Abstract
BackgroundWe evaluated adherence to dosing criteria for patients with atrial fibrillation (AF) taking dabigatran or rivaroxaban and the impact of off-label dosing on thromboembolic and bleeding risk.MethodsWe used data for a retrospective cohort from a large U.S. health plan for Medicare beneficiaries age > =65 years with AF who initiated dabigatran or rivaroxaban during 2010–2016. Stroke and major bleeding were quantified in patients who were eligible for low dose but received standard dose, and in patients who were eligible for standard dose but received low dose.ResultsWe identified 8035 and 19,712 patients who initiated dabigatran or rivaroxaban, respectively. Overall, 1401 (17.4%) and 7820 (39.7%) patients who received dabigatran and rivaroxaban met criteria for low dose, respectively. Of those, 959 (68.5%) and 3904 (49.9%) received standard dose. In contrast, 1013 (15.3%) and 2551 (21.5%) of patients eligible for standard dose dabigatran and rivaroxaban received low dose. Mean follow-up for patients eligible for low and standard dose dabigatran and rivaroxaban were 13.9, 15.1, 10.1, and 12.3 months, respectively. In unadjusted analyses, patients eligible for low or standard dose dabigatran and rivaroxaban but receiving off-label dose, had no differences in the rates of ischemic stroke. Among patients who met criteria for standard dose direct oral anticoagulants (DOAC), use of low dose was associated with significantly higher risk of any major bleeding (Dabigatran: HR = 1.44; 95% CI 1.14–1.8, P = 0.002, Rivaroxaban HR 1.34, 95% CI 1.11–1.6, P = 0.002) and gastrointestinal bleeding (Dabigatran: HR = 1.48; 95% CI 1.08–2, P = 0.016). In patients who met criteria for low dose DOACs, there was lower risk of major bleeding (Dabigatran: HR = 0.59; 95% CI 0.43–0.8, P < 0.001), gastrointestinal (Rivaroxaban: HR 0.79; 95% CI 0.64–0.98, P = 0.03) and intracranial bleeding (Dabigatran: HR = 0.33; 95% CI 0.12–0.9, P = 0.001) with standard dosing. After propensity matching, use of off-label doses was not associated with stroke, major, gastrointestinal or intracranial bleeding for either dabigatran or rivaroxaban.ConclusionsWhile a significant number of patients receive higher or lower dose of dabigatran and rivaroxaban than recommended, we found no evidence of significant impact on thromboembolic or hemorrhagic outcomes.
Highlights
We evaluated adherence to dosing criteria for patients with atrial fibrillation (AF) taking dabigatran or rivaroxaban and the impact of off-label dosing on thromboembolic and bleeding risk
Patient characteristic We identified 8035 patients with valid GFR measurements including 6580 on standard dabigatran dose and 1455 patients on low dose (18.1%); 19,712 patients were rivaroxaban including 13,245 on standard dose rivaroxaban and 6467 on low dose (32.8%)
Patients older than 75 years, females, African Americans, and patients with history of major bleeding or heart failure were more likely to receive lower than recommended dose of dabigatran or rivaroxaban (Tables 3, 4, 5 and 6)
Summary
We evaluated adherence to dosing criteria for patients with atrial fibrillation (AF) taking dabigatran or rivaroxaban and the impact of off-label dosing on thromboembolic and bleeding risk. Randomized controlled trials (RCT) of DOACs [Dabigatran, Rivaroxaban, Apixaban, and Edoxaban] have demonstrated similar protection against ischemic stroke but lower rates of ICH compared with VKAs [4,5,6,7]. A reduced dose of 75 mg twice daily of dabigatran is recommended to decrease bleeding risk in patients with creatinine clearance (CrCl) 15–30 mL/minute, or co- administration of a strong P-glycoprotein [P-gp] inhibitor (e.g., dronedarone) in patients with CrCl 30–50 mL/minute [8, 9]. Administration of lower apixaban dose 2.5 mg twice daily is indicated if 2 of the following 3 criteria are met: age > 80 years, weight < than 60 kg, and serum Creatinine > 1.5 mg/dl [11]
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