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Safety, Effectiveness, and Cost-Effectiveness of New Oral Anticoagulants Compared with Warfarin in Preventing Stroke and Other Cardiovascular Events in Patients with Atrial Fibrillation

CADTH Therapeutic Review

George Wells, PhD, Doug Coyle, PhD, Chris Cameron, MSc PhD (candidate), Sabine Steiner, MD MSc, Kathryn Coyle, BScPharm MSc, Shannon Kelly, MSc (candidate), Anthony Tang, MD FRCPC, Jeff Healey, MD FRCPC, Shu-Ching Hsieh, PhD, and Judith van Berkom, BA.

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Approximately 250,000 Canadians are affected by atrial fibrillation (AF). Stroke is a complication of AF, and Canadians with AF are five times more likely to have a stroke and are twice as likely to die than individuals without AF. AF and stroke are more common among the elderly.

Preventing thromboembolic events such as stroke is an important part of managing AF patients. Antithrombotic strategies for AF patients include anticoagulant drugs, notably the coumadin class of vitamin K antagonists (VKAs), such as warfarin, and antiplatelet agents, such as aspirin. VKAs reduce the risk of stroke in patients with AF by more than 60% when compared with no treatment, and by 30% to 40% when compared with low-dose aspirin. However, VKA use is associated with some drawbacks, including a need for laboratory monitoring, an increased risk of bleeding complications, and several food and drug interactions. An improved understanding of how the blood clotting cascade works has led to the development of new oral anticoagulants (NOACs) that exhibit more predictable pharmacokinetics and pharmacodynamics, thereby obviating the need for laboratory monitoring. The NOACs that have either been approved, or are under review by regulators, for the prevention of thromboembolic events in AF patients include dabigatran, a direct thrombin inhibitor, and the direct Factor Xa (FXa) inhibitors, rivaroxaban, apixaban, and edoxaban. Ximelagatran, a direct thrombin inhibitor, was the first NOAC to be approved for use, but was withdrawn from the market in 2006 because of safety concerns.

While dabigatran, apixaban, and rivaroxaban have been demonstrated to be effective in preventing stroke/systemic embolism (SE) in AF patients, the relative effectiveness and associated bleeding risks of these NOACs, both among themselves and in comparison to warfarin, is not clear. Therefore, the aim of this project was to systematically review and analyze the safety and effectiveness of three NOACs – namely dabigatran, rivaroxaban, and apixaban – compared with warfarin in patients with non-valvular AF. In addition, the cost-effectiveness of the NOACs and warfarin was assessed using economic modelling.

Contents

Authorship: George Wells wrote the protocol for this review and acted as the primary lead in the conception, design and implementation of the project, as well as all aspects of the development and writing of the report and responses to internal and external reviewers.

Doug Coyle planned and led the economic section, selected articles, and extracted data for the economic review; performed the primary economic analyses; wrote the economic sections; and contributed to revisions and responses to internal and external reviewers.

Chris Cameron extracted and checked data; performed Bayesian mixed treatment comparisons metaanalyses; wrote sections and prepared tables and figures for the clinical review; and contributed to revisions and responses to internal and external reviewers.

Sabine Steiner extracted and checked data; performed frequentist mixed treatment comparisons metaanalyses, wrote sections of the clinical review, and contributed to revisions and responses to internal and external reviewers.

Kathryn Coyle assisted with the development of the methods for the economic analysis; selected economic studies; extracted, tabulated, and analyzed data; and contributed to writing the economic sections of the report.

Shannon Kelly contributed to writing the protocol; led and participated in article selection, study quality assessment, data extraction and tabulation, subgroup appraisal and preparation of tables for the clinical review; wrote and edited sections of the clinical review; contributed to revisions and responses to internal and external reviewers; and edited the final draft.

Anthony Tang provided clinical guidance and feedback for this review; co-wrote the Introduction and Background section in the protocol and this review; assisted with the writing of the Discussion section; and contributed to revisions and responses to external reviewers.

Jeff Healey provided clinical guidance and feedback for this review; co-wrote the Introduction and Background section in the protocol and this review; assisted with the writing of the Discussion section; and contributed to revisions and responses to external reviewers.

Shu-Ching Hseih participated in article selection, study quality assessment, data extraction and checking, subgroup appraisal and preparation of tables for the clinical review; assisted with referencing of studies in the final draft; and contributed to revisions.

Judith van Berkom developed the literature search strategies and performed all searches, managed report referencing, and composed the search methodology sections.

The Canadian Collaborative for Drug Safety, Effectiveness and Network Meta-analysis is funded by a team grant from the Canadian Institute of Health Research Drug Safety and Effectiveness Network.

This report is based on research conducted by the Canadian Collaborative for Drug Safety, Effectiveness and Network Meta – Analysis in collaboration with the Canadian Agency for Drugs and Technologies in Health (CADTH).

This report is being used by CADTH for the purpose of informing formulary listing recommendations for new oral anticoagulant(s) for stroke prevention in patients with atrial fibrillation and for informing policy decisions and potentially optimal use of these agents by the publicly funded federal, provincial and territorial drug plans participating in the Common Drug Review.

The report contains a comprehensive review of the existing public literature, studies, materials, and other information and documentation (collectively, the source documentation) available at the time of report preparation, and was guided by expert input and advice throughout its preparation.

The Canadian Collaborative for Drug Safety, Effectiveness and Network Meta - Analysis granted CADTH a non-exclusive, irrevocable, indefinite and unlimited license to use the Therapeutic Review in any manner, any form and format and for any purpose that CADTH may deem appropriate and to publish or reproduce the same or any part thereof, with or without edits or modification, provided, however, that such license shall be non-assignable and non-transferable by CADTH.

The authors are not responsible for any errors or omissions or injury, loss, or damage arising from or as a result of the use (or misuse) of any information contained in or implied by the information in this report.

The information in this report should not be used as a substitute for the application of clinical judgment in respect of the care of a particular patient nor is it intended to replace professional medical advice.

Copyright © 2012 Canadian Collaborative for Drug Safety, Effectiveness and Network Meta-Analysis.

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/

PMID: 24279001

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