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

Abstract

nticoagulant-associated hemorrhage is one of the most common adverse drug reactions requiring hospitalization among individuals of advanced age, with a 2-fold increase among those older than 75 years. 1 Identification and avoidance of dangerous drug-drug interactions are associated with a significant reduction in adverse events and improvement in evidence-based prescription patterns.During the last decade, direct oral anticoagulants (DO-ACs) have supplanted traditional vitamin K antagonists as the anticoagulation drugs of choice. 2 Large phase 3 trials have demonstrated noninferiority or superiority of DOACs relative to traditional anticoagulants (warfarin) for effectiveness in stroke prevention for those who have atrial fibrillation and for pre-vention and treatment of venous thromboembolism. [3][4][5][6][7][8][9][10][11] Patient preferences for DOACs are based on their simplicity of use, with no need for routine bloodwork monitoring. 12 As such, recent guidelines recommend DOACs as the first-line agents for the prevention of stroke in patients with nonvalvular atrial fibrillation (strong recommendation; high-quality evidence) and the treatment of venous thromboembolism. 13,14 Direct oral anticoagulants have 2 predominant mechanisms of metabolism: P-glycoprotein (Pgp) cell transporters, which are involved in transcellular transportation, and the cytochrome P450 enzyme CYP3A4, which is involved in the metabolism in the human liver. 15 Dabigatran etexilate mesylate requires efflux transportation by the Pgp system but is independent of the cytochrome P450 enzyme system. 16 Apixaban and rivar-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 PARTICIPANTSThis 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 associa...

Characteristics and outcomes of patients on concurrent direct oral anticoagulants and targeted anticancer therapies—TacDOAC registry: Communication from the ISTH SSC Subcommittee on Hemostasis and Malignancy

“…For example, a recent large database analysis showed that the concurrent use of clarithromycin (increases DOAC levels) and DOACs led to an increase in clinically relevant bleeding events (adjusted hazard ratio [HR] 1.71, 95% confidence interval [CI] 1.20-2.45 for hemorrhage requiring hospitalization) compared to azithromycin (minimal effects on DOAC metabolism). 17 However, data regarding concurrent use of DOACs and targeted anticancer therapies are limited. In addition, some targeted anticancer therapies such as ibrutinib can increase the risk of bleeding in the absence of anticoagulants by other mechanisms.…”

“…Limited pharmacokinetic studies have shown that concurrent use of medications involving both P‐gp and CYP3A4 metabolism could influence DOAC drug levels in vitro , but whether these findings translate into clinically relevant events has not been established. For example, a recent large database analysis showed that the concurrent use of clarithromycin (increases DOAC levels) and DOACs led to an increase in clinically relevant bleeding events (adjusted hazard ratio [HR] 1.71, 95% confidence interval [CI] 1.20–2.45 for hemorrhage requiring hospitalization) compared to azithromycin (minimal effects on DOAC metabolism) 17 . However, data regarding concurrent use of DOACs and targeted anticancer therapies are limited.…”

Management of Cancer-Associated Thrombosis: Unmet Needs and Future Perspectives

“…Another study that examined concomitant use of DOACs with clarithromycin or azithromycin revealed that the use of clarithromycin, which is a potent inhibitor of CYP3A4 and P-gp, led to an increased rate of hemorrhage requiring hospitalization compared with azithromycin, a mild inhibitor of CYP3A4 and P-gp. 66,67 Antineoplastic agents that might influence the efficacy and safety of DOACs are paclitaxel, bicalutamide, enzalutamide, certain tyrosine kinase inhibitors, and abiraterone, and supportive care medications include dexamethasone, prednisone, azole antifungals, and neurokinin-1 antagonists. 68 While a recent posthoc analysis on participants in the CARAVAGGIO study showed comparative efficacy and safety of apixaban in patients treated or not treated with anticancer agents.…”

Approach to Cancer-Associated Thrombosis: Challenging Situations and Knowledge Gaps

“…In the general population, data addressing DDIs between DOACs and other medications are limited, but a few recent studies have provided some insights. A large database analysis showed that concomitant prescription of clarithromycin (a potent inhibitor of P‐gp and CYP3A4) and DOACs caused a 1.71‐fold increased risk of hospitalization for major hemorrhage within 30 days of concurrent use, compared with concomitant prescription of azithromycin (minimal effect on P‐gp and CYP3A4) or without concurrent use [18]. Another single‐center retrospective study showed that use of combined P‐gp and moderate CYP3A4 inhibitors (such as amiodarone, diltiazem, etc.)…”