1. Co-prescription of clarithromycin and direct oral anticoagulants was associated with a higher rate of 30-day hospitalization with hemorrhage when compared with co-prescription of azithromycin.
Evidence Rating Level: 2 (Good)
In recent years, direct oral anticoagulants (DOACs) like apixaban and rivaroxaban have overtaken vitamin K antagonists as the anti-coagulation drugs of choice. DOACs are known to be substrates of CYP3A4 enzyme complexes, and are thus susceptible to potentially dangerous drug-drug interactions. This retrospective cohort study involved 24,943 older adults (M [SD] age = 77.6 [7.2] years, 51.0% women) living in Ontario, Canada, taking DOACs, and assessed whether co-prescription of either clarithromycin or azithromycin, macrolide antibiotics commonly prescribed for respiratory infections and known to affect CYP3A4 complexes, were associated with an increased risk of hemorrhage requiring hospitalization. The primary outcome was hospitalization for major hemorrhage, defined as upper or lower gastrointestinal bleeds and intracerebral, subarachnoid, or other nontraumatic intracranial bleeds, within 30 days of either clarithromycin or azithromycin prescription. The most commonly prescribed DOACs among participants were rivaroxaban (n = 9,972 [40.0%]), followed by apixaban (n = 7,953 [31.9%]), and, lastly, dabigatran (n = 7,018 [28.1%]). The study found that major hemorrhage within 30 days occurred in 51 of 6,592 (0.77%) patients taking clarithromycin and 79 of 18,351 (0.43%) patients taking azithromycin (HR 1.81, 95% CI 1.27 to 2.57, absolute risk difference 0.34%). Adjustment for proton pump inhibitor use as well as DOAC type and dosage showed that the higher rate of hemorrhage in patients taking clarithromycin was consistent (aHR 1.71, 95% CI, 1.20 to 2.45). Among secondary analyses conducted, a broadening of the definition of hemorrhage to include any bleeding episode or receipt of a blood transfusion also showed a higher rate of bleeds (aHR 1.53, 95% CI 1.21 to 1.94) in patients taking clarithromycin (n = 109 [1.65%]) compared with patients taking azithromycin (n = 199 [1.08%]). Taken together, these findings suggest that among older adults, the co-prescription of clarithromycin and DOACs is associated with an increased risk of 30-day hospitalization for hemorrhage when compared with azithromycin. Providers should be aware of this potential risk when prescribing macrolide antibiotics to patients on DOACs.
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