Atrial fibrillation (AF) is a common cardiac arrhythmia associated with increased morbidity and mortality. Patients with AF are at increased risk of systemic embolism (SE) and stroke, which can cause death, disability, and impaired quality of life. Antithrombotic therapies, such as oral anticoagulant and antiplatelet drugs, can reduce the risk for stroke and systemic thromboembolism and are recommended for most AF patients with risk factors for stroke. Antithrombotic therapies are also associated with a risk of bleeding, and their efficacy for stroke prevention should always be balanced against a patient’s risk of hemorrhage.

Existing guidelines recommend antithrombotic therapy based on risk of stroke, and most patients with non-valvular AF benefit from some form of antithrombotic therapy with an anticoagulant or antiplatelet drug. However, each oral antithrombotic drug used for stroke prevention in AF has advantages and disadvantages. There are decades of experience with the use of the vitamin K antagonist (VKA) warfarin, as well as compelling evidence of efficacy with regard to stroke prevention. However, individualized dose adjustments and laboratory monitoring are required, and warfarin remains the most common cause of drug-related emergency hospitalization in the elderly. Because there is less clinical experience with the new oral anticoagulant (NOAC) drugs apixaban, dabigatran, and rivaroxaban outside of randomized controlled trials, it is not yet clear whether the NOACs show increased real-world benefits compared with warfarin. Although less effective at stroke prevention than anticoagulant therapy in most risk categories, antiplatelet agents may still be the best choice for selected patients.

Following individual recommendations for dabigatran and rivaroxaban in AF made by the Common Drug Review (CDR), the Canadian Agency for Drugs and Technologies in Health (CADTH) previously reviewed the clinical effectiveness and cost-effectiveness of the NOACs compared with warfarin for CDEC to develop recommendations for policy-makers regarding the NOACs and warfarin. At that time, apixaban was not approved for use in Canada, and was therefore not included in the CDEC recommendation; in addition, antiplatelet drugs were not included. The current review was undertaken to extend the previous review to allow CDEC to develop recommendations that include all the NOACs, as well as the antiplatelet drugs acetylsalicylic acid (ASA) and clopidogrel.

Contents

• [Report Authors and Reviewers]
• ABBREVIATIONS
• EXECUTIVE SUMMARY
• 1. CONTEXT AND POLICY ISSUES
  • 1.1 Atrial Fibrillation
  • 1.2 Stroke Prevention
  • 1.3 Antithrombotic Therapy
  • 1.4 Objectives of the Report
• 2. RESEARCH QUESTIONS
• 3. METHODS
  • 3.1 Systematic Review
  • 3.2 Indirect Comparisons
  • 3.3 Pharmacoeconomic Analysis
• 4. RESULTS
  • 4.1 Selection of Primary Studies
  • 4.2 Study and Patient Characteristics
  • 4.3 Critical Appraisal of Included Studies
  • 4.4 Indirect Comparisons
  • 4.5 Pharmacoeconomic Evaluation
• 5. DISCUSSION
  • 5.1 Summary of Evidence
  • 5.2 Interpretation of the Results
  • 5.3 Strengths and Limitations of the Systematic Review
• 6. CONCLUSIONS AND IMPLICATIONS FOR DECISION-OR POLICY-MAKING
• REFERENCES
• APPENDIX 1 LITERATURE SEARCH STRATEGY
• APPENDIX 2 MODELLING OF TRANSITION PROBABILITIES
• APPENDIX 3 CLINICAL PARAMETERS RELATED TO WARFARIN USE
• APPENDIX 4 ASSUMPTIONS USED IN THE ECONOMIC MODEL
• APPENDIX 5 UTILITY VALUES FORALL HEALTH STATES WITHIN THE ECONOMIC MODEL
• APPENDIX 6 RESOURCE COST ESTIMATES
• APPENDIX 7 UNIVARIATE SENSITIVITY ANALYSES
• APPENDIX 8 SELECTION OF INCLUDED STUDIES
• APPENDIX 9 INCLUDED STUDY LIST
• APPENDIX 10 EXCLUDED STUDY LIST
• APPENDIX 11 CRITICAL APPRAISAL OF INCLUDED STUDIES
• APPENDIX 12 EVIDENCE NETWORKS
• APPENDIX 13 SUMMARY OF RESULTS FOR PAIRWISE META-ANALYSIS AND NETWORK META-ANALYSIS
• APPENDIX 14 PAIRWISE COMPARISONS FROM NETWORK META-ANALYSIS
• APPENDIX 15 DETAILED DATA
• APPENDIX 16 COMPARISON OF MODEL FIT STATISTICS: FIXED-EFFECTS VS RANDOM-EFFECTS MODELS
• APPENDIX 17 RESULTS FROM RANDOM-EFFECTS NMA MODEL
• APPENDIX 18 SUMMARY OF CHADS2 SCORES IN INCLUDED TRIALS
• APPENDIX 19 RESULTS OF UNIVARIATE SENSITIVITY ANALYSES
• APPENDIX 20 UNIVARIATE SENSITIVITY ANALYSES: PARAMETERS THAT DID NOT SUBSTANTIALLY ALTER THE RESULTS
• APPENDIX 21 SENSITIVITY ANALYSES: INCLUSION OF AVERROES AND ACTIVE-A

Note regarding to changes to the report following stakeholder feedback: Several modifications were made to the text and data tables of this report following the receipt of feedback in response to the previous draft of this report. These modifications were minor changes and did not alter the results of the analyses or the conclusions of the report. The most notable change to the report is the addition of Appendix 21, which provides the results of an analysis in which two excluded trials, AVERROES and ACTIVE A, were included in a sensitivity analysis. The results of this sensitivity analysis concur with the conclusions based on the primary analysis; therefore, there were no changes made to the conclusions of the report based on this sensitivity analysis.

Suggested citation:

Canadian Agency for Drugs and Technologies in Health. Antithrombotic agents for the prevention of stroke and systemic embolism in patients with atrial fibrillation [Internet]. Ottawa: The Agency; 2013. [cited yyyy mmm dd]. (CADTH Therapeutic Review; vol.1, no. 1b). Available from: http://www.cadth.ca/media/pdf/TR0003_AntithromboticAgents-AF_ScienceReport_e.pdf

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