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The Importance of Initial Heparin Treatment on Long-term Clinical Outcomes of Antithrombotic Therapy:  The Emerging Theme of Delayed Recurrence

Russell D. Hull, MBBS, MSc; Gary E. Raskob, MSc; Rollin F. Brant, PhD; Graham F. Pineo, MD; Karen A. Valentine, MD, PhD
Arch Intern Med. 1997;157(20):2317-2321. doi:10.1001/archinte.1997.00440410049005.
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Background:  Recent clinical trials of venous thromboembolism treatment suggest inadequate initial heparin therapy predisposes patients to late recurrence of thromboembolism. However, a recent review article was unable to demonstrate a relationship between initial heparin therapy and late recurrence.

Objective:  To evaluate the relationship between initial heparin treatment and long-term clinical outcome in 3 consecutive, randomized, double-blind trials that used similar study designs and patient populations and objective documentation of recurrent venous thromboembolism.

Methods:  The trials were performed sequentially and compared the use of continuous intravenous with subcutaneous heparin, continuous intravenous heparin for 10 or 5 days, and continuous intravenous heparin with once-daily subcutaneous low-molecular-weight heparin. All patients were followed up for 3 months to assess the a priori hypothesis that inadequate initial heparin therapy could lead to recurrent venous thromboembolism during long-term therapy with warfarin sodium.

Results:  The following were the observed rates of recurrent venous thromboembolism: continuous intravenous heparin, 3 (5.2%) of 58 patients vs subcutaneous heparin, 11 (19.3%) of 57 patients; continuous intravenous heparin for 10 days, 7 (7.0%) of 100 patients or for 5 days, 7 (7.1%) of 99 patients; and continuous intravenous heparin, 15 (6.9%) of 219 patients vs low-molecular-weight heparin, 6 (2.8%) of 213 patients. Pooled analysis of the patients treated with continuous intravenous heparin showed that of the total 32 patients with recurrent venous thromboembolism, in 6 patients thromboembolism occurred early (<10 days) and in 26 patients thromboembolism occurred late. Of these patients, the majority (20/32 [62.5%]) had therapeutic prothrombin time or international normalized ratio values before or at the time of the recurrent thromboembolic event.

Conclusion:  Our findings demonstrate that the initial heparin treatment affects the long-term outcome. This conclusion applies when these data are analyzed for each individual study by treatment group, observed difference in outcome, and pooled analysis.Arch Intern Med. 1997;157:2317-2321

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