Outcomes of Discontinuing Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation: Analysis From the ROCKET AF Trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation)
What is the risk of discontinuation of rivaroxaban in patients being treated for thromboembolic prophylaxis in the setting of atrial fibrillation (AF)?
The authors reported the results of a post-hoc analysis of data from ROCKET-AF, a randomized, double-blind, double-dummy, event-driven study of rivaroxaban (20 mg daily or 15 mg daily in patients with creatinine clearance 30-49 ml/min), versus adjusted-dose warfarin (target international normalized ratio [INR], 2.0-3.0). Endpoints of interest were stroke or systemic embolism within 30 days after any temporary interruption of 3 days or more, after early permanent study-drug discontinuation, or end-of-study transition to open-label therapy. Cox proportional hazards models were used to create hazard ratios for rivaroxaban and warfarin.
Out of the study population of 14,624 subjects, stroke and systemic embolism occurred at similar rates after temporary interruptions (rivaroxaban: n = 9, warfarin: n = 8; hazard ratio [HR], 1.28; 95% confidence interval [CI], 0.49-3.31; p = 0.62) and after early permanent discontinuation (rivaroxaban: n = 42, warfarin: n = 36, HR, 1.10; 95% CI, 0.71-1.72; p = 0.66). Subjects transitioning to open-label therapy at the end of the study had more strokes transitioning from rivaroxaban (n = 22) versus warfarin (n = 6, HR, 3.72; 95% CI, 1.51-9.16; p < 0.0044). Subjects transitioning from rivaroxaban also took longer to reach therapeutic INR compared with those finishing warfarin therapy (p < 0.001). Total thrombotic events within 30 days of study drug cessation (including stroke, systemic embolism, myocardial infarction, and vascular death) were similar between groups (HR, 1.02; 95% CI, 0.83-1.26; p = 0.85).
The authors concluded that in AF patients who temporarily or permanently discontinued anticoagulation, the risk of stroke or systemic embolism was similar with rivaroxaban or warfarin. The authors further observed that an increased risk of stroke and systemic embolism was observed in rivaroxaban-treated patients compared with warfarin-treated patients after the end of the study, underscoring the importance of therapeutic anticoagulation coverage during such a transition.
With the usual concerns about post-hoc analyses in mind, this important analysis offers insight about the relative safety of discontinuing rivaroxaban in the setting of AF. There did not appear to be any statistically significant difference between agents after temporary interruptions or early permanent discontinuation. However, for the single endpoint of stroke, when transitioning from rivaroxaban to open-label therapy at the end of the study, there appeared to be significantly more strokes observed transitioning from rivaroxaban to warfarin, than when continuing with warfarin. (A difference was not seen when all potentially thrombotic events—including myocardial infarction and vascular death—within 30 days of study drug cessation were evaluated.) These data strongly suggest an increased risk of stroke when transitioning from rivaroxaban to warfarin in AF patients. What remains unclear at this point, however, is whether the discontinuation of rivaroxaban while transitioning to warfarin therapy induces a prothrombotic or hypercoagulable state, or merely results in a period of therapeutic under-anticoagulation. Further study is clearly needed to clarify this important point. If the problem is simply the potential for under-anticoagulation during transition, then this would suggest that the initiation of anticoagulation with warfarin in patients with AF may require bridging anticoagulation. If, on the other hand, cessation of rivaroxaban appears to induce a prothrombotic state, such drug cessation will have to be handled with care, or with a tapered reduction of therapy.
Clinical Topics: Anticoagulation Management
Keywords: Vitamin K, Risk, Stroke, Myocardial Infarction, Morpholines, Thiophenes, Warfarin, Creatinine, Blood Coagulation, Cardiology, Embolism
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