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Multicenter Study
. 2022 Jan 1;7(1):75-83.
doi: 10.1001/jamacardio.2021.4234.

Analysis of Respiratory Fluoroquinolones and the Risk of Sudden Cardiac Death Among Patients Receiving Hemodialysis

Magdalene M Assimon  1 , Patrick H Pun  2   3 , Lily Chin-Hua Wang  4 , Sana M Al-Khatib  3   5 , M Alan Brookhart  6 , David J Weber  7 , Wolfgang C Winkelmayer  8 , Jennifer E Flythe  1   4
Affiliations
Multicenter Study

Analysis of Respiratory Fluoroquinolones and the Risk of Sudden Cardiac Death Among Patients Receiving Hemodialysis

Magdalene M Assimon et al. JAMA Cardiol. .

Abstract

Importance: Respiratory fluoroquinolone antibiotics are some of the most common medications with QT interval-prolonging potential prescribed to patients with hemodialysis-dependent kidney failure-individuals who have a very high risk of sudden cardiac death (SCD). To date, there have been no large-scale, population-specific studies evaluating the cardiac safety of respiratory fluoroquinolones in the hemodialysis population.

Objective: To investigate the cardiac safety of respiratory fluoroquinolones among individuals with hemodialysis-dependent kidney failure.

Design, setting, and participants: A retrospective cohort study examining safety using an active comparator new-user design was conducted using administrative claims data from a US-wide kidney failure registry from January 1, 2007, to December 31, 2016, including 264 968 Medicare beneficiaries receiving in-center maintenance hemodialysis. Data analysis was performed from January 4 to August 16, 2021.

Exposures: Respiratory fluoroquinolone (levofloxacin or moxifloxacin) vs amoxicillin-based (amoxicillin or amoxicillin with clavulanic acid) antibiotic treatment.

Main outcomes and measures: Sudden cardiac death within 5 days of outpatient initiation of a study antibiotic. Inverse probability of treatment-weighted survival models to estimate hazard ratios (HRs), risk differences (RDs), and corresponding 95% CIs. Death due to a cause other than SCD was treated as a competing event. Fracture was considered as a negative control outcome.

Results: The study cohort included 264 968 unique in-center hemodialysis patients and 626 322 study antibiotic treatment episodes: 251 726 respiratory fluoroquinolone treatment episodes (40.2%) and 374 596 amoxicillin-based treatment episodes (59.8%). Of the 264 968 patients, 135 236 (51.0%) were men, and the mean (SD) age was 61 (15) years. Respiratory fluoroquinolone vs amoxicillin-based antibiotic treatment was associated with a higher relative and absolute 5-day risk of SCD (weighted HR, 1.95; 95% CI, 1.57-2.41; and weighted RD per 100 000 treatment episodes, 44.0; 95% CI, 31.0-59.2). Respiratory fluoroquinolone vs amoxicillin-based antibiotic treatment was not associated with the 5-day risk of fracture.

Conclusions and relevance: In this study, compared with amoxicillin-based antibiotic treatment, respiratory fluoroquinolone treatment was associated with a higher short-term risk of SCD among patients with hemodialysis-dependent kidney failure. This finding suggests that decisions between the use of respiratory fluoroquinolones and amoxicillin-based antibiotics should be individualized, with prescribers considering both the clinical benefits and potential cardiac risks.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Assimon reported receiving grants from the Renal Research Institute, a subsidiary of Fresenius Medical Care, honoraria from the International Society of Nephrology for serving as a statistical reviewer for Kidney International Reports, and honoraria from the American Society of Nephrology for serving as an editorial fellow for the Journal of the American Society of Nephrology outside the submitted work. Dr Pun reported receiving grants from the National Institutes of Health (NIH) and Medtronic during the conduct of the study and honoraria for scientific consulting services from Fresenius Kidney Care NA, AstraZeneca, Janssen, Relypsa, and Ardelyx outside the submitted work. Dr Brookhart reported receiving honoraria from Merck, Amgen, Atara Biosciences, Gilead, and Kite for serving on their scientific advisory boards; honoraria from Target RWE for consulting services outside the submitted work; and owning equity in Target RWE. Dr Winkelmayer reported receiving grants from the NIH National Heart, Lung, and Blood Institute during the conduct of the study and personal fees for scientific consulting services from Akebia/Otsuka, AstraZeneca, Bayer, Janssen, Lilly/Boehringer Ingelheim, Merck, Reata, and Vifor Fresenius Medical Care Renal Pharma/Relypsa outside the submitted work. Dr Flythe reported receiving a grant from the Renal Research Institute/Fresenius Medical Care, scientific consulting fees from Fresenius Medical Care for serving on a medical advisory board, honoraria for serving on the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Data Safety and Monitoring Board, and honoraria from multiple universities and the American Society of Nephrology for speaking services outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Design
Antibiotic treatment episodes for an oral respiratory fluoroquinolone (levofloxacin or moxifloxacin) and an oral amoxicillin-based antibiotic (amoxicillin or amoxicillin with clavulanic acid) were identified based on initiation of one of these medications after a 30-day washout period free of documented prescription fills for either medication class. The index date was defined as the date of study antibiotic initiation. Baseline covariates were identified in the 180-day period before the index date and study follow-up began on the index date.
Figure 2.
Figure 2.. Respiratory Fluoroquinolone (Resp FQ) vs Amoxicillin (AMOX)–Based Antibiotic Treatment and Sudden Cardiac Death (SCD)
Associations between resp FQ vs AMOX-based antibiotic treatment and SCD at 5, 7, 10, and 14 days of follow-up are displayed. An intention-to-treat analytic approach was used in all analyses. Fine and Gray proportional subdistribution hazards models were used to estimate hazard ratios (HRs) and 95% CIs. Inverse probability of treatment weighting was used for confounding control. Weighted (ie, adjusted) HRs are presented. Corresponding weighted risk differences (95% CI) per 100 000 treatment episodes are listed in Table 2.
Figure 3.
Figure 3.. Individual Respiratory Fluoroquinolone Treatment vs Amoxicillin-Based Antibiotic Treatment and 5-day Sudden Cardiac Death
Associations between levofloxacin and moxifloxacin treatment vs amoxicillin-based antibiotic treatment (considered separately) and sudden cardiac death at 5 days of follow-up. An intention-to-treat analytic approach was used in all analyses. Fine and Gray proportional subdistribution hazards models were used to estimate hazard ratios (HRs) and 95% CIs. Inverse probability of treatment weighting was used for confounding control. Weighted (ie, adjusted) HRs are presented. Corresponding weighted risk differences (95% CI) per 100 000 treatment episodes are listed in eTable 7 in the Supplement.
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