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Therapeutics

Subcutaneous low-molecular-weight heparin compared with standard heparin for deep-venous thrombosis had similar rates of recurrence and lower mortality and bleeding rates

ACP J Club. 1992 July-Aug;117:7. doi:10.7326/ACPJC-1992-117-1-007

Related Content in this Issue
• Companion Abstract and Commentary: Subcutaneous low-molecular-weight heparin for deep-venous thrombosis both reduced recurrence and pulmonary embolism


Source Citation

Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med. 1992 Apr 9;326:975-82.


Abstract

Objective

To evaluate single daily sub-cutaneous injections of low-molecular-weight heparin (LMWH) compared with continuous intravenous standard heparin (SH) for proximal-venous thrombosis.

Design

Randomized, double-blind, controlled trial with 3-month follow-up.

Setting

15 centers in North America.

Patients

Eligibility criteria included ≥ 18 years of age; venographically documented thrombosis of the proximal leg veins; no contraindications to anticoagulant therapy; ≤ 1 previous episode of thrombosis; and no recent treatment with anticoagulants. 432 of 845 consecutive patients met these criteria and were enrolled.

Intervention

219 patients were randomized to intravenous SH, given as a 5000-U bolus, followed by a continuous infusion of 40 320 U/d or 29 760 U/d (depending on the patient's risk for bleeding) and adjusted by a nonstudy physician to maintain partial thromboplastin time (PTT) between 1.5 and 2.5 times the control value. 213 patients were randomized to single daily subcutaneous injections of LMWH (Logiparin), 175 U/kg body weight per day. Patients were also given a placebo alternate treatment. Patients received warfarin for ≥ 3 months beginning on day 2 of heparin therapy at 10 mg/d and adjusted to maintain the international normalized ratio (INR) between 2.0 and 3.0. Heparin was discontinued on day 6 if the INR was > 2.0.

Main outcome measures

Recurrence of symptomatic deep-venous thrombosis confirmed by venography; pulmonary embolism confirmed by lung scanning or angiography; bleeding; and death. End point adjudication was blinded.

Main results

15 patients (7%) on SH and 6 patients (3%) on LMWH had new episodes of venous thromboembolism (95% CI for the difference, 0.02% to 8.1%, P = 0.07). 21 patients (5%) in the LMWH group died compared with 10 patients (5%) in the control group. {This absolute risk reduction (ARR) of 5% means that 20 patients would need to be treated (NNT) with LMWH rather than SH to save 1 additional life, CI 10 to 3608; the relative risk reduction (RRR) was 51% CI 0.3% to 76%.}* Major bleeding was also less in the LMWH group: (0.4% vs 5%, P < 0.05; {ARR 4.6%; NNT 22, CI 12 to 56; RRR, CI 45% to 98%.}*

Conclusions

Treatment for proximal-venous thrombosis with low-molecular-weight heparin given once per day was as effective and safe as intravenous heparin therapy more major bleeding and deaths occured in the standard heparin group.

Sources of funding: Heart and Stroke Foundation of Alberta and Novo Nordisk.

Address for article reprint: Dr. R.D. Hull, University of Calgary, Department of Medicine, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.

*Numbers calculated from data in article.


Commentary

LMWH preparations have potential advantages over SH in the treatment of deep-vein thrombosis because they can be administered subcutaneously as a fixed dose once or twice daily without the need for PTT monitoring. Early studies have shown LMWH to be as effective as SH in preventing thrombosis extension and embolic events. The studies by Prandoni and colleagues and by Hull and colleagues show, in addition, the efficacy of 2 different LMWH preparations in the management of deep-vein thrombosis using the important clinical outcomes of bleeding and recurrent thromboembolic events.

In the first report, during a 6-month follow-up, the investigators found no significant difference in the incidence of symptomatic extension or recurrent thromboembolic events between the patients who received LMWH (7%) and the patients who received SH (14%). It is possible, however, that a clinically important difference was missed because of the small number of patients enrolled in the study. The investigators also reported no significant difference in bleeding (LMWH, 1.1%, vs SH, 3.5%).

For logistic reasons Prandoni did not do a double-blind trial. To avoid bias all patients had repeat venography, lung scanning, and chest radiography at 10 days to determine early extension and recurrent events. Subsequent events, however, were investigated only if the patient had symptoms. Whether tests were done could have been influenced by the physician's knowledge of which drug the patient had received. For this reason caution should be used in accepting any trends in favor of LMWH based on this report.

The second report is a double-blind, randomized trial including a larger patient sample and shows a significant advantage of a LMWH preparation over SH. The investigators found a difference in the incidence of symptomatic recurrent venous thromboembolism between patients who received LMWH (3%) and patients who received SH (7%). Of importance, they also found a significant reduction in the incidence of major bleeding during heparin therapy favoring the LMWH group (LMWH, 0.5%, vs SH, 5.0%), although the incidence of minor bleeding did not differ.

A clinical difference between the 2 reports is the time when warfarin therapy was begun, which influenced the duration of heparin therapy. In the first report, warfarin therapy was started on day 7 of treatment with heparin, and patients received a minimum of 10 days of heparin. In the second report, warfarin was started on day 2, and heparin was given for a minimum of 6 days. 2 previous reports have shown that warfarin therapy may safely be begun between day 1 and day 3 of treatment with heparin (1, 2). This regimen is gradually becoming standard practice.

The results of these clinical trials cannot be applied directly to all LMWH preparations. LMWHs are made by enzymatic or chemical hydrolysis of standard heparin. Each preparation may vary in its molecular weight and availability. For example, LMWH CY 216 (Fraxiparine), used in the first trial, required twice-daily administration as compared with once-daily administration of Logiparin, used in the second report. At present, 5 LMWH preparations are licensed for use in Europe and 3 are being evaluated in North America. The higher cost of LMWH preparations may be partly offset by the potential for outpatient therapy, although studies evaluating the safety of these regimens in outpatient settings have not been reported.

Moira Cruickshank, MD
University HospitalLondon, Ontario, Canada

Moira Cruickshank, MD
University Hospital
London, Ontario, Canada


References

1. Gallus A, Jackaman J, Tillett J, Mills W, Wycherley A. Safety and efficacy of warfarin started early after submassive venous thrombosis of pulmonary embolism. Lancet. 1986;2:1293-6.

2. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med. 1990;322:1260-4.