSAIDs combined showed a few minor adverse events compared with placebo, no serious systemic events were reported.

WHAT’S NEW: Topical NSAIDs are a useful alternative

Patients now have another option when seeking treatment for acute musculoskeletal pain. In addition to those who are unable to take oral NSAIDs, some patients may prefer a topical preparation because of perceived or actual side effects and safety profiles.

CAVEATS: Dosing intervals were not established

This meta-analysis included studies that examined a variety of dosing strategies and conditions, so an optimal dosing interval is not clear. However, the studies generally found evidence of benefit regardless of the acute condition and the amount and type of topical NSAID used. Diclofenac had the best results compared with other topical NSAIDs. Benzydamine, which is not sold in the United States, was the only topical NSAID not found to be statistically beneficial compared with placebo, based on 3 studies.

Topical NSAIDs have a small amount of systemic absorption, with blood concentrations about 5% of those from oral NSAIDs. However, patients with a strict contraindication to oral NSAIDs (for example, severe allergy) may also have a contraindication to topical NSAIDs. Also, all patients should be cautioned to avoid oral NSAIDs while using a topical preparation.⁶

CHALLENGES TO IMPLEMENTATION: Topical NSAIDs are costly

In the United States, topical diclofenac is available only by prescription. This may create accessibility and cost differences between oral and topical NSAIDs. The average cost of a typical 10-day acute injury treatment of an adult with oral ibuprofen would be about $3 for plain tablets ($10 for extended release and enteric coated), vs about $65 for diclofenac gel, $113 for a diclofenac patch, and $66 for a diclofenac topical solution (www.drugstore.com, accessed December 2, 2010).

Physician inertia may also interfere with implementation. Physicians may not add a new medication to current prescribing options, although there appear to be no medical barriers to topical NSAIDs. This meta-analysis shows that topical NSAIDs are safe and effective for pain relief from acute injuries.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 26-year-old nonsmoking woman with a single sexual partner comes in with the second bout of bacterial vaginosis (BV) she’s had this year. What can you give her to prevent a recurrence?

Bacterial vaginosis is the most common cause of vaginal discharge in women, responsible for 40% to 50% of clinical cases. Among American women ages 14 to 49, the general prevalence—including asymptomatic cases—is close to 30%.²

Recurrence rate, as well as prevalence, is high
BV is caused by a shift in vaginal flora from hydrogen peroxide-producing Lactobacillus species to anaerobes that raise the vaginal pH. Multiple species of anaerobic bacteria are implicated. The drug of choice for treatment of BV continues to be metronidazole, a drug prescribed for the past 45 years with minimal resistance.³ However, there is growing resistance among Bacteroides species. Oral or intravaginal clindamycin is another option for treating BV.⁴

Even with the use of metronidazole, recurrence is common—with as many as 50% of symptomatic infections recurring within a year.⁵ A randomized, double-blind placebo-controlled trial published in 2006 compared the results of 1 week of oral metronidazole (500 mg) twice daily plus 30 days of oral probiotics vs the same dose and duration of metronidazole plus 30 days of placebo.⁶ The rate of recurrence at the end of 1 month was 12% in the antibiotic/probiotic group vs 60% in the antibiotic/placebo group.

The RCT reviewed here evaluated the effectiveness of a vaginal probiotic capsule in preventing recurrent BV.

STUDY SUMMARY: Probiotic use lowered recurrence rate

Ya et al enrolled 120 Chinese women with a history of recurrent BV in a double-blind RCT.¹ To be eligible, women had to be healthy, between the ages of 18 and 55, and free from BV (but have a history of ≥2 episodes in the previous year). They also could not have had any antibiotic treatment within a week of study participation, and had to be willing to refrain from using other intravaginal products during the course of the study.

The researchers excluded women who were found to have other causes of vulvovaginitis or urogenital infection within 21 days of participation, were pregnant or lactating, ate yogurt or fermented milk on a daily basis, were allergic to study product ingredients, or were immunosuppressed.

Participants were assigned to either BV prophylaxis with the vaginal probiotic capsule Probaclac Vaginal (a lactose capsule containing 8 billion colony-forming units [CFUs] of Lactobacillus rhamnosus, L acidophilus, and Streptococcus thermophilus) (n=58) or a placebo capsule containing lactose alone (n=62). Both groups had similar baseline characteristics; most of the women were nonsmokers who had had either one sexual partner or no partners within the previous year.

After a baseline evaluation, the participants used the vaginal capsules daily for 7 days, skipped usage for 7 days, and then used them again for a final 7 days. The women then returned for follow-up visits at 30 and 60 days after treatment began for the collection of vaginal swabs, an assessment of vaginal flora, and a report of adverse events. Researchers also contacted them by phone roughly 11 months after treatment started to ask about BV symptoms or diagnosis after treatment.

The primary end point was the diagnosis in the first 2 months of BV using Amsel criteria: the presence of thin, grey-white homogenous discharge coating the vaginal walls; vaginal pH >4.5; a positive whiff-amine test (presence of “fish smell” with potassium hydroxide [KOH] or KOH prep); and the presence of clue cells on normal saline wet mount.⁷

This end point—based on the presence of 3 of the 4 criteria—was reached in 15.8% of women in the probiotic group and 45% in the control group (odds ratio [OR]=0.23; 95% confidence interval [CI], 0.10-0.55; P<.001), with a number needed to treat (NNT) of 3.4.

A secondary end point was the confirmed diagnosis of BV between 2 and 11 months; only 10.6% of women in the probiotic group and 27.7% of women in the control group had confirmed BV (OR=0.31, 95% CI, 0.11-0.93; P=.04), with an NNT of 5.8. No adverse advents were reported.

WHAT’S NEW: A new use for probiotics is established

This trial supports the use of probiotic vaginal capsules in the prevention of recurrent BV. We found the specific formulation (Probaclac Vaginal) that was tested in this RCT on an online natural health site (http://www.lady tobaby.com/show.php?item=219). This Web site sells Probaclac Vaginal at a cost of $28 for 10 capsules. A full course of a week’s treatment, repeated once, would cost approximately $56.

CAVEATS: Will other formulations work?

This study was funded by the makers of Probaclac Vaginal, so we will be watching for independent replication of these findings in other populations. The vaginal probiotic tested had 80 times the current recommended concentration of lactobacilli required to restore and maintain normal vaginal flora, so we are unsure as to whether less concentrated formulations would be equally effective.

Probiotic formulations differ widely, although some are similar to the species/ concentration used in Probaclac Vaginal, including LactoViden ID by Metagenics (http://www.metagenics.com/products/az-products-list/LactoViden-ID), with 15 billion CFUs, and Therbiotic by Klaire Labs (http://www.klaire.com/prod/proddetail. asp?id=V775-06-CN), with 25 billion CFUs.

Also, this intervention has not been tested in populations outside of China, in heavy smokers, or in women with more than one sexual partner, so there is a small risk that these findings may not be confirmed in subsequent RCTs or may not be generalizable to other populations. Nonetheless, we think the potential benefit outweighs any possible harm, and we will be watching for studies that confirm or challenge these findings.

CHALLENGES TO IMPLEMENTATION: Finding the right probiotic

The brand used in the study is available only on the Web, which may be difficult for some patients to access, and some patients will find the probiotic to be fairly expensive. In addition, other brands of probiotics may not be available as a vaginal capsule with applicator. It should be noted, though, that it is possible to use an applicator to insert an oral probiotic capsule into the vagina.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 26-year-old nonsmoking woman with a single sexual partner comes in with the second bout of bacterial vaginosis (BV) she’s had this year. What can you give her to prevent a recurrence?

Bacterial vaginosis is the most common cause of vaginal discharge in women, responsible for 40% to 50% of clinical cases. Among American women ages 14 to 49, the general prevalence—including asymptomatic cases—is close to 30%.²

Recurrence rate, as well as prevalence, is high
BV is caused by a shift in vaginal flora from hydrogen peroxide-producing Lactobacillus species to anaerobes that raise the vaginal pH. Multiple species of anaerobic bacteria are implicated. The drug of choice for treatment of BV continues to be metronidazole, a drug prescribed for the past 45 years with minimal resistance.³ However, there is growing resistance among Bacteroides species. Oral or intravaginal clindamycin is another option for treating BV.⁴

Even with the use of metronidazole, recurrence is common—with as many as 50% of symptomatic infections recurring within a year.⁵ A randomized, double-blind placebo-controlled trial published in 2006 compared the results of 1 week of oral metronidazole (500 mg) twice daily plus 30 days of oral probiotics vs the same dose and duration of metronidazole plus 30 days of placebo.⁶ The rate of recurrence at the end of 1 month was 12% in the antibiotic/probiotic group vs 60% in the antibiotic/placebo group.

The RCT reviewed here evaluated the effectiveness of a vaginal probiotic capsule in preventing recurrent BV.

STUDY SUMMARY: Probiotic use lowered recurrence rate

Ya et al enrolled 120 Chinese women with a history of recurrent BV in a double-blind RCT.¹ To be eligible, women had to be healthy, between the ages of 18 and 55, and free from BV (but have a history of ≥2 episodes in the previous year). They also could not have had any antibiotic treatment within a week of study participation, and had to be willing to refrain from using other intravaginal products during the course of the study.

The researchers excluded women who were found to have other causes of vulvovaginitis or urogenital infection within 21 days of participation, were pregnant or lactating, ate yogurt or fermented milk on a daily basis, were allergic to study product ingredients, or were immunosuppressed.

Participants were assigned to either BV prophylaxis with the vaginal probiotic capsule Probaclac Vaginal (a lactose capsule containing 8 billion colony-forming units [CFUs] of Lactobacillus rhamnosus, L acidophilus, and Streptococcus thermophilus) (n=58) or a placebo capsule containing lactose alone (n=62). Both groups had similar baseline characteristics; most of the women were nonsmokers who had had either one sexual partner or no partners within the previous year.

After a baseline evaluation, the participants used the vaginal capsules daily for 7 days, skipped usage for 7 days, and then used them again for a final 7 days. The women then returned for follow-up visits at 30 and 60 days after treatment began for the collection of vaginal swabs, an assessment of vaginal flora, and a report of adverse events. Researchers also contacted them by phone roughly 11 months after treatment started to ask about BV symptoms or diagnosis after treatment.

The primary end point was the diagnosis in the first 2 months of BV using Amsel criteria: the presence of thin, grey-white homogenous discharge coating the vaginal walls; vaginal pH >4.5; a positive whiff-amine test (presence of “fish smell” with potassium hydroxide [KOH] or KOH prep); and the presence of clue cells on normal saline wet mount.⁷

This end point—based on the presence of 3 of the 4 criteria—was reached in 15.8% of women in the probiotic group and 45% in the control group (odds ratio [OR]=0.23; 95% confidence interval [CI], 0.10-0.55; P<.001), with a number needed to treat (NNT) of 3.4.

A secondary end point was the confirmed diagnosis of BV between 2 and 11 months; only 10.6% of women in the probiotic group and 27.7% of women in the control group had confirmed BV (OR=0.31, 95% CI, 0.11-0.93; P=.04), with an NNT of 5.8. No adverse advents were reported.

WHAT’S NEW: A new use for probiotics is established

This trial supports the use of probiotic vaginal capsules in the prevention of recurrent BV. We found the specific formulation (Probaclac Vaginal) that was tested in this RCT on an online natural health site (http://www.lady tobaby.com/show.php?item=219). This Web site sells Probaclac Vaginal at a cost of $28 for 10 capsules. A full course of a week’s treatment, repeated once, would cost approximately $56.

CAVEATS: Will other formulations work?

This study was funded by the makers of Probaclac Vaginal, so we will be watching for independent replication of these findings in other populations. The vaginal probiotic tested had 80 times the current recommended concentration of lactobacilli required to restore and maintain normal vaginal flora, so we are unsure as to whether less concentrated formulations would be equally effective.

Probiotic formulations differ widely, although some are similar to the species/ concentration used in Probaclac Vaginal, including LactoViden ID by Metagenics (http://www.metagenics.com/products/az-products-list/LactoViden-ID), with 15 billion CFUs, and Therbiotic by Klaire Labs (http://www.klaire.com/prod/proddetail. asp?id=V775-06-CN), with 25 billion CFUs.

Also, this intervention has not been tested in populations outside of China, in heavy smokers, or in women with more than one sexual partner, so there is a small risk that these findings may not be confirmed in subsequent RCTs or may not be generalizable to other populations. Nonetheless, we think the potential benefit outweighs any possible harm, and we will be watching for studies that confirm or challenge these findings.

CHALLENGES TO IMPLEMENTATION: Finding the right probiotic

The brand used in the study is available only on the Web, which may be difficult for some patients to access, and some patients will find the probiotic to be fairly expensive. In addition, other brands of probiotics may not be available as a vaginal capsule with applicator. It should be noted, though, that it is possible to use an applicator to insert an oral probiotic capsule into the vagina.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

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ILLUSTRATIVE CASE

A 26-year-old nonsmoking woman with a single sexual partner comes in with the second bout of bacterial vaginosis (BV) she’s had this year. What can you give her to prevent a recurrence?

Bacterial vaginosis is the most common cause of vaginal discharge in women, responsible for 40% to 50% of clinical cases. Among American women ages 14 to 49, the general prevalence—including asymptomatic cases—is close to 30%.²

Recurrence rate, as well as prevalence, is high
BV is caused by a shift in vaginal flora from hydrogen peroxide-producing Lactobacillus species to anaerobes that raise the vaginal pH. Multiple species of anaerobic bacteria are implicated. The drug of choice for treatment of BV continues to be metronidazole, a drug prescribed for the past 45 years with minimal resistance.³ However, there is growing resistance among Bacteroides species. Oral or intravaginal clindamycin is another option for treating BV.⁴

Even with the use of metronidazole, recurrence is common—with as many as 50% of symptomatic infections recurring within a year.⁵ A randomized, double-blind placebo-controlled trial published in 2006 compared the results of 1 week of oral metronidazole (500 mg) twice daily plus 30 days of oral probiotics vs the same dose and duration of metronidazole plus 30 days of placebo.⁶ The rate of recurrence at the end of 1 month was 12% in the antibiotic/probiotic group vs 60% in the antibiotic/placebo group.

The RCT reviewed here evaluated the effectiveness of a vaginal probiotic capsule in preventing recurrent BV.

STUDY SUMMARY: Probiotic use lowered recurrence rate

Ya et al enrolled 120 Chinese women with a history of recurrent BV in a double-blind RCT.¹ To be eligible, women had to be healthy, between the ages of 18 and 55, and free from BV (but have a history of ≥2 episodes in the previous year). They also could not have had any antibiotic treatment within a week of study participation, and had to be willing to refrain from using other intravaginal products during the course of the study.

The researchers excluded women who were found to have other causes of vulvovaginitis or urogenital infection within 21 days of participation, were pregnant or lactating, ate yogurt or fermented milk on a daily basis, were allergic to study product ingredients, or were immunosuppressed.

Participants were assigned to either BV prophylaxis with the vaginal probiotic capsule Probaclac Vaginal (a lactose capsule containing 8 billion colony-forming units [CFUs] of Lactobacillus rhamnosus, L acidophilus, and Streptococcus thermophilus) (n=58) or a placebo capsule containing lactose alone (n=62). Both groups had similar baseline characteristics; most of the women were nonsmokers who had had either one sexual partner or no partners within the previous year.

After a baseline evaluation, the participants used the vaginal capsules daily for 7 days, skipped usage for 7 days, and then used them again for a final 7 days. The women then returned for follow-up visits at 30 and 60 days after treatment began for the collection of vaginal swabs, an assessment of vaginal flora, and a report of adverse events. Researchers also contacted them by phone roughly 11 months after treatment started to ask about BV symptoms or diagnosis after treatment.

The primary end point was the diagnosis in the first 2 months of BV using Amsel criteria: the presence of thin, grey-white homogenous discharge coating the vaginal walls; vaginal pH >4.5; a positive whiff-amine test (presence of “fish smell” with potassium hydroxide [KOH] or KOH prep); and the presence of clue cells on normal saline wet mount.⁷

This end point—based on the presence of 3 of the 4 criteria—was reached in 15.8% of women in the probiotic group and 45% in the control group (odds ratio [OR]=0.23; 95% confidence interval [CI], 0.10-0.55; P<.001), with a number needed to treat (NNT) of 3.4.

A secondary end point was the confirmed diagnosis of BV between 2 and 11 months; only 10.6% of women in the probiotic group and 27.7% of women in the control group had confirmed BV (OR=0.31, 95% CI, 0.11-0.93; P=.04), with an NNT of 5.8. No adverse advents were reported.

WHAT’S NEW: A new use for probiotics is established

This trial supports the use of probiotic vaginal capsules in the prevention of recurrent BV. We found the specific formulation (Probaclac Vaginal) that was tested in this RCT on an online natural health site (http://www.lady tobaby.com/show.php?item=219). This Web site sells Probaclac Vaginal at a cost of $28 for 10 capsules. A full course of a week’s treatment, repeated once, would cost approximately $56.

CAVEATS: Will other formulations work?

This study was funded by the makers of Probaclac Vaginal, so we will be watching for independent replication of these findings in other populations. The vaginal probiotic tested had 80 times the current recommended concentration of lactobacilli required to restore and maintain normal vaginal flora, so we are unsure as to whether less concentrated formulations would be equally effective.

Probiotic formulations differ widely, although some are similar to the species/ concentration used in Probaclac Vaginal, including LactoViden ID by Metagenics (http://www.metagenics.com/products/az-products-list/LactoViden-ID), with 15 billion CFUs, and Therbiotic by Klaire Labs (http://www.klaire.com/prod/proddetail. asp?id=V775-06-CN), with 25 billion CFUs.

Also, this intervention has not been tested in populations outside of China, in heavy smokers, or in women with more than one sexual partner, so there is a small risk that these findings may not be confirmed in subsequent RCTs or may not be generalizable to other populations. Nonetheless, we think the potential benefit outweighs any possible harm, and we will be watching for studies that confirm or challenge these findings.

CHALLENGES TO IMPLEMENTATION: Finding the right probiotic

The brand used in the study is available only on the Web, which may be difficult for some patients to access, and some patients will find the probiotic to be fairly expensive. In addition, other brands of probiotics may not be available as a vaginal capsule with applicator. It should be noted, though, that it is possible to use an applicator to insert an oral probiotic capsule into the vagina.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY