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(Circulation. 2009;120:1569-1576.)
© 2009 American Heart Association, Inc.

Epidemiology and Prevention

Bleeding Increases the Risk of Ischemic Events in Patients With Peripheral Arterial Disease

Eline S. van Hattum, MD; Ale Algra, MD, PhD; James A. Lawson, MD, PhD; Bert C. Eikelboom, MD, PhD; Frans L. Moll, MD, PhD; Marco J.D. Tangelder, MD, PhD

From the Department of Vascular Surgery (E.S.v.H., B.C.E., F.L.M., M.J.D.T.), Department of Clinical Epidemiology, Julius Center for Health Sciences and Primary Care (A.A.), and Department of Neurology, Rudolf Magnus Institute (A.A.), University Medical Center Utrecht, Utrecht, and Department of Vascular Surgery, Hospital Amstelland, Amstelveen (J.A.L.), the Netherlands.

Correspondence to E.S. van Hattum, MD, University Medical Center Utrecht, Department of Vascular Surgery (G.04.129), PO Box 85500, 3508 GA Utrecht, the Netherlands. E-mail e.vanhattum{at}umcutrecht.nl

Received September 25, 2008; accepted July 31, 2009.

Background— Patients with peripheral arterial disease are at high risk of ischemic events and therefore are treated with antithrombotics. In patients with coronary artery disease or cerebrovascular disease, bleeding is related to the subsequent occurrence of ischemic events. Our objective was to assess whether this is also the case in patients with peripheral arterial disease.

Methods and Results— All patients from the Dutch Bypass and Oral Anticoagulants or Aspirin (BOA) Study, a multicenter randomized trial comparing oral anticoagulants with aspirin after infrainguinal bypass surgery, were included. The primary outcome event was the composite of nonfatal myocardial infarction, nonfatal ischemic stroke, major amputation, and cardiovascular death. To identify major bleeding as an independent predictor for ischemic events, crude and adjusted hazard ratios with 95% confidence intervals were calculated with multivariable Cox regression models. From 1995 until 1998, 2650 patients were included with 101 nonfatal major bleedings. During a mean follow-up of 14 months, the primary outcome event occurred in 218 patients; 22 events were preceded by a major bleeding. The mean time between major bleeding and the primary outcome event was 4 months. Major bleeding was associated with a 3-fold increased risk of subsequent ischemic events (crude hazard ratio, 3.0; 95% confidence interval, 1.9 to 4.6; adjusted hazard ratio, 3.0; 95% confidence interval, 1.9 to 4.7).

Conclusions— In patients with peripheral arterial disease, as in patients with coronary artery disease or cerebrovascular disease, major bleeding was independently associated with major ischemic complications. Without compromising the benefits of antithrombotics, these findings call for caution relative to the risks of major bleeding.

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