Systematic Review, Meta-analysis, and Network Meta-analysis of the Cardiovascular Safety of Macrolides

Abstract

Studies reporting an increased risk for cardiac toxicities with macrolide antibiotics have raised concern regarding their cardiovascular safety. We sought to assess the cardiac safety of macrolide antibiotics as a class and of the individual agents by conducting a systematic review and network meta-analysis. Medline, Embase, and the Cochrane Library were searched up to February 2018 for studies reporting on cardiovascular outcomes with macrolides. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random-effects models and odds ratios (OR), and 95% confidence intervals (CI) were calculated for arrhythmia, cardiovascular death, and myocardial infarction (MI). A total of 33 studies and data on 22,601,032 subjects were retrieved and included in the current meta-analyses. Macrolide use was not associated with the risk of arrhythmia or cardiovascular mortality. In the primary analysis, macrolide use was associated with a small but statistically significant 15% increase in risk for MI (OR = 1.15 [95% CI, 1.01 to 1.30]). In indirect network meta-analysis, erythromycin and clarithromycin were ranked considerably more likely to be associated with a higher risk for MI and significantly associated with increased risk of MI compared to azithromycin (OR = 1.58 [95% CI, 1.18 to 2.11] and OR = 1.41 [95% CI, 1.11 to 1.81], respectively). Our findings indicate that macrolide antibiotics as a group are associated with a significant risk for MI but not for arrhythmia and cardiovascular mortality. Among the macrolides, erythromycin and clarithromycin were associated with a greater risk of MI. However, it is possible that the association between macrolide use and risk of MI is the result of residual confounding.

Azithromycin in the treatment of COVID-19: a review

“…The use of loop diuretic drugs, baseline QTc ≥450 ms, more than 2 systemic inflammatory response syndrome criteria, and intensive care status at the time of test were associated with a higher risk of developing QTc ≥500 ms [89]. The use of other medications that prolong the QTc, electrolyte disturbances, female gender, older age, personal or family history of QT interval prolongation and other diagnoses as chronic renal failure, cardiac heart failure, structural heart disease, genetic polymorphisms, and congenital long QT syndrome are other potential risk factors [80,93].…”

“…Its use, as occurs with other macrolides, has been related to QTc interval prolongation, torsade de Pointes (TdP), ventricular tachycardia, and sudden cardiac death [79]. The proarrhythmic mechanism of azithromycin is thought to be due to intracellular sodium overload [80]. A study showing an increased risk of cardiovascular death prompted the FDA to introduce a black box warning [9].…”

“…In hospitalized patients, the use of hydroxychloroquine and azithromycin has been related to a higher incidence of cardiac adverse events. This combination has been associated with a higher risk of QTc prolongation, ventricular arrhythmia, TdP (with an incidence of 0.4%), atrial fibrillation, atrioventricular block, or cardiac arrest [68, 71,80,89,90]. These abnormal findings appear to be developed at day 3-4 of the treatment [80,90,91].…”

“…This combination has been associated with a higher risk of QTc prolongation, ventricular arrhythmia, TdP (with an incidence of 0.4%), atrial fibrillation, atrioventricular block, or cardiac arrest [68, 71,80,89,90]. These abnormal findings appear to be developed at day 3-4 of the treatment [80,90,91]. Rosenberg et al showed that patients treated with hydroxychloroquine alone presented a higher risk of cardiac arrest (aOR 2.97 [95% CI 1.56-5.64]) than those treated with azithromycin [71].…”

Make Sure You Have a Safety Net: Updates in the Prevention and Management of Infectious Complications in Stem Cell Transplant Recipients

“…Since 2008, the US FDA has issued six safety alerts regarding potential adverse effects associated with reception of FQs, which include risk of tendinitis and tendon rupture; peripheral neuropathy; hypoglycemia; central nervous system effects; and most recently, aortic dissection and aneurysm. In addition, FQs have been reported to be associated with arrhythmia and QT prolongation [76], and neutropenic patients may be at particular risk due to concomitant reception of azole class antifungals for prophylaxis [23,30,75].…”