The Net Clinical Benefit of Warfarin Anticoagulation in Atrial Fibrillation

  1. Daniel E. Singer, MD;
  2. Yuchiao Chang, PhD;
  3. Margaret C. Fang, MD, MPH;
  4. Leila H. Borowsky, MPH;
  5. Niela K. Pomernacki, RD;
  6. Natalia Udaltsova, PhD; and
  7. Alan S. Go, MD
  1. From Massachusetts General Hospital, Boston, Massachussetts, and University of California, San Francisco, San Francisco, and Kaiser Permanente of Northern California, Oakland, California.

    Abstract

    Background: Guidelines recommend warfarin use in patients with atrial fibrillation solely on the basis of risk for ischemic stroke without antithrombotic therapy. These guidelines rely on ischemic stroke rates observed in older trials and do not explicitly account for increased risk for hemorrhage.

    Objective: To quantify the net clinical benefit of warfarin therapy in a cohort of patients with atrial fibrillation.

    Design: Mixed retrospective and prospective cohort study of patients with atrial fibrillation between 1996 and 2003.

    Setting: An integrated health care delivery system.

    Patients: 13 559 adults with nonvalvular atrial fibrillation.

    Measurements: Warfarin exposure, patient characteristics, CHADS2 score (1 point for each of congestive heart failure, hypertension, age, and diabetes and 2 points for stroke), and outcome events were ascertained from health plan records and databases. Net clinical benefit was defined as the annual rate of ischemic strokes and systemic emboli prevented by warfarin minus intracranial hemorrhages attributable to warfarin, multiplied by an impact weight. The base-case impact weight was 1.5, reflecting the greater clinical impact of intracranial hemorrhage versus thromboembolism.

    Results: Patients accumulated more than 66 000 person-years of follow-up. The adjusted net clinical benefit of warfarin for the cohort overall was 0.68% per year (95% CI, 0.34% to 0.87%). Adjusted net clinical benefit was greatest for patients with a history of ischemic stroke (2.48% per year [CI, 0.75% to 4.22%]) and for those 85 years or older (2.34% per year [CI, 1.29% to 3.30%]). The net clinical benefit of warfarin increased from essentially zero in CHADS2 stroke risk categories 0 and 1 to 2.22% per year (CI, 0.58% to 3.75%) in CHADS2 categories 4 to 6. The patterns of results were preserved when weighting factors for intracranial hemorrhage of 1.0 and 2.0 were used.

    Limitations: Residual confounding is a possibility. Some outcome events were probably missed by the screening algorithm or when medical records were unavailable.

    Conclusion: Expected net clinical benefit of warfarin therapy is highest among patients with the highest untreated risk for stroke, which includes the oldest age category. Risk assessment that incorporates both risk for thromboembolism and risk for intracranial hemorrhage provides a more quantitatively informed basis for the decision on antithrombotic therapy in patients with atrial fibrillation.

    Primary Funding Source: National Institute on Aging; National Heart, Lung, and Blood Institute; and Massachusetts General Hospital.

    Article and Author Information

    • Grant Support: By the National Institute on Aging (R01 AG15478); the National Heart, Lung, and Blood Institute (U19 HL091179); and the Eliot B. and Edith C. Shoolman fund of the Massachusetts General Hospital. Dr. Fang's efforts were also partially supported by the National Institute on Aging (K23 AG28978).

    • Potential Financial Conflicts of Interest: Consultancies: D.E. Singer (Boehringer Ingelheim, Bayer, AstraZeneca, Sanofi-Aventis, Daiichi Sankyo, Johnson & Johnson). Honoraria: D.E. Singer (Bristol-Myers Squibb, Pfizer). Grants received: D.E. Singer (Daiichi Sankyo), A.S. Go (Johnson & Johnson).

    • Reproducible Research Statement: Study protocol and statistical code: Available from Dr. Singer (e-mail, dsinger{at}partners.org). Data set: Not available.

    • Requests for Single Reprints: Daniel E. Singer, MD, Clinical Epidemiology Unit, Massachusetts General Hospital, 50 Staniford Street, 9th Floor, Boston, MA 02114; e-mail, dsinger{at}partners.org.

    • Current Author Addresses: Drs. Singer and Chang and Ms. Borowsky: Clinical Epidemiology Unit, Massachusetts General Hospital, 50 Staniford Street, 9th Floor, Boston, MA 02114.

    • Dr. Fang: University of California, San Francisco, 505 Parnassus Avenue, Box 0131, San Francisco, CA 94143.

    • Ms. Pomernacki and Drs. Udaltsova and Go: Division of Research, Kaiser Permanente of Northern California, 2000 Broadway Street, Oakland, CA 94612-2304.

    • Author Contributions: Conception and design: D.E. Singer, Y. Chang, M.C. Fang, A.S. Go.

    • Analysis and interpretation of the data: D.E. Singer, Y. Chang, M.C. Fang, L.H. Borowsky, N.K. Pomernacki, N. Udaltsova, A.S. Go.

    • Drafting of the article: D.E. Singer.

    • Critical revision of the article for important intellectual content: D.E. Singer, Y. Chang, M.C. Fang, L.H. Borowsky, A.S. Go.

    • Final approval of the article: D.E. Singer, Y. Chang, M.C. Fang, L.H. Borowsky, N.K. Pomernacki, N. Udaltsova, A.S. Go.

    • Provision of study materials or patients: A.S. Go.

    • Statistical expertise: D.E. Singer, Y. Chang.

    • Obtaining of funding: D.E. Singer, A.S. Go.

    • Administrative, technical, or logistic support: D.E. Singer, L.H. Borowsky, N.K. Pomernacki, A.S. Go.

    • Collection and assembly of data: D.E. Singer, M.C. Fang, N. Udaltsova, A.S. Go.

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    1. Ann Intern Med September 1, 2009 vol. 151 no. 5 297-305
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