American-Canadian Thrombosis Study

Subcutaneous low-molecular-weight heparin vs. standard heparin in the treatment of proximal DVT (1996)


Initial treatment of acute proximal DVT

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To compare the efficacy and safety of a single subcutaneous injection of fixed-dose low-molecular-weight heparin per day with those of continuous intravenous standard heparin for the initial treatment of proximal DVT

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Trial design

Randomized, double-blind, placebo-controlled study
Active treatment: Tinzaparin 175 anti-factor Xa IU/kg s.c. once daily for 6 days, provided INR was ≥2.0; intravenous UFH placebo (n=213)
Control treatment: UFH 5000 IU i.v. bolus, followed by continuous infusion of 40,320 IU every 24 hours for patients without the designated risk factors for bleeding, and 29,760 IU every 24 hours for patients who had one or more designated risk factors, to target an aPTT of 1.5–2.5 times the control value of 30 s, for 6 days, provided INR was ≥2.0; subcutaneous tinzaparin placebo (n=219)

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Primary efficacy endpoint: symptomatic recurrent VTE during 3-month follow-up
Primary safety endpoints: major and minor bleeding

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Trial participants

432 consecutive symptomatic patients (≥18 years of age) with acute proximal DVT documented by venography

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Efficacy outcome: 6 of the 213 patients assigned to tinzaparin (2.8%) and 15 of the 219 patients receiving standard heparin (6.9%) had new episodes of symptomatic VTE. Time-to-event analysis by the log-rank test showed a significant difference in the frequency of VTE (p=0.049)
Safety outcome: In the tinzaparin group, there were significantly fewer major bleeding complications during initial therapy than in the UFH group (0.5% vs. 5.0%, relative risk reduction 91%). This benefit was lost during long-term therapy. Minor hemorrhages occurred in 7 patients given tinzaparin (3.3%) and in 7 patients given UFH (3.2%). The UFH group had a higher overall mortality: 9.6% (21/219) patients receiving UFH died, as compared with 4.7% (10/213) patients assigned to tinzaparin (relative risk reduction 51%)

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Efficacy: Treatment of proximal DVT with fixed-dose subcutaneous tinzaparin was as least as effective as continuous intravenous treatment with standard heparin but more convenient to administer
Safety: During initial treatment, rates of major bleeding were higher in patients receiving UFH

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Hull RD, Raskob GE, Pineo GF, Green D, Trowbridge AA, Elliott CG, Lerner RG, Hall J, Sparling T, Brettell HR, Norton J, Carter CJ, George R, Merli G, Ward J, Mayo W, Rosenblom D, Brant R. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992;326:975-982

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Corresponding author

Russell D. Hull, MD, University of Calgary, Department of Medicine, Foothills Hospital, 3330 Hospital Drive, N.W., Calgary, AB T2N 4N1, Canada

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