Azithromycin for COPD exacerbations: Clinical Update

Azithromycin to Prevent COPD Exacerbations: What's New?

By Abhishek Biswas, MD

Multiple previous studies have suggested likely benefits from using azithromycin as an immunomodulator for cystic fibrosis, bronchiectasis, diffuse panbronchiolitis, post-transplant obliterative bronchiolitis and COPD. This month, a new Cochrane analysis and clinical review in JAMA concludes that "continuous macrolide antibiotic use for prophylaxis [is] associated with a clinically significant reduction in COPD exacerbations." So why not start prescribing azithromycin as standard therapy for COPD? Macrolide antibiotics carry a risk of qTc prolongation with resulting malignant arrhythmia (such as torsades de points) and sudden cardiac death. Although azithromycin's risk is very low on a per-dose basis, with almost 300,000 prescriptions in 2009 alone, the population effects must be at least considered.moral Azithromycin carries the least risk of qTc prolongation among all macrolides, with the highest risk associated with erythromycin. Thus, azithromycin is probably the safest macrolide. Even then, the calculated risk of cardiovascular death associated with long term azithromycin prophylaxis in COPD patients is reported to be 1 in 20,000. Some have suggested the risks may be significantly higher (perhaps 1 in 5,000 or so) in patients with significant preexisting cardiac disease. Another side effect noted from azithromycin is hearing loss, which although being small in magnitude, is nonetheless important. It was reported that an absolute 5% excess in hearing loss occurred in the azithromycin-treated arm of a landmark randomized trial (25% vs. 20%). Given the risks, long term prophylaxis with azithromycin should not be provided for everybody with COPD. Thus it becomes very important to identify the group of patients who would be optimal on the risk-benefit scale. With that in mind, I present a synopsis of three new papers that shed some more light on the risk-benefit status of azithromycin: A recently published review of the cardiovascular risks of macrolide therapy indicates a lack of consensus on this topic. It points out the fact that most studies have used different patient population as study subjects which in turn could be contributing to conflicting results. For example, Ray and colleagues reported a high risk of cardiovascular mortality and sudden cardiac death in the first 5 days of starting therapy among those receiving azithromycin compared to those taking placebo or amoxicillin. There were multiple criticisms that could limit the generalizability of this result. These included the observational nature of this study and the fact that the study was not designed to take into the account the impact of other cardiotoxic medications such as co-administration of antipsychotics. On the other hand, Svanstrom et al studied the effects of azithromycin among young healthy adults. They similarly reported a higher risk of cardiovascular death within the initial 5 days of receiving azithromycin, compared to those patients who received a placebo. The risk was found to be similar to those patients taking penicillin V, however. The study suggested that this increased cardiovascular risk was secondary to the disease process itself and not specific to the effects of azithromycin. The second article is a retrospective cohort study using data from VA system published in the June edition of JAMA by Mortensen et al. These authors found that azithromycin, if used as a part of the treatment of pneumonia, reduced 90 day mortality. There was however, a significantly increased risk of nonfatal acute myocardial infarction reported with use of azithromycin. In spite of this result, the incidence of cardiac arrhythmias and heart failure was not higher in the azithromycin arm. These results seem contradictory since azithromycin reduced the risk of death but increased the incidence of cardiac events. The author surmises that it would be difficult to distinguish the contribution of the primary disease to cardiac events. The NNT reported for azithromycin to prevent one death was 21 compared to the number needed to harm of 144 for myocardial infarctions. Thus azithromycin treatment averted seven deaths for every myocardial infarction it induces. In the final study, Han et al attempted to find out the subgroups of patients with COPD who benefit from long term azithromycin therapy. A summary of their recently published results indicate that:

• Azithromycin is effective as a prophylactic therapy to prevent exacerbations. Patients randomized to receive azithromycin for a year had a modest 17% fewer exacerbations requiring antibiotics or corticosteroids, compared to those receiving placebo. Azithromycin also showed a trend towards preventing the most severe exacerbations, i.e, those leading to hospitalizations.

• Greater benefit was obtained with milder forms of the disease as per GOLD criteria.

• Although fewer exacerbations were noted in the azithromycin arm across all ages, effects were more pronounced in the older (>65 years) subjects. Unfortunately, this is also the age group that seems most susceptible to the cardiotoxic effects of this drug.

An important point from this study is that azithromycin did not seem to provide any benefit (defined as time to first exacerbation) to those who continued to smoke (hazard ratio of 0.99). The authors accept that the study has some limitations because the study was not specifically powered for subgroup analysis. In view of the discussion above, it seems clear that sufficient evidence exists to recommend azithromycin as a practical choice for prophylactic therapy in selected patients with frequent COPD exacerbations. Questions to ponder:

• Should azithromycin be prescribed indefinitely?

• If so, then what would be the possible side effects?

• Do we use azithromycin daily versus three times a week?

• At this time, inadequate evidence exists to prescribe a pulse dose therapy although it might carry a lower risk of cardiac toxicity.

Clinical Takeaway: In the properly selected patient azithromycin appears to be a safe and effective means of prophylaxis against COPD exacerbations. However, the prevalence of cardiovascular disease and risk factors among people with COPD makes "proper selection" of patients a challenge. A cautious approach would exclude patients with known risks of cardiovascular disease, qTc prolongation on initial EKGs or follow up EKGs with qTc prolongation, and those on other medications known to prolong QTc. Smoking cessation is the first line therapy for COPD, and active smokers might not derive benefit from azithromycin prophylaxis. More: Azithromycin to prevent COPD exacerbations: Review Azithromycin associated with sudden cardiac death Azithromycin prophylaxis: original article FDA warns about sudden cardiac death from azithromycin