Macrolides and Cardiovascular Disease (2015)

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Cheng YJ, et al. "The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk". JACC. 2015. 66(20):2173-2184.
PubMed

Clinical Question

Does use of macrolide antibiotics increase the risk of cardiovascular-related morbidity and mortality?

Bottom Line

Administration of macrolide antibiotics is associated with a slight increased risk for sudden cardiac death, ventricular tachyarrhythmias and cardiovascular death but not all-cause mortality.

Major Points

Macrolide antibiotics are one of the most widely used class of antibiotics for treating bacterial infections in the upper and lower respiratory tract, as well as certain sexually transmitted diseases. These antibiotics have undergone extensive evaluation due to evidence of cardiovascular toxicity and arrhythmia-related cardiac effects. To investigate these claims, Cheng Y.J., et al performed a meta-analysis to determine the correlation of macrolide antibiotics with the risk of developing sudden cardiac death (SCD), or ventricular tachyarrhythmias (VTA) and cardiovascular death.[1]

The authors conducted their research by searching MEDLINE and EMBASE through the parameters of January 1, 1966, to April 30, 2015 and terms/key-words. A meta-analysis on thirty-three studies involving 20,779,963 patients was performed from such. Trials included in the study were required to be independent, contain information necessary for correlating relative risk with macrolide antibiotics with a corresponding measure of uncertainty, and not be a case report or prevalence study. A Newcastle-Ottawa quality assessment scale (ranging from 0 to 9) was used as a quality assessment tool. The scores ranged from 5 to 9, and 11 studies had scores of 7 or higher (a higher score indicating higher study quality).

Significant findings were found in support of macrolide antibiotics causing increased risks of developing SCD or VTA, and no association was found between macrolides use and all-cause death or any cardiovascular events. Although this link was established, the study mentioned possible issues that may have exaggerated the findings. Some of these confounding variables include: limited data on the macrolide dose that was given to each patient, other possible drug-drug adverse reactions, and variable baseline health complications existed between patients.

Guidelines

As of July 2016, no guidelines have been published that reflect the results of this meta-analysis.

Design

  • Trial Type: Systematic review and meta-analysis (33 large cohort studies)
  • N = 20,779,963 participants
    • Macrolides = Unspecified
    • Non-macrolide = Unspecified
  • Setting: 33 centers worldwide (16 studies were based in Europe, 9 in North America, 2 in East Asia, 1 in South America, 1 in Asia, and 1 in Africa, and 3 were multinational)
  • Enrollment: Studies published between 1966-2015
  • Mean Follow-Up: None reported for individual trials
  • Analysis: Intention-to-treat
  • Primary Outcome: SCD or VTA

Population

Inclusion Criteria

  • Included studies were required to:
    • Contain the minimum information necessary to estimate the relative risk (RR) associated with macrolides and a corresponding measure of uncertainty (i.e., 95% confidence interval [CI], SE, variance, or p value)
    • To be cohort studies, case-control studies, or randomized controlled trials (RCTs) published as original articles (case reports and prevalence studies were excluded)
    • To be independent

Exclusion Criteria

  • Studies were excluded if:
    • They contained irrelevant data
    • They contained duplicate data
    • There was not enough data to estimate relative risk

Baseline Characteristics

  • 59.9% women
  • 16 studies recruited participants with bacterial infection; 17 studies were designed to examine whether macrolides could prevent cardiac events in patients with CHD or peripheral artery disease.
  • 19 studies evaluated the endpoints of cardiovascular risk or all-cause death for azithromycin, 12 clarithromycin, 8 roxithromycin, and 4 erythromycin.
  • Endpoints included: SCD, VTS, cardiovascular death, death of any cause, non-cardiovascular death, MI, stroke, and any cardiovascular events

Interventions

  • Macrolides vs. no macrolides
  • Macrolides included (number of trials)
    • Azithromycin (19)
    • Roxithromycin (7)
    • Clarithromycin (11)
    • Erythromycin (3)

Outcomes

Comparisons are macrolides vs no macrolides

Primary Outcomes

Sudden cardiac death or ventricular tachyarrhythmia
RR: 2.42; 95% CI: 1.60 TO 3.63; p< 0.001
NNH = 41

Secondary Outcomes

Cardiovascular death
RR: 1.31; 95% CI: 1.06 to 1.62; p= 0.01
NNH = 76
All cause mortality
RR: 1.03; 95% CI: 0.86 to 1.22; p= 0.77
MI, stroke, any CV event
RR: 1.02; 95% CI: 0.91 to 1.14; p=0.73

Subgroup Analysis

  • Subgroup analyses and metaregression models were carried out to investigate potential sources of between-study heterogeneity
  • Analysis showed risk of SCD or VTA was still significantly increased in RCTs for CHD (RR: 2.35; 95% CI: 1.61 - 3.42)

Criticisms

  • Evidence of high heterogeneity across these studies. Even after stratified analyses were performed across various key study characteristics, heterogeneity remained to be a problem for all cause mortality.
  • Systematic differences in health could be linked to an increased amount of cardiovascular events in patients taking macrolides. These patients tend to be sicker than patients not taking antibiotics, so this increased risk could be attributed to the acute infection itself.
  • There was limited data on the macrolide dose that was given to each patient.
  • Original studies did not report data on electrocardiographic monitoring or QT intervals.
  • VTA was likely monitored on patients taking antiarrhythmic agents, who have a higher risk of having a detectable VTA.
  • The lack of individual participant data may preclude exploring in depth the interaction of CYP3 inhibitors and macrolides, and other individual variables that may influence outcomes.

Funding

National Natural Science Foundation of China grant, Guandong Province Science and Technology Program grant, Guangzhou City Science and Technology grant, Grant to Dr. Xaio; All authors have reported that they have no relationship relevant to the content of this paper.

Further Reading

  1. Cheng YJ et al. The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk. J. Am. Coll. Cardiol. 2015. 66:2173-84.