Cardiovascular events and safety outcomes associated with azithromycin therapy: a meta-analysis of randomized controlled trials.

Azithromycin is a broad-spectrum macrolide antibiotic that is frequently used to prevent or treat a wide range of bacterial infections, including upper and lower respiratory infections, skin and soft-tissue infections, as well as some sexually transmitted infections.1,2 Azithromycin was introduced in the early 1950s as the first member of a new subclass of macrolides known as azalide.1 Azithromycin was approved by the US Food and Drug Administration (FDA) in late 1991 as the first once-daily antibiotic with a 5-day course of therapy indicated for acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD), community-acquired pneumonia, pharyngitis/tonsillitis, uncomplicated skin and skin structure infections, urethritis and cervicitis, genital ulcer disease in men, and acute otitis media in children.1,2 The off-label use of azithromycin for the prevention of coronary events has been found in the recent literature, and there may be an association between Chlamydia pneumoniae infection and atherogenesis.3,4 Compared with its parent macrolide erythromycin, azithromycin is more effective against gram-negative pathogens (eg, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, and Bordetella pertussis) and has better pharmacokinetic properties.1 Azithromycin has an attractive safety proﬁle. It has been shown to be relatively free of cardiotoxic effects, thus providing an advantage over other drugs in the same class.5 As a result, azithromycin has become one of the 15 most prescribed drugs and one of the best-selling antibiotics in the United States.6 According to the IMS Institute for Healthcare Informatics, approximately 48.6 million patients in the United States received a prescription for azithromycin in 2013.6 By contrast, in March 2013 an alert was issued by the FDA that warranted serious attention.7 The alert was in response to the results of an observational study by Ray and colleagues indicating that the use of azithromycin was associated with 2-fold and 3-fold increased risks for cardiovascular (CV) death compared with placebo and amoxicillin, respectively, in patients with a high baseline risk.8 That study involved patients in Tennessee with Medicaid coverage who had a high baseline risk of CV events and showed an increased risk for such events among patients who received azithromycin therapy.8 Generalizing this association to patients with a lower baseline risk of CV disease was uncertain until a nationwide historic cohort study was conducted to examine the safety of azithromycin in Danish adults aged 18 to 64 years over a period from 1997 through 2010.5 The study showed that treatment with azithromycin was not associated with an increased risk of death from CV causes among young and middle-aged patients.5 Both studies agreed that patients who had the greatest baseline risk for CV disease were at highest risk for the disease from taking azithromycin.5,8 Any antibiotic is going to have risks and benefits; however, both studies were observational, and even the most carefully executed observational study can be misleading. A double-blind, placebo-controlled trial is the best way to eliminate such potentially misleading information.9 Therefore, we conducted this current meta-analysis of all English-language published and unpublished, randomized, controlled, short- and long-term trials involving high-risk patients to investigate whether azithromycin is associated with increased CV death among this patient population.