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Risk Factors for Complications of Chronic Anticoagulation: A Multicenter Study

Stephan D. Fihn, MD, MPH; Mary McDonell, MS; Donald Martin, PhD; Jorja Henikoff, MS; Domokos Vermes, PhD; Daniel Kent, MD; Richard H. White, MD, Warfarin Optimized Outpatient Follow-up Study Group*
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From the Health Services Research and Development Field Program, Seattle Veterans Affairs Medical Center, Seattle, Washington. University of California, Davis, Medical Center, Sacramento, California. For current author addresses, see end of text. * See the Appendix for a complete listing of members. Requests for Reprints: Stephan Fihn, MD, MPH, Section of General Internal Medicine (111M), Seattle Veterans Affairs Medical Center, 1660 South Columbian Way, Seattle, WA 98108. Grant Support: In part by grants IIR 87-063 and IIR 90-036 from the Health Services and Research Development Program of the Department of Veterans Affairs; by the Center for Outcomes Research in Elderly Persons—A Veterans Affairs Health Services and Research Development Field Program; and by an unrestricted educational grant from Du Pont Pharmaceuticals.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1993;118(7):511-520. doi:10.7326/0003-4819-118-7-199304010-00005
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Objective: To define risk factors for complications that occur during warfarin therapy.

Design: Retrospective cohort study.

Setting: Five anticoagulation clinics.

Patients: Nine hundred twenty-eight consecutive patients receiving 1103 courses of warfarin.

Main Outcome Measures: Hemorrhagic and thromboembolic complications.

Results: In 1950 patient-years of follow-up, there were 1332 bleeding events (4 were classified as fatal, 31 as life-threatening, 226 as serious, and 1071 as minor). The cumulative incidence of fatal bleeding was 1% at 1 year and 2% at 3 years. The cumulative incidences of first episodes of life-threatening and serious bleeding at 1, 2, 4, and 8 years were 1%, 2%, 5%, and 9% and 12%, 20%, 28%, and 40%, respectively. Of 156 patients who had a serious or life-threatening hemorrhage, 32% suffered a recurrence, typically within 1 year. Independent predictors of a first episode of serious bleeding included a mean prothrombin time ratio (PTR) of 2.0 or more during the course of treatment (relative risk, 3.0; 95% CI, 1.9 to 4.7); recent initiation of warfarin therapy (relative risk during the first 3 months compared with the rest of the first year, the second year, and anytime thereafter, 1.9 [CI, 1.3 to 3.0], 3.0 (CI, 1.8 to 4.8), and 5.9 [CI, 3.8 to 9.3], respectively); variability of the PTR over time (relative risk for the highest compared with the lowest tertile, 1.6 [CI, 1.2 to 2.7]); and the presence of 3 or more comorbid conditions (RR, 1.4 [CI, 1.1 to 2.5]). Age, reason for anticoagulation, use of interfering drugs, and hypertension were not associated with risk for bleeding. The risk for a thromboembolic complication at a PTR of less than 1.3 was 3.6 (CI, 2.1 to 6.4) times higher than at a PTR of 1.3 to 1.5.

Conclusions: The incidence of warfarin-associated bleeding may be reduced by attending to modifiable risk factors (that is, highly variable PTRs and values greater than 2.0), frequent monitoring early in treatment, and careful patient selection. Older age, in and of itself, is not a risk factor.


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Figure 4.
Cumulative incidence of serious bleeding by mean prothrombin time ratio <2. 0 or ≥ 2.0 before the bleeding event.

PTR = prothrombin time ratio.

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Figure 1.
Distribution of follow-up durations.

Distributions are based on the percentage of courses of therapy.

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Figure 3.
Cumulative incidence of recurrent serious or life-threatening hemorrhage after an initial serious or life-threatening hemorrhage.
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Figure 5.
Cumulative incidence of serious bleeding among patients taking warfarin for 12 or more weeks who had low, moderate, or high variability in the prothrombin time ratio before the bleeding event.

(See text for explanation of variance growth rate).

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Figure 2.
Cumulative incidence of serious (top panel), life-threatening (middle panel), and fatal bleeding (bottom panel) events.

Note the differences in ordinate scales.

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