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Original Research |

Net Clinical Benefit of Adding Clopidogrel to Aspirin Therapy in Patients With Atrial Fibrillation for Whom Vitamin K Antagonists Are Unsuitable

Stuart J. Connolly, MD; John W. Eikelboom, MBBS; Jennifer Ng, MSc; Jack Hirsh, MD; Salim Yusuf, MD; Janice Pogue, MSc, MA; Raffaele de Caterina, MD, PhD; Stefan Hohnloser, MD; Robert G. Hart, MD, on behalf of the ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) Steering Committee and Investigators
[+] Article and Author Information

From McMaster University, Hamilton, Ontario, Canada; Gabriele d'Annunzio University, Chieti, Italy; and Goethe University, Frankfurt, Germany.


Note: Drs. Hart and Connolly contributed equally to this article.

Grant Support: By Bristol-Myers Squibb and sanofi-aventis.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-2986.

Reproducible Research Statement:Study protocol: Available from Dr. Connolly (e-mail, Stuart.Connolly@phri.ca). Statistical code: Available from Dr. Connolly for some noncommerical uses. Data set: Not available.

Requests for Single Reprints: Stuart J. Connolly, MD, Population Health Research Institute, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada; e-mail, Stuart.Connolly@phri.ca.

Current Author Addresses: Drs. Connolly, Eikelboom, Hirsh, Yusuf, and Hart; Ms. Ng; and Ms. Pogue: Population Health Research Institute, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

Dr. de Caterina: Institute of Cardiology, Gabriele d'Annunzio University–Chieti-Pescara, Via dei Vestini, 66013 Chieti, Italy.

Dr. Hohnloser: Department of Cardiology, Division of Clinical Electrophysiology, Johann Wolfgang Goethe University, Theodor Stern Kai 7, 60590 Frankfurt, Germany.

Author Contributions: Conception and design: S.J. Connolly, J.W. Eikelboom, S. Yusuf, J. Pogue, R.G. Hart.

Analysis and interpretation of the data: S.J. Connolly, J.W. Eikelboom, J. Ng, J. Hirsh, S. Yusuf, J. Pogue, R. de Caterina, S. Hohnloser, R.G. Hart.

Drafting of the article: J.W. Eikelboom, J. Ng, J. Pogue, R.G. Hart.

Critical revision of the article for important intellectual content: S.J. Connolly, J.W. Eikelboom, S. Yusuf, J. Pogue, R. de Caterina, S. Hohnloser, R.G. Hart.

Final approval of the article: S.J. Connolly, J.W. Eikelboom, S. Yusuf, J. Pogue, R. de Caterina, S. Hohnloser, R.G. Hart.

Statistical expertise: J. Ng, J. Pogue.

Obtaining of funding: S.J. Connolly, S. Yusuf.

Collection and assembly of data: S.J. Connolly, J.W. Eikelboom, S. Yusuf, J. Pogue, S. Hohnloser.


Ann Intern Med. 2011;155(9):579-586. doi:10.7326/0003-4819-155-9-201111010-00004
Text Size: A A A

Background: Adding clopidogrel to aspirin therapy reduces stroke in patients with atrial fibrillation (AF) but increases hemorrhage.

Objective: To quantify the net benefit of adding clopidogrel to aspirin therapy, accounting for differences in clinical significance between ischemic and hemorrhagic events.

Design: Observational cohort study to assign the relative weighting of events and post hoc analysis of randomized trial data to assess net benefit of dual antiplatelet therapy in the ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) clinical trials.

Setting: Global randomized clinical trial.

Patients: 10 041 patients with AF, 7554 of whom were not candidates for warfarin therapy.

Measurements: Ischemic events (ischemic stroke or myocardial infarction) and hemorrhagic events (hemorrhagic stroke or subdural or extracranial bleeding), weighted by the hazard ratio for death (or death or disability) after an event relative to death (or death or disability) after ischemic stroke. The net clinical benefit of dual antiplatelet therapy in the ACTIVE A trial participants was defined as the sum of weighted event incidence with dual antiplatelet therapy subtracted from the sum of weighted event incidence on control treatment, expressed as ischemic stroke equivalents prevented per 100 patients years.

Results: Adding clopidogrel to aspirin therapy prevented 0.57 ischemic stroke equivalent (95% CI, −0.12 to 1.24) per 100 patient-years of treatment when weighted by hazard for death after ischemia or hemorrhage and 0.67 ischemic stroke equivalent (CI, −0.03 to 1.18) when weighted by death or disability after ischemia or hemorrhage.

Limitation: No attempt was made to relate deaths used for weighting to events; disability data were missing for more than one half of patients.

Conclusion: Adding clopidogrel to aspirin therapy resulted in a modest net benefit among patients with AF for whom warfarin was unsuitable. The benefit would probably be clinically relevant for some patients, but estimates could not exclude the possibility of either no benefit or very small harm in this population.

Primary Funding Source: Bristol-Myers Squibb and sanofi-aventis.

Figures

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Figure.
Ischemic stroke equivalents prevented by adding clopidogrel to aspirin therapy, assessed by using a weighting system based on death or disability.

No significant subgroup interactions were observed. CAD = coronary artery disease; CHF = congestive heart failure; MI = myocardial infarction; TIA = transient ischemic attack.

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