Pharmacology Watch

Does Azithromycin Cause Cardiovascular Death?

In this issue: Azithromycin and cardiac risk; warfarin and heart failure; aspirin and VTE; effectiveness of long-acting contraceptives; and FDA actions.

New study finds increased risk

Is azithromycin proarrhythmic? Macrolide antibiotics are associated with an increased risk of sudden cardiac death, but azithromycin (Zithromax), the popular "Z pack" macrolide, has been considered safe. That may change based on the results of a new study from Vanderbilt. Researchers reviewed the records of patients in the Tennessee Medicaid cohort to detect an increased risk of death related to short-term cardiac effects of azithromycin and several control antibiotics. Patients with serious noncardiovascular illness and hospitalized patients were excluded. Over the study period, there were almost 350,000 patients who took azithromycin, 1.35 million patients who took amoxicillin, 265,000 patients who took ciprofloxacin, nearly 200,000 patients who took levofloxacin, and nearly 1.4 million control patients. Five days of therapy with azithromycin compared to no antibiotics significantly increased the risk of cardiovascular death (hazard ratio [HR] 2.88, confidence interval [CI], 1.79 to 4.63; P < 0.001) and death from any cause (HR 1.85; 95% CI, 1.25 to 2.75; P = 0.002). Use of amoxicillin was not associated with increased risk of death. Relative to amoxicillin patients, patients taking azithromycin were at 2.5 times higher risk of cardiovascular death and 2 times higher risk of death from any cause, although the absolute risk was low with an estimated 47 additional cardiovascular deaths per million courses. Patients at risk for cardiovascular disease were at higher risk, with an estimated 245 additional cardiovascular deaths per 1 million courses. Cardiovascular death risk was higher with azithromycin compared to ciprofloxacin, but the death rate from levofloxacin was roughly the same. The authors conclude that 5 days of azithromycin was associated with a small but absolute increased risk of cardiovascular death, which was most pronounced in patients with a high baseline risk for cardiovascular disease (N Engl J Med 2012;366:1881-1890). Soon after this study was published, the FDA issued a statement urging patients to continue taking azithromycin unless instructed otherwise by their health care professional. The FDA will review the results of the study and will communicate any new information on azithromycin, including the potential risk of QT interval prolongation, to health care professionals and the public. Health care professionals are urged to report any adverse effects related to the use of azithromycin to the FDA's MedWatch Safety program.

Warfarin doesn't prevent death

Warfarin is no more effective than aspirin in preventing mortality in patients with heart failure who are not in atrial fibrillation (AF), according to a new study. More than 2300 patients with a left ventricular ejection fraction less than 35% (average 25%) and a mean age of 61 years were randomized to warfarin with a target INR of 2.0-3.5 or aspirin 325 mg per day. The primary outcome was ischemic stroke, intracerebral hemorrhage, or death from any cause. Patients were followed for up to 6 years with a mean follow-up of 3.5 years. There was no difference in the primary outcome (7.47 events per 100 patient years for warfarin, 7.93 for aspirin; HR with warfarin 0.93, CI, 0.79 to 1.10, P = 0.40). Warfarin was associated with a significant reduction in the rate of ischemic stroke but was associated with a higher rate of hemorrhage. The authors conclude that among patients with heart failure who are in sinus rhythm, there was no difference in outcome between warfarin and aspirin, but note that since warfarin was associated with a lower risk of ischemic stroke, the choice between the two drugs should be individualized (N Engl J Med 2012;366:1859-1869). An accompanying editorial asks, "Could there be some patients with heart failure who would benefit from warfarin?" Those with AF, a history of cardioembolic stroke, history of left ventricular thrombus, and perhaps those with atherothrombotic coronary artery disease may benefit, but in general, warfarin cannot be recommended for patients with heart failure who are not in AF (N Engl J Med 2012;366:1936-1938).

Aspirin and venous thromboembolism

Aspirin may be protective in patients who have had an unprovoked venous thromboembolism (VTE) to prevent recurrence after they finish oral anticoagulant therapy. In a double-blind study, patients with first-ever unprovoked VTE who had completed 6-18 months of oral anticoagulant treatment were randomly assigned to aspirin 100 mg daily or placebo for 2 years. The primary endpoint was recurrent VTE with major bleeding being the primary safety outcome. Recurrent VTE occurred in 6.6% of patients on aspirin and 11.2% of patients on placebo (HR 0.58; 95% CI, 0.36 to 0.93). One patient in each group had a major bleeding episode. The authors conclude that aspirin reduces the risk of recurrence in patients with unprovoked VTE after they have finished anticoagulant therapy, with no apparent increase in risk of major bleeding (N Engl J Med 2012;366:1959-1967). This study is important because about 20% of patients with unprovoked VTE have a recurrence within 2 years. It also shows that taking low-dose aspirin safely reduces that risk by nearly half. An accompanying editorial points out that a similar but larger study is currently ongoing in Australia and New Zealand with results due later this year (N Engl J Med 2012;366:2028-2030).

Long-acting contraceptives are better

Long-acting contraceptives, such as IUDs and implants, are up to 20 times more effective than oral contraceptives and other short-acting contraceptive methods, according to a new study. In a large, prospective cohort study, women participants were provided with the reversible contraception of their choice at no cost for 3 years. The endpoint was failure of long-acting reversible contraception (IUDs and implants) compared with commonly prescribed contraceptive methods, including oral contraceptive pills, transdermal patches, contraceptive vaginal rings, and depot medroxyprogesterone acetate injection (DMPA). In the nearly 7500 women participants, there were 334 unintended pregnancies. The failure rate among participants who used pills, patch, or ring was 4.55 per 100 participants years as compared with 0.27 among participants using long-acting reversible contraception (HR after adjustment for age, educational level, and history with respect to unintended pregnancy 21.8; 95% CI, 13.7 to 34.9). The rate for DMPA was also low at 0.22. Younger women (< 21 years) who used a short-acting contraceptive had a pregnancy rate almost twice as high as older participants. The pregnancy rate among women who used DMPA, an IUD, or implant were similarly low regardless of age. The authors conclude that the effectiveness of long-acting reversible contraception is superior to that of contraceptive pills, patch, or ring and is not altered in adolescents or young woman (N Engl J Med 2012;366:1998-2007). This study not only points out the reliability of long-acting contraceptives, but also the surprisingly high failure rate of short-acting contaceptives, especially in young women.

FDA actions

In the biggest generic launch since last year's atorvastatin (Lipitor), the FDA has approved generic clopidogrel (Plavix). The popular antiplatelet drug, with sales of more than $9 billion last year, will be available from seven generic manufacturers in the 75 mg strength and four manufacturers in the 300 mg strengths. The immediate "multisource" status of the generic approval should result in dramatic cost reductions for patients, from an average of $200 per month to about $40 per month. The drug is approved for treatment of acute coronary syndrome and prevention of thrombotic events in patients who have had a recent myocardial infarction, recent stroke, or peripheral artery disease.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5404. E-mail: