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Original Investigation
June 8, 2020

Risk of Hospitalization With Hemorrhage Among Older Adults Taking Clarithromycin vs Azithromycin and Direct Oral Anticoagulants

Author Affiliations
  • 1Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  • 2Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
  • 3Division of Nephrology, Department of Medicine, Health Sciences Centre, London, Ontario, Canada
  • 4Epidemiology and Biostatistics, Western University, London, Ontario, Canada
  • 5Division of Nephrology, Department of Medicine, St Michael’s Hospital, Toronto, Canada
  • 6Division of Nephrology, Department of Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada
  • 7Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada
JAMA Intern Med. Published online June 8, 2020. doi:10.1001/jamainternmed.2020.1835
Key Points

Question  Is the concurrent use of clarithromycin among older adult patients taking direct oral anticoagulants associated with a higher 30-day risk of hospitalization for major hemorrhage compared with azithromycin?

Findings  In this population-level cohort study of 24 943 older adults taking direct oral anticoagulants, clarithromycin was associated with an adjusted 1.71-fold higher rate of hospitalization (absolute risk difference, 0.34%) within 30 days for a major hemorrhage event compared with azithromycin.

Meaning  The use of clarithromycin was associated with a high rate of hemorrhage among older adults taking direct oral anticoagulants compared with azithromycin and poses a potential drug-drug interaction.


Importance  Clarithromycin is a commonly prescribed antibiotic associated with higher levels of direct oral anticoagulants (DOACs) in the blood, with the potential to increase the risk of hemorrhage.

Objective  To assess the 30-day risk of a hospital admission with hemorrhage after coprescription of clarithromycin compared with azithromycin among older adults taking a DOAC.

Design, Setting, and Participants  This population-based, retrospective cohort study was conducted among adults of advanced age (mean [SD] age, 77.6 [7.2] years) who were newly coprescribed clarithromycin (n = 6592) vs azithromycin (n = 18 351) while taking a DOAC (dabigatran, apixaban, or rivaroxaban) in Ontario, Canada, from June 23, 2009, to December 31, 2016. Cox proportional hazards regression was used to examine the association between hemorrhage and antibiotic use (clarithromycin vs azithromycin). Statistical analysis was performed from December 23, 2019, to March 25, 2020.

Main Outcomes and Measures  Hospital admission with major hemorrhage (upper or lower gastrointestinal tract or intracranial). Outcomes were assessed within 30 days of a coprescription.

Results  Among the 24 943 patients (12 493 women; mean [SD] age, 77.6 [7.2] years) in the study, rivaroxaban was the most commonly prescribed DOAC (9972 patients [40.0%]), followed by apixaban (7953 [31.9%]) and dabigatran (7018 [28.1%]). Coprescribing clarithromycin vs azithromycin with a DOAC was associated with a higher risk of a hospital admission with major hemorrhage (51 of 6592 patients [0.77%] taking clarithromycin vs 79 of 18 351 patients [0.43%] taking azithromycin; adjusted hazard ratio, 1.71 [95% CI, 1.20-2.45]; absolute risk difference, 0.34%). Results were consistent in multiple additional analyses.

Conclusions and Relevance  This study suggests that, among adults of advanced age taking a DOAC, concurrent use of clarithromycin compared with azithromycin was associated with a small but statistically significantly greater 30-day risk of hospital admission with major hemorrhage.

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    1 Comment for this article
    Interaction of DOACS with clarithromycin and azithromycin
    J David Spence, M.D. | Robarts Research Institute, Western University, London, ON, Canada
    Hill et al.[1] report that the risk of bleeding was increased among persons prescribed direct-acting oral anticoagulants (DOACs) and clarithromycin or azithromycin. They suggest that blood levels of rivaroxaban and apixaban should be increased more than those of dabigatran by macrolides, because dabigatran is not metabolized by CYP3A4. However, dabigatran is affected by p-glycoprotein (Pgp); indeed that may account for the very low bioavailability of dabigatran (only 7%, compared with 50% for apixaban and 80% for rivaroxaban). Clarithromycin, in addition to inhibiting CYP3A4, is also a potent inhibitor of Pgp.[2]

    Drugs with a low bioavailability are subject to very
    large changes in blood levels with drug interactions. This is illustrated by the interaction of statins and grapefruit, a potent inhibitor of CYP3A4.[3] Simvastatin is only 5% bioavailable because of first pass metabolism by CYP3A4 in the intestinal wall. Theoretically, if CYP3A4 were completely blocked, blood levels could increase 20-fold. Indeed, the AUC of simvastatin increases 15-fold with grapefruit juice.[4] Atorvastatin is 50% bioavailable, so its AUC “only” doubles with grapefruit.[5]

    Drieier et al. described a case of rhabdomyolysis with simvastatin after only 4 days of consuming one grapefruit daily.[6] Furthermore, CYP3A4 is not only affected by grapefruit, but by many drugs;[7] that is why simvastatin should be regarded as a dangerous drug. The low bioavailability of dabigatran may be one reason why there was a drastic increase in plasma levels of dabigatran with administration of intravenous immunoglobulin. Perhaps dabigatran should also be so regarded. It has been suggested that dabigatran blood levels should be monitored.[8]

    1. Hill K, Sucha E, Rhodes E, Carrier M, Garg AX, Harel Z, et al. Risk of Hospitalization With Hemorrhage Among Older Adults Taking Clarithromycin vs Azithromycin and Direct Oral Anticoagulants. JAMA Intern Med. 2020.
    2. Gessner A, König J, Fromm MF. Clinical Aspects of Transporter-Mediated Drug-Drug Interactions. Clin Pharmacol Ther. 2019;105(6):1386-94.
    3. Bailey DG, Spence JD, Munoz C, Arnold JM. Bailey DG, Spence JD, Munoz C, Arnold JM. Interaction of citrus juices with felodipine and nifedipine. Lancet 1991;337(8736):268-9. Lancet. 1991;337:268-9.
    4. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther. 1998;64(5):477-83.
    5. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther. 1999;66(2):118-27.
    6. Dreier JP, Endres M. Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology. 2004;62(4):670.
    7. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000;38(1):41-57.
    8. Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63(4):321-8.