Physicians' Academy for Cardiovascular Education

Increase in events after apixaban discontinuation likely due to initiation of VKA therapy

Granger CB et al., Am Heart J. 2015

Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial

Granger CB, Lopes RD, Hanna M, et al.
Am Heart J. 2015 Jan;169(1):25-30. doi: 10.1016/j.ahj.2014.09.006



Periods of initiation and discontinuation of oral anticoagulants and transition between different oral coagulants may be associated with increased risk of bleeding and/or thromboembolism.
In the ROCKET AF trial, an increase in thrombotic events was observed after discontinuation of rivaroxaban and transition to open-label warfarin at the end of the study [1], even though rivaroxaban was found to be noninferior to warfarin for the prevention of stroke and systemic embolism (SE) in patients with nonvalvular AF at moderate-to-high risk for stroke [2]. This has led to a boxed warning, also for dabigatran and apixaban [3] as well as a Risk Evaluation and Management Strategy Plan approved by the US Food and Drug Administration [4].
This study aimed to assess and understand the occurrence of clinical events after blinded study drug (apixaban or warfarin) discontinuation and during transition to open-label warfarin (as per standard practice) at the end of the ARISTOTLE trial.


Main results

  • At the end of the trial, 21 strokes or SE (4.02%/year) and 26 major bleeding (4.97%/year) events were observed in the apixaban group in the 30 days after discontinuation of the study drug, as compared with 5 strokes or SE (0.99%/year) and 10 major bleedings (1.97%/year) in the warfarin group.
    Most of the imbalance was observed after the first week.
  • Similar results (14 vs. 2 events with apixaban vs. warfarin) were seen when the analysis was restricted to the 84% of patients who completed study treatment and who received VKA therapy.
  • Clinical outcomes in the warfarin-assigned patients at the beginning of the trial in warfarin-naïve patients was compared with warfarin-experienced patients, to assess VKA initiation and continuation. Patients initiating warfarin had a higher rate of stroke/SE (5.41%) than patients who continued warfarin treatment (1.42%).
    Events were similar (about 1.5%/year) for patients on apixaban, who were either warfarin-naïve or warfarin-experienced.
  • Bleeding also showed an excess in the warfarin-naïve population (5.18%/year) as compared with the warfarin-experienced patients (3.12%/year). Bleeding with apixaban was about 2%/year in both groups.



These analyses show an increased risk of stroke upon discontinuation of apixaban at the end of the ARISTOTLE trial. Most events occurred longer than one week after discontinuation, both an increase in thrombotic and bleeding events is seen. Analyses suggest that not discontinuation of apixaban per se causes risk, but rather that initiation of VKA is associated with higher risk of stroke and bleeding, as compared to a group who continues stable VKA therapy. In case of transition from novel anticoagulants to VKA, careful monitoring should be employed to achieve a therapeutic target INR, as transition to VKA appears to have similar challenges as initiating warfarin treatment de novo.
Find this article online at Am Heart J


1. Patel MR, Hellkamp AS, Lokhnygina Y, et al. 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). J Am Coll Cardiol 2013;61:651-8.
2. Patel MR,Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
3. ELIQUIS (apixaban) label. Available at, [Accessed
October 30, 2013].
4. XARELTO (rivaroxaban) Risk Evaluation and Mitigation Strategy. Available at, [Accessed October 30, 2013].