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QT-Prolonging Antibiotics, Serum-to-Dialysate Potassium Gradient, and Risk of Sudden Cardiac Death Among Patients
Patrick H Pun1, Magdalene M Assimon2, Lily Wang3
1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
Rationale & Objective:
Treatment with certain QT interval-prolonging antibiotics is associated with a higher risk of sudden cardiac death among individuals with hemodialysis-dependent kidney failure. Concurrent exposure to large serum-to-dialysate potassium gradients, which promote large potassium shifts, may augment the proarrhythmic effects of these medications. The primary objective of this study was to examine whether the serum-to-dialysate gradient modifies the cardiac safety of azithromycin, and separately, levofloxacin/moxifloxacin.
Study Design:
Retrospective observational cohort study using a new-user study design.
Setting & Population:
Adult in-center hemodialysis patients with Medicare coverage in the US Renal Data System (2007-2017).
Exposure:
Initiation of azithromycin (or levofloxacin/moxifloxacin) as compared to amoxicillin-based antibiotics (exposure). Serum-to-dialysate potassium gradient (effect modifier). Individual patients could contribute multiple study antibiotic treatment episodes to the analyses.
Outcomes:
Sudden cardiac death (14 days).
Analytical Approach:
Inverse probability of treatment-weighted survival models to estimate HRs and robust 95% CIs.
Results:
The azithromycin versus amoxicillin-based antibiotic cohort included 89,379 unique patients with 113,516 azithromycin and 103,493 amoxicillin-based treatment episodes. Azithromycin versus amoxicillin-based antibiotic treatment was associated with a higher risk of sudden cardiac death overall, HR, 1.68; 95% CI, 1.31-2.16. The risk was numerically higher when the baseline serum-to-dialysate potassium gradient was ≥3 mEq/L compared with <3 mEq/L (HR, 2.22; 95% CI, 1.46-3.40 vs HR, 1.43; 95% CI. 1.04-1.96, P interaction = 0.07). Analogous analyses in a respiratory fluoroquinolone (levofloxacin/moxifloxacin) versus amoxicillin-based antibiotic cohort with 79,449 unique patients and 65,959 respiratory fluoroquinolone and 103,776 amoxicillin-based treatment episodes yielded similar results.
Limitations:
Residual confounding.
Conclusions:
Although treatment with azithromycin and, separately, respiratory fluoroquinolones were each associated with a heightened risk of sudden cardiac death, this risk was augmented in the setting of larger serum-to-dialysate potassium gradients. Minimizing the potassium gradient may be an approach to reduce the cardiac risk of these antibiotics.
Insights
QT interval-prolonging antibiotics like azithromycin increase sudden cardiac death risk in hemodialysis patients. This risk is amplified by large serum-to-dialysate potassium gradients, suggesting gradient management may improve cardiac safety.
Area of Science:
- Nephrology
- Cardiology
- Pharmacology
Background:
- Certain antibiotics prolonging the QT interval are linked to sudden cardiac death in hemodialysis patients.
- Large serum-to-dialysate potassium gradients may exacerbate the proarrhythmic effects of these antibiotics.
Purpose of the Study:
- To investigate if the serum-to-dialysate potassium gradient modifies the cardiac safety of azithromycin.
- To separately examine the effect on levofloxacin/moxifloxacin.
Main Methods:
- Retrospective observational cohort study of adult in-center hemodialysis patients (US Renal Data System, 2007-2017).
- New-user design comparing azithromycin or fluoroquinolones to amoxicillin-based antibiotics.
- Inverse probability of treatment-weighted survival models used to analyze sudden cardiac death (14-day outcome).
Main Results:
- Azithromycin use was associated with a higher risk of sudden cardiac death (HR, 1.68).
- This risk was numerically higher with gradients ≥3 mEq/L (HR, 2.22) vs <3 mEq/L (HR, 1.43), with a trend toward interaction (P=0.07).
- Similar findings were observed for respiratory fluoroquinolones.
Conclusions:
- Azithromycin and respiratory fluoroquinolones are associated with increased sudden cardiac death risk in hemodialysis patients.
- This risk is augmented by larger serum-to-dialysate potassium gradients.
- Minimizing potassium gradients may reduce the cardiac risk of these antibiotics.
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