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How Well Do Randomized Trials Translate Into Clinical Practice?

Alan S. Go, MD; Elaine M. Hylek, MD, MPH; Yuchiao Chang, PhD; Kathleen A. Phillips; Lori E. Henault, MPH; Angela M. Capra, MA; Nancy G. Jensvold, MPH; Joe V. Selby, MD, MPH; Daniel E. Singer, MD

JAMA. 2003;290:2685-2692.

Context  Warfarin has been shown to be highly efficacious for preventing thromboembolism in atrial fibrillation in randomized trials, but its effectiveness and safety in clinical practice is less clear.

Objective  To evaluate the effect of warfarin on risk of thromboembolism, hemorrhage, and death in atrial fibrillation within a usual care setting.

Design  Cohort study assembled between July 1, 1996, and December 31, 1997, and followed up through August 31, 1999.

Setting  Large integrated health care system in Northern California.

Patients  Of 13 559 adults with nonvalvular atrial fibrillation, 11 526 were studied, 43% of whom were women, mean age 71 years, with no known contraindications to anticoagulation at baseline.

Main Outcomes  Ischemic stroke, peripheral embolism, hemorrhage, and death according to warfarin use and comorbidity status, as determined by automated databases, review of medical records, and state mortality files.

Results  Among 11 526 patients, 397 incident thromboembolic events (372 ischemic strokes, 25 peripheral embolism) occurred during 25 341 person-years of follow-up, and warfarin therapy was associated with a 51% (95% confidence interval [CI], 39%-60%) lower risk of thromboembolism compared with no warfarin therapy (either no antithrombotic therapy or aspirin) after adjusting for potential confounders and likelihood of receiving warfarin. Warfarin was effective in reducing thromboembolic risk in the presence or absence of risk factors for stroke. A nested case-control analysis estimated a 64% reduction in odds of thromboembolism with warfarin compared with no antithrombotic therapy. Warfarin was also associated with a reduced risk of all-cause mortality (adjusted hazard ratio, 0.69; 95% CI, 0.61-0.77). Intracranial hemorrhage was uncommon, but the rate was moderately higher among those taking vs those not taking warfarin (0.46 vs 0.23 per 100 person-years, respectively; P = .003, adjusted hazard ratio, 1.97; 95% CI, 1.24-3.13). However, warfarin therapy was not associated with an increased adjusted risk of nonintracranial major hemorrhage. The effects of warfarin were similar when patients with contraindications at baseline were analyzed separately or combined with those without contraindications (total cohort of 13 559).

Conclusions  Warfarin is very effective for preventing ischemic stroke in patients with atrial fibrillation in clinical practice while the absolute increase in the risk of intracranial hemorrhage is small. Results of randomized trials of anticoagulation translate well into clinical care for patients with atrial fibrillation.

Author Affiliations: Division of Research, Kaiser Permanente of Northern California, Oakland (Drs Go and Selby, Mss Phillips, Capra, and Jensvold); Departments of Epidemiology, Biostatistics, and Medicine, University of California at San Francisco, San Francisco (Dr Go); Clinical Epidemiology Unit, General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (Drs Hylek, Chang, and Singer and Ms Henault).

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