Cardiovascular, Bleeding, and Mortality Risks in Elderly Medicare Patients Treated With Dabigatran or Warfarin for Nonvalvular Atrial Fibrillation

Abstract

W arfarin, a vitamin K antagonist, is a commonly used anticoagulant in patients with atrial fibrillation (AF). Metaanalyses of randomized trials have shown that it reduces the risk of embolic stroke by 40% to 80% and of mortality by ≈30% but also doubles the risk of intracranial hemorrhage and increases the risk of extracranial bleeding by up to 66%. [1][2][3] It can be difficult to maintain patients in the therapeutic range (international normalized ratio of 2-3). A meta-analysis found that warfarintreated patients were in the therapeutic range 61% of the time. 4 In this study, an international normalized ratio <2 was associated with a 5-fold increase in stroke risk, and an international normalized ratio >3 was associated with a 3-fold increase in bleeding risk. Clinical Perspective on p 164Dabigatran is a competitive direct thrombin inhibitor approved in the United States to reduce the risk of stroke and systemic embolization in patients with nonvalvular AF. 5 In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, patients with AF were randomized to dabigatran doses of 110 or 150 mg twice daily or adjusted-dose warfarin. 6 At the dose subsequently approved in the United States (150 mg twice daily), dabigatran reduced the risk of stroke and intracranial hemorrhage and increased the risk of major gastrointestinal hemorrhage compared with warfarin. 6 Although dabigatranBackground-The comparative safety of dabigatran versus warfarin for treatment of nonvalvular atrial fibrillation in general practice settings has not been established. Methods and Results-We formed new-user cohorts of propensity score-matched elderly patients enrolled in Medicare who initiated dabigatran or warfarin for treatment of nonvalvular atrial fibrillation between October 2010 and December 2012. Among 134 414 patients with 37 587 person-years of follow-up, there were 2715 primary outcome events. The hazard ratios (95% confidence intervals) comparing dabigatran with warfarin (reference) were as follows: ischemic stroke, 0.80 (0.67-0.96); intracranial hemorrhage, 0.34 (0.26-0.46); major gastrointestinal bleeding, 1.28 (1.14-1.44); acute myocardial infarction, 0.92 (0.78-1.08) ; and death, 0.86 (0.77-0.96). In the subgroup treated with dabigatran 75 mg twice daily, there was no difference in risk compared with warfarin for any outcome except intracranial hemorrhage, in which case dabigatran risk was reduced. Most patients treated with dabigatran 75 mg twice daily appeared not to have severe renal impairment, the intended population for this dose. In the dabigatran 150-mg twice daily subgroup, the magnitude of effect for each outcome was greater than in the combined-dose analysis. Conclusions-In general practice settings, dabigatran was associated with reduced risk of ischemic stroke, intracranial hemorrhage, and death and increased risk of major gastrointestinal hemorrhage compared with warfarin in elderly patients with nonvalvular atrial fibrillation. These associations were most pronounced in patients treated...

Major Bleeding Complications and Persistence With Oral Anticoagulation in Non‐Valvular Atrial Fibrillation: Contemporary Findings in Real‐Life Danish Patients

“…A recent post‐hoc analysis of ROCKET‐AF showed that rivaroxaban users had significantly higher risk of major and nonmajor gastrointestinal bleeding compared with warfarin users (HR, 1.42), which support potential differences found between apixaban and rivaroxaban in the present study 18. A study of elderly Medicare beneficiaries found that dabigatran users had increased gastrointestinal bleeding compared to warfarin users, although overall major bleeding risk was similar 19. In contrast to the clinical trials, we found the increased major bleeding risk most pronounced for females taking dabigatran and warfarin compared to apixaban.…”

“…This is in contrast to RE‐LY and partly in contrast to results from a Medicare claims analysis 19. The latter study consisted of an elderly AF population (aged >65 years) using the nontrial dosage of dabigatran 75 mg BID and reported only gastrointestinal (nonsignificant increase in bleeding with high‐dose dabigatran) and intracranial bleeding (nonsignificant increase in bleeding with low‐dose dabigatran).…”

Frequency and Outcomes of Reduced Dose Non–Vitamin K Antagonist Anticoagulants: Results From ORBIT‐AF II (The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II)

“…Both studies suggested a high rate of inappropriate dosing for patients with AF receiving NOACs but were limited to fewer than 300 patients and not specifically designed to address inappropriate dose reductions. A Medicare analysis of dabigatran use found that among patients receiving reduced‐dose dabigatran, only a minority carried a diagnosis of significant kidney disease 17. However, the prescribers did not have detailed data on renal function and therefore could not determine true expected versus observed rates of dose reductions.…”

Rationale and design of a phase III safety trial of idarucizumab in children receiving dabigatran etexilate for venous thromboembolism

“…Dabigatran exhibited a similar efficacy when compared with VKA, with an improved bleeding profile in adult patients with VTE 22, 23, 24. The efficacy and safety of dabigatran was also demonstrated in trials for stroke prevention in patients with atrial fibrillation4 and in real‐world studies, such as in elderly Medicare patients 25…”