A Comparison of Low-Molecular-Weight Heparin With Unfractionated Heparin for Acute Pulmonary Embolism - THESEE


The goal of this study was to assess the safety and efficacy of anticoagulation with tinzaparin, a low-molecular-weight heparin (LMWH), compared to unfractionated heparin among patients with acute symptomatic pulmonary embolism.


Because LMWH was known to be at least as effective as unfractionated heparin in the treatment of deep venous thrombosis, it was hypothesized that the same would be true for the use of LMWH in the setting of acute pulmonary embolism.

Study Design

Study Design:

Patients Screened: 1,482
Patients Enrolled: 612
Mean Follow Up: 90 days
Mean Patient Age: Mean 67 years
Female: 55

Patient Populations:

Individuals over the age of 18 who presented with acute pulmonary embolism documented by pulmonary angiography, high probability ventilation-perfusion imaging, or by intermediate probability ventilation-perfusion imaging and a deep venous thrombosis diagnosed by venography or ultrasound were eligible.


Exclusion criteria for this study included the presence of a massive pulmonary embolism requiring pulmonary embolectomy or thrombolysis, contraindications to anticoagulation therapy, life expectancy <3 months, severe renal or hepatic disease, anticipated problems with compliance, and pregnancy.

Primary Endpoints:

The combined primary endpoint was the incidence of recurrent thromboembolism, major bleeding, and death at eight and 90 days.

Secondary Endpoints:

The secondary endpoint was the change in scintigraphically detectible pulmonary vascular obstruction between day 1 and day 8.

Drug/Procedures Used:

Eligible patients were randomized to receive either LMWH or unfractionated heparin. Those randomized to LMWH received tinzaparin at a fixed dose of 175 international antifactor Xa U/kg subcutaneously once daily. Those randomized to the unfractionated heparin arm received an initial bolus of 50 IU/kg followed by an infusion at a rate adjusted to keep the activated partial thromboplastin time 2-3 times the control value. The study medication was continued until the international normalized ratio on oral anticoagulation therapy was >2.0 on two consecutive measurements made at least 24 hours apart and after at least five days of therapy with the study medication.

Concomitant Medications:

Oral anticoagulation therapy was initiated in all patients between the first and third day after initiation of the study medication, and the dose was titrated to an international normalized ratio of 2.0 to 3.0. Oral anticoagulation was continued for at least three months.

Principal Findings:

In the first eight days, the incidence of the combined primary endpoint of recurrent thromboembolism, major bleeding, and death was not significant in patients receiving unfractionated heparin and those receiving tinzaparin (2.9% vs. 3.0%; absolute difference 0.1%; 95% confidence interval [CI] -2.7% to 2.6%). This difference remained nonsignificant at 90-day follow-up (7.1% vs. 5.9%; absolute difference 1.2%; 95% CI -2.7% to 5.1%; p=0.54).

During the entire follow-up period, there was no significant difference between unfractionated heparin and tinzaparin in the individual endpoints of death (4.5% vs. 3.9%, absolute difference 0.6%; 95% CI -2.6% to 3.8%), recurrent thromboembolism (1.9% vs. 1.6%; absolute difference 0.3%; 95% CI; -1.8% to 2.4%), or major bleeding (2.6% vs. 2.0%; absolute difference 0.6%; 95% CI -1.8% to 3.0%).


Among patients with acute pulmonary embolism, LMWH was not associated with a significant difference in the primary combined or individual endpoints of death, major bleeding, or symptomatic recurrent thromboembolism at eight and 90 days compared to unfractionated heparin.


Simonneau G, Sors H, Charbonnier B, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire. N Engl J Med 1997;337:663-9.

Clinical Topics: Anticoagulation Management, Noninvasive Imaging, Vascular Medicine, Angiography, Nuclear Imaging

Keywords: Follow-Up Studies, Pulmonary Embolism, Heparin, Low-Molecular-Weight, Fibrinolytic Agents, Perfusion Imaging, International Normalized Ratio, Thromboembolism, Phlebography, Partial Thromboplastin Time, Venous Thrombosis, Probability, Confidence Intervals

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