Pharmacotherapy: The Journal of Human Pharmacology and Drug TherapyAdverse Events with Co-prescription of Angiotensin Receptor Blockers and Clarithromycin Compared to Azithromycin: A Population-based Retrospective Cohort Study

This large retrospective cohort study (n=106,322) demonstrates significant OATP-mediated drug interactions between angiotensin receptor blockers and clarithromycin, with doubled hyperkalemia risk and 75% increased acute kidney injury risk compared to azithromycin. The study provides robust evidence for transporter-based mechanisms underlying clinically relevant adverse drug reactions in older adults.

⚕️ Key Clinical Considerations ⚕️

• Statistical Significance: Adjusted relative risk of 2.05 for hyperkalemia (95% CI 1.32-3.18) and 1.75 for AKI (95% CI 1.41-2.17) with clarithromycin versus azithromycin co-prescription.
• Mechanism Validation: OATP1B1/1B3 inhibition by clarithromycin reduces hepatic clearance of ARB substrates (candesartan, olmesartan, telmisartan, valsartan), leading to drug accumulation.
• Effect Modification: Kidney dysfunction significantly amplifies hyperkalemia risk through multiplicative interaction (p=0.01), creating “double hit” on OATP activity from uremia plus inhibition.
• Study Robustness: E-value analysis indicates substantial unmeasured confounding would be required to explain observed associations, supporting causal inference.
• Population Scope: 14-day follow-up period captured acute toxicities in community-dwelling older adults with continuous ARB therapy across Ontario healthcare system.

🎯 Clinical Practice Impact 🎯

• Patient Communication: Counsel patients on ARB therapy about increased monitoring needs when clarithromycin is prescribed, particularly those with existing kidney dysfunction. Emphasize importance of reporting symptoms like weakness, fatigue, or changes in urination patterns that may indicate electrolyte disturbances or kidney injury.
• Practice Integration: Implement systematic drug interaction screening for OATP substrates when clarithromycin is prescribed. Consider azithromycin as preferred alternative for respiratory tract infections in patients on ARBs, especially those with eGFR <60 mL/min/1.73m². Establish protocols for enhanced monitoring when clarithromycin co-prescription is unavoidable.
• Risk Management: Prioritize laboratory monitoring (serum potassium, creatinine) within 3-7 days for high-risk patients (CKD stages 3-5) receiving ARB-clarithromycin combinations. Document clinical decision-making rationale when alternative antibiotics are selected to mitigate drug interaction risks.
• Action Items: Review current antibiotic selection protocols for patients on ARBs. Train staff on OATP-mediated interactions and appropriate alternative therapies. Develop patient counseling materials highlighting signs/symptoms of hyperkalemia and AKI for at-risk populations.

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