Azithromycin use increases the risk of sudden cardiac death in patients with hemodialysis-dependent kidney failure

Abstract

Azithromycin is an antibiotic with QT-prolonging potential commonly prescribed to individuals receiving hemodialysis. Hemodialysis patients have a high prevalence of clinical conditions, such as structural heart disease, that can enhance the pro-arrhythmic effects azithromycin, but were excluded from prior investigations evaluating the cardiac safety of azithromycin. Using data from the United States Renal Data System (2007-2017), we conducted two cohort studies to examine the cardiac safety of azithromycin relative to amoxicillin-based antibiotics (amoxicillin, amoxicillin/clavulanic acid) and levofloxacin (a fluoroquinolone antibiotic known to prolong the QT-interval) in the hemodialysis population. The primary outcome was five-day sudden cardiac death. Using inverse probability of treatment weighted survival models, we estimated hazard ratios, risk differences, and 95% confidence intervals. The azithromycin vs. amoxicillin-based antibiotic cohort included 282,899 patients and 725,431 treatment episodes (381,306 azithromycin and 344,125 amoxicillin-based episodes). Azithromycin vs. amoxicillin-based antibiotic treatment was associated with higher relative and absolute risks of sudden cardiac death, weighted hazard ratio of 1.70 (95% Confidence Interval, 1.36 to 2.11) and weighted risk difference per 100,000 treatment episodes of 25.0 (15.5 to 36.5). The azithromycin vs. levofloxacin cohort included 245,143 patients and 554,557 treatment episodes (387,382 azithromycin and 167,175 levofloxacin episodes). Azithromycin vs. levofloxacin treatment was associated with lower relative and absolute risks of sudden cardiac death, weighted hazard ratio of 0.79 (0.64 to 0.96) and weighted risk difference per 100,000 treatment episodes of -18.9 (-35.5 to -3.8). Thus, when selecting among azithromycin, levofloxacin, and amoxicillin-based antibiotics, clinicians should weigh the relative antimicrobial benefits of these drugs against their potential cardiac risks.

Keywords: USRDS; amoxicillin; azithromycin; hemodialysis; levofloxacin; sudden cardiac death.

Figure 1.. Study design

Two separate new-user cohorts were created to compare: 1) azithromycin vs. amoxicillin-based antibiotics (amoxicillin and amoxicillin/clavulanic acid) and 2) azithromycin vs. levofloxacin. The figure depicts how a single antibiotic treatment episode was identified. In each cohort, the index date was defined as the date of study antibiotic initiation after a 30-day washout period free of relevant antibiotic use. In the azithromycin vs. amoxicillin-based antibiotic cohort, the index date was defined as the date of azithromycin or amoxicillin-based antibiotic initiation after a 30-day washout period free of both azithromycin and amoxicillin-based antibiotic use. In the azithromycin vs. levofloxacin cohort, the index date was defined as the date of azithromycin or levofloxacin initiation after a 30-day washout period free of both azithromycin and levofloxacin use. In each cohort, baseline covariates were obtained in the 180-day period prior to the index date. During the follow-up period, outcome, censoring, and competing events were identified.

Figure 2.. Azithromycin vs. comparator antibiotic treatment and sudden cardiac death

Fine and Gray proportional subdistribution hazards models were used to estimate HRs. Inverse probability of treatment weighting was used for confounding control. Weighed (i.e., adjusted) hazard ratios are presented. Corresponding weighted RDs (95% CIs) per 100,000 treatment episodes for days 1–5 are presented in Table S5. Abbreviations: Amox-based, amoxicillin-based; azith, azithromycin; CI, confidence interval; HR, hazard ratio; levoflox; levofloxacin; RD, risk differences; SCD, sudden cardiac death.

Figure 3.. Higher and lower dose levofloxacin vs. azithromycin and sudden cardiac death

Fine and Gray proportional subdistribution hazards models were used to estimate HRs. Inverse probability of treatment weighting was used for confounding control. Weighed (i.e., adjusted) hazard ratios are presented. Corresponding weighted RDs (95% CIs) per 100,000 treatment episodes for days 1–5 are presented in Table S9. Abbreviations: Amox-based, amoxicillin-based; azith, azithromycin; CI, confidence interval; HR, hazard ratio; levoflox; levofloxacin; RD, risk differences; SCD, sudden cardiac death.

Figure 4.. Levofloxacin and azithromycin vs. amoxicillin-based antibiotics and sudden cardiac death during days 1–5

Fine and Gray proportional subdistribution hazards models were used to estimate HRs. Inverse probability of treatment weighting was used for confounding control. Weighed (i.e., adjusted) hazard ratios are presented. Corresponding weighted RDs (95% CIs) per 100,000 treatment episodes for days 1–5 are presented in Table S11. Abbreviations: Amox-based, amoxicillin-based; azith, azithromycin; CI, confidence interval; HR, hazard ratio; levoflox; levofloxacin; RD, risk differences; SCD, sudden cardiac death.