Published Online
on October 27, 2008

A more recent version of this article appeared on November 11, 2008

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Submitted on November 6, 2007
Accepted on August 27, 2008

Benefit of Oral Anticoagulant Over Antiplatelet Therapy in Atrial Fibrillation Depends on the Quality of International Normalized Ratio Control Achieved by Centers and Countries as Measured by Time in Therapeutic Range

Stuart J. Connolly MA, MD, FRCPC^*, Janice Pogue MA, MSc, John Eikelboom MBBS, MSc, FRACP, FRCPA, Gregory Flaker MD, Patrick Commerford MB, ChB, FCP(SA), Maria Grazia Franzosi PhD, Jeffrey S. Healey MD, FRCPC, Salim Yusuf DPhil, FRCPC, on behalf of the ACTIVE W Investigators

From the Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada (S.J.C., J.P., J.E., J.S.H., S.Y.); University of Missouri, Columbia (G.F.); Cardiac Clinic, Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa (P.C.); and Department of Cardiovascular Research, Istituto Mario Negri, Milano, Italy (M.G.F.).

^* To whom correspondence should be addressed. E-mail: connostu{at}phri.ca.

Background—Oral anticoagulation (OAC) therapy is effective in atrial fibrillation but requires vigilance to maintain the international normalized ratio in the therapeutic range. This report examines how differences in time in therapeutic range (TTR) between centers and between countries affect the outcomes of OAC therapy.

Methods and Results—In a posthoc analysis, the TTRs of patients on OAC in a randomized trial of OAC versus clopidogrel plus aspirin (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events [ACTIVE W]) were used to calculate the mean TTR for each of 526 centers and 15 countries. Proportional-hazards analysis, with and without adjustment for baseline variables, was performed, with patients stratified by TTR quartile and country. A wide variation in TTRs was found between centers, with mean TTRs for centers in the 4 quartiles of 44%, 60%, 69%, and 78%. For patients at centers below the median TTR (65%), no treatment benefit was demonstrated as measured by relative risk for vascular events of clopidogrel plus aspirin versus OAC (relative risk, 0.93; 95% confidence interval, 0.70 to 1.24; P=0.61). However, for patients at centers with a TTR above the study median, OAC had a marked benefit, reducing vascular events by >2-fold (relative risk, 2.14; 95% confidence interval, 1.61 to 2.85; P<0.0001). Mean TTR also varied between countries from 46% to 78%; relative risk (clopidogrel plus aspirin versus OAC) varied from 0.6 to 3.6 (a 5-fold difference). A population-average model predicted that a TTR of 58% would be needed to be confident that patients would benefit from being on OAC.

Conclusions—A wide variation exists in international normalized ratio control, as measured by TTR, between clinical centers and between countries, which has a major impact on the treatment benefit of OAC therapy. For centers and countries, a target threshold TTR exists (estimated between 58% and 65%) below which there appears to be little benefit of OAC over antiplatelet therapy.

Key words: anticoagulants • atrial fibrillation • arrhythmia • prevention • stroke

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