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Long-Term Risk of Acute Myocardial Infarction, Stroke, and Death With Outpatient Use of Clarithromycin: A
Andrew D Mosholder1, Joo-Yeon Lee2, Esther H Zhou1
1Office of Pharmacovigilance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.
Insights
Long-term clarithromycin use increases mortality risk in adults. This antibiotic, commonly prescribed, showed higher death rates compared to doxycycline, with similar but smaller risks for erythromycin.
Area of Science:
- Pharmacovigilance
- Cardiovascular Epidemiology
- Infectious Disease Treatment
Background:
- Macrolide antibiotics like clarithromycin are widely used for respiratory and other infections.
- Concerns exist regarding the long-term cardiovascular safety of macrolides.
- Previous studies have yielded conflicting results on clarithromycin's safety profile.
Purpose of the Study:
- To evaluate the long-term risks of mortality, stroke, and acute myocardial infarction (AMI) associated with outpatient clarithromycin use.
- To compare these risks with those of other commonly prescribed antibiotics, including doxycycline and erythromycin.
- To assess risks related to clarithromycin-based Helicobacter pylori eradication therapy.
Main Methods:
- Retrospective cohort study utilizing the UK Clinical Practice Research Datalink (2000-2013).
- Inclusion of adult outpatients (40-85 years) prescribed clarithromycin, doxycycline, or erythromycin.
- Analysis of time-to-event data for death, stroke, and AMI using Cox proportional hazards regression.
Main Results:
- Clarithromycin prescriptions were associated with increased long-term mortality compared to doxycycline, with risk escalating with higher prescription counts (HR 1.62 for ≥5 prescriptions).
- Erythromycin also showed increased mortality risk versus doxycycline, though smaller than clarithromycin.
- Increased incidences of stroke and AMI were observed with clarithromycin, but with lower hazard ratios than for mortality.
Conclusions:
- Outpatient clarithromycin use is linked to increased long-term mortality.
- A similar, albeit smaller, increased mortality risk was observed with erythromycin.
- Further research into the cardiovascular safety of macrolide antibiotics is warranted.
Abstract:
In a retrospective cohort study of patients enrolled in the UK Clinical Practice Research Datalink during 2000-2013, we evaluated long-term risks of death, stroke, and acute myocardial infarction (AMI) in adults prescribed clarithromycin. Patients were outpatients aged 40-85 years, who were prescribed clarithromycin (n = 287,748), doxycycline (n = 267,729), or erythromycin (n = 442,999), or Helicobacter pylori eradication therapy with a proton pump inhibitor, amoxicillin, and either clarithromycin (n = 27,639) or metronidazole (n = 14,863). We analyzed time to death, stroke, or AMI with Cox proportional hazards regression. The long-term hazard ratio for death following 1 clarithromycin versus 1 doxycycline prescription was 1.29 (95% confidence interval (CI): 1.21, 1.25), increasing to 1.62 (95% CI: 1.43, 1.84) for ≥5 prescriptions of clarithromycin versus ≥5 prescriptions for doxycycline. Erythromycin showed smaller risks in comparison with doxycycline. Stroke and AMI incidences were also increased after clarithromycin but with smaller hazard ratios than for mortality. For H. pylori eradication, the hazard ratio for mortality following clarithromycin versus metronidazole regimens was 1.09 (95% CI: 1.00, 1.18) overall, and it was higher (hazard ratio = 1.65, 95% CI: 0.88, 3.08) following ≥2 prescriptions in subjects not on statins at baseline. Outpatient clarithromycin use was associated with long-term mortality increases, with evidence for a similar, smaller increase with erythromycin.