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Original Research |

Clinical Outcomes With Rivaroxaban in Patients Transitioned From Vitamin K Antagonist Therapy: A Subgroup Analysis of a Randomized Trial

Kenneth W. Mahaffey, MD; Daniel Wojdyla, MS; Graeme J. Hankey, MD; Harvey D. White, DSc; Christopher C. Nessel, MD; Jonathan P. Piccini, MD; Manesh R. Patel, MD; Scott D. Berkowitz, MD; Richard C. Becker, MD; Jonathan L. Halperin, MD; Daniel E. Singer, MD; Robert M. Califf, MD; Keith A.A. Fox, MBChB; Günter Breithardt, MD; and Werner Hacke, MD, PhD
[+] Article and Author Information

From Duke Clinical Research Institute and Duke Translational Medicine Institute, Duke University Medical Center, Durham, North Carolina; Royal Perth Hospital, Perth, Western Australia, Australia; Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand; Johnson & Johnson Pharmaceutical Research and Development, Raritan, New Jersey; Bayer HealthCare Pharmaceuticals, Montville, New Jersey; Cardiovascular Institute, Mount Sinai Medical Center, New York, New York; Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; University of Edinburgh and Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; Hospital of the University of Münster, Münster, Germany; and Ruprecht-Karls-University, Heidelberg, Germany.

Acknowledgment: The authors thank Morgan deBlecourt and Elizabeth Cook of the Duke Clinical Research Institute for editorial support and the ROCKET AF Steering Committee and Investigators.

Grant Support: By Johnson & Johnson Pharmaceutical Research and Development and Bayer HealthCare.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1644.

Reproducible Research Statement: Study protocol: Available from reference 4. Statistical code and data set: Available from Dr. Mahaffey (e-mail, kenneth.mahaffey@dm.duke.edu).

Requests for Single Reprints: Kenneth W. Mahaffey, MD, Duke Clinical Research Institute, Room 0311 Terrace Level, 2400 Pratt Street, Durham, NC 27705; e-mail, kenneth.mahaffey@dm.duke.edu.

Current Author Addresses: Drs. Mahaffey, Piccini, Patel, and Becker and Mr. Wojdyla: Duke Clinical Research Institute, Room 0311 Terrace Level, 2400 Pratt Street, Durham, NC 27705.

Dr. Hankey: School of Medicine and Pharmacology, The University of Western Australia, 35 Stirling Highway, Crawley, Perth, Western Australia 6009, Australia.

Dr. White: Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92024, 1030 Auckland, New Zealand.

Dr. Nessel: Janssen Research & Development, 920 Route 202, Raritan, NJ 08869.

Dr. Berkowitz: Bayer HealthCare Pharmaceuticals, PO Box 1000, Mailstop M2/2-7, Montville, NJ 07045-1000.

Dr. Halperin: The Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, Mount Sinai Medical Center, Box 1030, Fifth Avenue at 100th Street, New York, NY 10029-6574.

Dr. Singer: Clinical Epidemiology Unit, General Medicine Division, S50-9, Massachusetts General Hospital, Boston, MA 02114.

Dr. Califf: Duke Translational Medicine Institute, Box 3850 Medical Center, Durham, NC 27710.

Dr. Fox: Centre for Cardiovascular Science, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, United Kingdom.

Dr. Breithardt: Universitätsklinikum Münster (UKM), Von-Esmarch-Strasse 117, 48149 Münster, Germany.

Dr. Hacke: Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany.

Author Contributions: Conception and design: K.W. Mahaffey, G.J. Hankey, H.D. White, C.C. Nessel, M.R. Patel, S.D. Berkowitz, R.C. Becker, C.L. Halperin, D.E. Singer, K.A.A. Fox, G. Breithardt.

Analysis and interpretation of the data: K.W. Mahaffey, D. Wojdyla, H.D. White, C.C. Nessel, J.P. Piccini, M.R. Patel, S.D. Berkowitz, R.C. Becker, C.L. Halperin, D.E. Singer, K.A.A. Fox, G. Breithardt.

Drafting of the article: K.W. Mahaffey, R.C. Becker, R.M. Califf.

Critical revision of the article for important intellectual content: K.W. Mahaffey, D. Wojdyla, G.J. Hankey, H.D. White, J.P. Piccini, M.R. Patel, R.C. Becker, C.L. Halperin, D.E. Singer, K.A.A. Fox, G. Breithardt, W. Hacke.

Final approval of the article: K.W. Mahaffey, D. Wojdyla, G.J. Hankey, H.D. White, C.C. Nessel, J.P. Piccini, M.R. Patel, S.D. Berkowitz, R.C. Becker, C.L. Halperin, D.E. Singer, R.M. Califf, K.A.A. Fox, G. Breithardt, W. Hacke.

Provision of study materials or patients: K.W. Mahaffey, C.C. Nessel, S.D. Berkowitz, R.C. Becker.

Statistical expertise: D. Wojdyla.

Obtaining of funding: K.W. Mahaffey, S.D. Berkowitz.

Administrative, technical, or logistic support: K.W. Mahaffey, R.C. Becker, C.L. Halperin.

Collection and assembly of data: K.W. Mahaffey, H.D. White, C.C. Nessel, J.P. Piccini, S.D. Berkowitz, R.C. Becker.


Ann Intern Med. 2013;158(12):861-868. doi:10.7326/0003-4819-158-12-201306180-00003
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Chinese translation

Background: In 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), a large randomized, clinical trial, rivaroxaban was noninferior to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation.

Objective: To determine the efficacy and safety of rivaroxaban compared with warfarin among vitamin K antagonist (VKA)–naive and VKA-experienced patients.

Design: Prespecified subgroup analysis. (ClinicalTrials.gov: NCT00403767)

Setting: Global.

Patients: 14 264 persons with atrial fibrillation.

Measurements: Interaction of the relative treatment effect of rivaroxaban and warfarin on stroke or systemic embolism among VKA-naive and VKA-experienced patients.

Results: Overall, 7897 (55.4%) patients were VKA-experienced and 6367 (44.6%) were VKA-naive. The effect of rivaroxaban versus warfarin on stroke or systemic embolism was consistent: Rates per 100 patient-years of follow-up were 2.32 versus 2.87 for VKA-naive patients (hazard ratio [HR], 0.81 [95% CI, 0.64 to 1.03]) and 1.98 versus 2.09 for VKA-experienced patients (HR, 0.94 [CI, 0.75 to 1.18]; interaction P = 0.36). During the first 7 days, rivaroxaban was associated with more bleeding than warfarin (HR in VKA-naive patients, 5.83 [CI, 3.25 to 10.44], and in VKA-experienced patients, 6.66 [CI, 3.83 to 11.58]; interaction P = 0.53). After 30 days, rivaroxaban was associated with less bleeding than warfarin in VKA-naive patients (HR, 0.84 [CI, 0.74 to 0.95]) and similar bleeding in VKA-experienced patients (HR, 1.06 [CI, 0.96 to 1.17]; interaction P = 0.003).

Limitation: The trial was not designed to detect differences in these subgroups.

Conclusion: The efficacy of rivaroxaban in VKA-experienced and VKA-naive patients was similar to that of the overall trial. There were more bleeding events within 7 days of study drug initiation with rivaroxaban, but after 30 days, rivaroxaban was associated with less bleeding in VKA-naive patients and similar bleeding in VKA-experienced patients. This information may be useful to clinicians considering a transition to rivaroxaban for patients receiving VKA therapy.

Primary Funding Source: Johnson & Johnson and Bayer HealthCare.

Figures

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Figure 1.

Kaplan–Meier estimates for the primary efficacy outcome, by VKA status and randomized treatment, in the intention-to-treat population.

The hazard ratio of the effect of rivaroxaban vs. warfarin was 0.809 (95% CI, 0.637 to 1.025) in VKA-naive patients and 0.944 (CI, 0.753 to 1.184) in VKA-experienced patients. VKA = vitamin K antagonist.

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Appendix Figure.

Kaplan–Meier curves in the per-protocol, on-treatment population.

VKA = vitamin K antagonist.

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Figure 2.

Major bleeding events and NMCR bleeding events during the first 30 d after initiation of therapy with the study drug among VKA-experienced patients.

VKA = vitamin K antagonist; NMCR = nonmajor clinically relevant.

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The transition from vitamin K antagonist to Rivaroxaban
Posted on July 17, 2013
Simone Vidale
Department of Neurology & Stroke Unit, Sant'Anna Hospital, Como - Italy
Conflict of Interest: None Declared

New oral anticoagulants provide new therapeutical perspectives to clinicians in patients with atrial fibrillation (AF). Results of recent randomized trials contributed to demonstrate effective alternatives to warfarin for the prevention of stroke and systemic embolism in these patients.1 In the recent subgroup analysis of ROCKET AF trial, a similar efficacy of rivaroxaban to the overall trial was observed.2 It is interesting to note that stroke rates were more reduced in VKA experienced patients than naive subjects, in the rivaroxaban group particularly. This finding could be probably related to a higher patient’s disposition to therapy compliance, an optimal INR value already reached or a better control of concomitant risk factors.

Authors reported a similar rate of early therapy discontinuation in rivaroxaban group, while in warfarin group the naive patients discontinuated the therapy more easily. Therefore it could be interesting to analyze the reasons for this discontinuation in early phase of treatment, considering that in the past some studies identified age, fewer stroke risk factors and uncontrolled INR as possible causes.3

A second point of reflection is concerning about the safety outcomes and intracranial bleeding particularly. In naive patients the rivaroxaban group presented a 41% decreasing in cerebral haemorrhage risk than warfarin group. A different temporal trend was also observed: a higher rate of major bleedings occurred early, while after one month the risk decreased significantly. Therefore it could be interesting to identify some characteristics of patients with an early or late major bleedings. Some previous studies developed models to estimate this risk, considering age, history of stroke or gastrointestinal bleeding, an uncontrolled hypertension or high level of anticoagulation.4

For this reason the personalization of the treatment and its possible changing may increase the safety and efficacy of the new anticoagulants when used in the real world and not only in a trial setting.

References

1.Miller CS, Grandi SM, Shimony A, et al. Meta-analysis of efficacy and safety of new oral anticoagulants (Dabigatran, Rivaroxaban, Apixaban) versus Warfarin in patients with atrial fibrillation. Am J Cardiol 2012; 110: 453-460.

2.Mahaffey KW, Wojdyla D, Hankey GJ, et al. Clinical outcomes with Rivaroxaban in patients transitioned from vitamin K antagonist therapy. Ann Intern Med 2013; 158: 861-868.

3.Fan MC, Go AS, Chang Y, et al. Warfarin discontinuation after starting warfarin for atrial fibrillation. Circ Cardiovasc Qual Outcomes 2010; 3: 642-631.

4.Roldan V, Marin F, Fernandez H, et al. Predictive value of the Has-BLED and ATRIA bleeding scores for the risk of serious bleeding in a “real world” population with atrial fibrillation receiving anticoagulant therapy. Chest 2013; 143: 179-184.

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Summary for Patients

Rivaroxaban in Patients Transitioned From Vitamin K Antagonist Therapy

The full report is titled “Clinical Outcomes With Rivaroxaban in Patients Transitioned From Vitamin K Antagonist Therapy. A Subgroup Analysis of a Randomized Trial.” It is in the 18 June 2013 issue of Annals of Internal Medicine (volume 159, pages 861-868). The authors are K.W. Mahaffey, D. Wojdyla, G.J. Hankey, H.D. White, C.C. Nessel, J.P. Piccini, M.R. Patel, S.D. Berkowitz, R.C. Becker, J.L. Halperin, D.E. Singer, R.M. Califf, K.A.A. Fox, G. Breithardt, and W. Hacke.

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