Which Type of Heparin for Acute Pulmonary Embolism?
ABSTRACT & COMMENTARY
Synopsis: In this study of patients with acute pulmonary thromboembolism who were hemodynamically stable, low-molecular weight heparin was as efficacious as standard unfractionated heparin with respect to acute complications, mortality, and recurrence.
Source: Simonneau G, et al. N Engl J Med 1997;337: 663-669.
This study was a randomized, controlled unblinded study carried out in 57 European medical centers. Consecutive patients diagnosed with acute pulmonary embolism (positive pulmonary angiography, high-probability ventilation-perfusion scan, or indeterminate scan with deep venous thrombosis documented by venography or compression ultrasonography) were randomized to either 175 international anti-factor Xa units/kg of tinzaparin daily or unfractionated heparin given as a bolus of 50 IU/kg followed by continuous infusion of 500 IU/kg per day. Activated partial thromboplastin time (PTT) was monitored in the unfractionated heparin group, and the heparin dose was titrated to a PTT of 2-3 times the control value. All patients were started on oral anticoagulant therapy between the first and third day of heparin therapy and continued for three months.
Out of 1482 consecutive patients with pulmonary embolism who met the criteria for enrollment, 766 were excluded: 232 patients had "massive pulmonary embolism" requiring thrombolytics or inferior vena cava filter placement, 81 had contraindications to anticoagulant therapy, 266 had received previous anticoagulant therapy in the prior 24 hours, 51 had a life expectancy of less than three months (an exclusion criterion), 101 had "any reason that rendered follow-up impracticable," and 35 were excluded for unspecified reasons. A further 104 patients refused to participate, leaving 612 patients for randomization. There were no differences between treatment groups with regard to age, gender, predisposing factors, or clinical symptoms. Of note, the pulmonary emboli were large in both groups: the mean pulmonary vascular obstruction was 46 ± 21% in the unfractionated heparin group and 47 ± 20% in the low-molecular weight hepain (LMWH) group, and severe symptoms such as right heart failure, syncope, cyanosis, and cardiovascular collapse occurred in 27% and 29% of patients, respectively.
At eight days and at 90 days there were no significant differences between the two treatment groups in any of the three endpoints. Total mortality at 90 days follow-up was 4.5% in the unfractionated heparin group and 3.9% in the LMWH group. This difference was not statistically significant. The rate of major bleeding at days 1-8 was 5% and 3%, respectively, and 4% and 2% for days 9-90, respectively. Recurrent thromboembolism was documented in 1.9% of the patients treated with unfractionated heparin and in 1.6% of those treated with LMWH. Heparin-induced thrombocytopenia occurred in only one patient who was receiving unfractionated heparin. Simonneau and colleagues conclude that patients with a hemodynamically stable pulmonary embolism may be treated with LMWH.
COMMENT BY MARK T. GLADWIN, MD
Both unfractionated heparin and LMWH are glycosaminoglycans containing pentasaccharide sequences that bind to antithrombin. Antithrombin binds to and inhibits both Factor Xa and Thrombin (IIa). This inhibitory effect is dramatically enhanced when heparin is bound to antithrombin. LMWH is smaller than unfractionated heparin (5000 kD vs 3000-30,000 kD) and binds Factor Xa to a greater extent than to thrombin. The major advantage of LMWH over unfractionated heparin lies in its pharmacokinetics. LMWH has decreased binding to plasma proteins, endothelial cells, and macrophages, and is cleared renally in a dose-independent fashion. These factors explain its greater bioavailability, prolonged half-life, and more predictable anticoagulant effect than standard, unfractionated heparin. Laboratory monitoring is not necessary unless a patient has renal insufficiency or weight less than 50kg or more than 80kg, in which case plasma anti-factor Xa concentrations should be measured (Weitz JI. N Engl J Med 1997;337:688-698).
Heparin induced thrombocytopenia (HIT) is a complication of heparin therapy characterized by thrombocytopenia and thrombosis. Heparin and platelet factor 4 complexes form on the platelet surface, giving rise to antiplatelet antibodies. The antibody coated platelets are consumed by the reticuloendothelial system in the spleen and form platelet clots. HIT occurs de novo less frequently in patients treated with LMWH than in those treated with unfractionated heparin (Warkentin TE, et al. N Engl J Med 1995;332:1330-1352), but LMWH should not be used in patients who already have HIT because there is substantial cross reactivity between the antibody and LMWH.
Studies have demonstrated that LMWH is superior to or as effective as low-dose unfractionated heparin for DVT prophylaxis after general surgery, orthopedic surgery (more effective than warfarin after total knee replacement), acute spinal cord injury, trauma, and for elderly and general medical patients. For prophylaxis, LMWH is dosed hours prior to surgery and then once daily without laboratory monitoring.
It has proven as effective as unfractionated heparin for the treatment of DVT, unstable angina, and now pulmonary embolism. The reader is referred to a recent comprehensive review for doses and preparations of LMWH (Weitz JI. N Engl J Med 1997;337:688-698).
The current study by Simonneau et al suggests that we can now add pulmonary embolism to the growing list of thrombotic disorders effectively treated with LMWH. This study was funded by the makers of tinaparin and has a few limitations, namely a lack of blinding (difficult to do with differing monitoring plans) and the exclusion of a large number of patients for both specified and unspecified reasons.
The exclusion of 232 patients with "massive pulmonary embolism" (undefined, with 177 "requiring" thrombolytic therapy) limits the applicability of this study to patients with more stable hemodynamics, although it is important to note that 28% of patients had symptoms suggesting a severe pulmonary embolism (defined above). It also calls attention to an aggressive practice of thrombolytic use that is to date unsupported by large clinical trials.