Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Subcutaneous low-molecular-weight heparin for deep-vein thrombosis both reduced recurrence and pulmonary embolism

ACP J Club. 1992 July-Aug;117:6. doi:10.7326/ACPJC-1992-117-1-006

Related Content in this Issue
• Companion Abstract and Commentary: Subcutaneous low molecular weight heparin compared with standard heparin for deep venous thrombosis had similar rates of recurrence and lower mortality and bleeding rates


Source Citation

Prandoni P, Lensing AW, Büller HR, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet. 1992 Feb 22;339:441-5.


Abstract

Objective

To determine the efficacy and safety of subcutaneous low-molecular-weight heparin (LMWH) compared with intravenous standard heparin (SH) in the treatment of deep-venous thrombosis.

Design

Randomized controlled trial with 6-month follow-up.

Setting

University hospital department of internal medicine in Italy.

Patients

Consecutive patients with venographically confirmed proximal deep-venous thrombosis were eligible (n = 211). Reasons for exclusion were suspected pulmonary embolism (n = 10); recent venous thrombosis in the same leg (n = 8); contraindications to heparin or contrast material (n = 8); pregnancy (n = 1); and ongoing anticoagulant treatment (n = 6). 170 patients with a duration of symptoms of ≤ 45 days were randomized. Follow-up was 100%.

Intervention

85 patients were assigned to an intravenous bolus of 100 U/kg body weight unfractionated heparin, followed by a continuous infusion of 35 000 U/d. Partial thromboplastin time (PTT) was maintained at 1.5 to 2.0 times the pretreatment value. 85 patients were randomized to subcutaneous injections, every 12 hours, of 0.5 mL to 0.7 mL of LMWH (Fraxiparine) adjusted for body weight. Oral coumarin, 5 mg/d, was given after 6 days and was adjusted daily to maintain the international normalized ratio (INR) between 2.0 and 3.0. Heparin was discontinued on day 10 if the INR was ≥ 2.0.

Main outcome measures

Recurrence or extension of symptomatic deep-venous thrombosis or fatal and nonfatal pulmonary embolism; severe bleeding up to 48 hours after the end of heparin treatment. End points were determined by 3 blinded, independent adjudicators.

Main results

Recurrence or extension of venous thromboembolism developed in 12 patients (14%) receiving SH compared with 6 patients (7%) in the LMWH group (95% CI for difference -3% to 15%, P = 0.13). During the period of heparin treatment, pulmonary emboli caused 3 deaths in each group (3.5%). Severe bleeding occurred in 3 patients treated with SH (4%) compared with 1 patient (1%) assigned to LMWH (CI for difference -3% to 5%, P > 0.2). The groups did not differ in severe or minor bleeding or mortality when on coumarin.

Conclusion

Fixed-dose, subcutaneous low-molecular-weight heparin was as effective as adjusted-dose intravenous heparin in preventing recurrence or development of pulmonary emboli in patients with deep-venous thrombosis, without greater risk for bleeding.

Source of funding: Not stated.

Address for article reprint: Dr. A.W. Lensing, Academic Medical Centre, F4-237, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.


Commentary

LMWH preparations have potential advantages over SH in the treatment of deep-venous 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.