Physicians' Academy for Cardiovascular Education

Bleeding risk of rivaroxaban vs. warfarin changes over time and with prior VKA-use

Literature - Mahaffey KW, Wojdyla D, Hankey GJ et al. - Ann Intern Med. 2013 Jun 18;158(12):861-8

Clinical outcomes with rivaroxaban in patients transitioned from vitamin k antagonist therapy: a subgroup analysis of a randomized trial.

Mahaffey KW, Wojdyla D, Hankey GJ et al.
Ann Intern Med. 2013 Jun 18;158(12):861-8. doi: 10.7326/0003-4819-158-12-201306180-00003.


Patients with atrial fibrillation who already receive warfarin, can either continue using warfarin, or transition to one of the new agents dabigatran, apixaban or rivaroxaban. Subgroup analysis in ACTIVE W (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events) [1] suggested that warfarin treatment was more beneficial for patients already receiving oral anticoagulant therapy before randomization, as opposed to other antithrombotic agents. However, the more recent RE-LY trial did not confirm this finding [2].
This is a prespecified subanalysis of the ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct
Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial, in which 20 mg of rivaroxaban, an oral direct factor Xa inhibitor, was tested for its effect on prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation [3,4]. The efficacy and safety of rivaroxaban is evaluated among 7897 (55.4%) vitamin K-antagonist (VKA)-experienced (at least 6 weeks) and 6367 (44.6%) VKA-naïve patients, as compared to warfarin.

Main results

  • VKA-experienced patients tended to have lower stroke and cardiovascular event rates than VKA-naïve patients.
  • There was no difference in the primary efficacy outcome between VKA-naïve and VKA-experienced patients. A borderline significantly higher rate of myocardial infarction among VKA-experienced patients who had previously received warfarin was seen.
  • In the first 30 days after randomisation, 15 strokes or systemic embolic events occurred in VKA-experienced patients, of which 6 in patients receiving rivaroxaban and 9 in patients receiving warfarin (HR: 0.68, 95%CI: 0.28-1.65).
  • In the first 7 days after initiation of the study drug, more major or nonmajor clinically relevant (NMCR) bleedings were observed with rivaroxaban as compared to warfarin, irrespective of prior VKA therapy. After 30 days, however, rivaroxaban appeared associated with less bleeding in VKA-naive patients than warfarin, and similar bleeding rates in VKA-experienced patients.


With similar efficacy results for rivaroxaban and warfarin for both VKA-naive and VKA-experienced patients, rivaroxaban was associated with more major or NMCR bleeding events than warfarin in the first 7 days after initiation of therapy, regardless of prior VKA status. After 30 days however, rivaroxaban was associated with less bleeding than warfarin in VKA-naive patients. Overall, event rates were low in the first 30 days, and similar in number between VKA-experienced and VKA-naive patients and across treatment groups. These data suggest that patients who already receive warfarin can also be considered for treatment with rivaroxaban. The transition should be guided based on international normalised ration (INR) monitoring.


1. Connolly S, Pogue J, Hart R et al; ACTIVE Writing Group of the ACTIVE Investigators. Clopidogrel plus aspirin
versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367:1903-12. [PMID: 16765759]
2. Connolly SJ, Ezekowitz MD, Yusuf S,  et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51. [PMID: 19717844]
3. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159:340-347. [PMID: 20211293]
4. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-91. [PMID: 21830957]

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