Low Molecular Weight Heparin Preferred for Pulmonary Embolism?
Lisa E. Farnett, Pharm.D.
Edited by Henry I. Bussey, Pharm.D.
February, 2004
Review:
Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism; A meta-analysis of randomized, controlled trials.
Qunilan DJ, McQuillan A, Eikelboom JW. Ann Intern Med 2004;140:175-183.
Several studies have evaluated the efficacy of low-molecular-weight heparins (LMWH) in the treatment of symptomatic or asymptomatic pulmonary embolism (PE). Despite the number of publications indicating efficacy of LMWH for treatment of PE, many consider the data inconclusive because the small numbers of patients in the study (over half with less than 100 patients) leads to a lack of statistical power.
By combining the data in a meta-analysis, the authors hoped to increase the power of the studies to show a difference between unfractionated heparin (UFH) and LMWH in the treatment of acute PE. From an extensive search of the literature, 34 potential trials were identified, 12 of which that met the criteria of a randomized controlled clinical trial, using LMWH administered subcutaneously, compared with intravenously administered unfractionated heparin (UFH) in the treatment of symptomatic or asymptomatic PE. These 12 studies included 1,951 patients with pulmonary embolus
Although the meta-analysis showed differences that favored LMWH in most cases, none of these differences were statistically significant (Table 1). However, despite the ability to combine results in the meta-analysis, the problem of a lack of statistical power remained due to the small numbers of events in the study.
The results of this study are consistent with those seen in LMWH treatment of deep vein thrombosis, and present reasonable assurance that LMWHs are safe and effective in the treatment of non-massive pulmonary embolism.
There are several cautions to interpretation of this paper. First, duration of treatment may significantly affect recurrence rates. Although the meta-analysis standardizes the follow-up by looking at data for each patient, patients with shorter treatment courses may have had higher recurrence rates. The paper did not account clearly for this potential variability.
Second, the dose of heparin used may have been inadequate. The advent of more sensitive thromboplastins used in determining the aPTT in recent years has necessitated a change in the accepted therapeutic aPTT range. The accepted range of 1.5-2.0 was determined using the old type of thromboplastins, and current empiric use of this range may not reflect accurate anticoagulation with heparin. It is recommended now that all aPTT assays for heparin be correlated to an anti-Xa level, and the range determined in each lab individually.2,3
Third, different LMWHs were used in the studies. The LMWHs are known to differ pharmacologically, but it is not clear if the differences are clinically significant. The authors took this issue into consideration, and found no effect of heterogeneity to affect the outcomes.
Fourth, the immediate efficacy of LMWH may be a distinct advantage in the first day of treatment. It has been shown that a therapeutic heparin level in the first 24 hours is a significant determinant to decreasing recurrence of venous thrombotic events. At treatment doses, LMWH achieves a therapeutic effect within 4 hours. Unfractionated heparin requires dosage adjustments every 6 hours to achieve the therapeutic goal. The meta-analysis does not examine which unfractionated heparin patients were therapeutic at the 24 hour point. In addition, the potential adverse event of heparin induced-thrombocytopenia (HIT) occurs more often with heparin than with LMWH, but the incidence is very small and difficult to measure with statistical power in small studies. However, HIT poses a real and significant risk to individual patients.
Summary:
While none of the differences were statistically significant, the absolute rates of complications suggest that LMWH is at least as safe and effective as unfractionated heparin in the treatment of PE. This meta-analysis presents the strongest evidence to date that LMWHs are a viable and effective treatment of non-massive pulmonary embolism.
References:
1. Raschke R, Hirsh J, Guidry JR. Suboptimal monitoring and dosing of unfractionated heparin in comparative studies with low-molecular-weight heparin. Ann Intern Med 2003;138:720-3.
2. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2001;119:Suppl:176S-193S.
3. Olson JD, Arkin CF, Brandt JT, et al. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of unfractionated heparin therapy. Arch Pathol Lab Med 1998;122:782-98.
Table 1: Event rates among 1,951 patients
|
Outcome
|
LMWH
n/n (%)
|
UFH
n/n (%)
|
Odds Ratio
(95% CI)
|
|
Any VTE at end of treatment
|
14/1023 (1.4%)
|
22/928 (2.4)
|
0.63 (0.33-1.18)
|
|
Any VTE at 3 mo.
|
30/988 (3.0)
|
39/895 (4.4)
|
0.68 (0.42-1.09)
|
|
DVT at end of treatment
|
1/926 (0.1)
|
7/825 (0.8)
|
0.47 (0.17-1.26)
|
|
DVT at 3 mo.
|
15/891 (1.7)
|
19/792 (2.4)
|
0.64 (0.33-1.25)
|
|
PE at end of treatment
|
13/926 (1.4)
|
14/825 (1.7)
|
0.91 (0.45-1.85)
|
|
PE at 3 mo.
|
16/891 (1.8)
|
20/792 (2.5)
|
0.78 (0.41-1.47)
|
|
Major bleeding
|
14/1023 (1.4)
|
21/928 (2.3)
|
0.67 (0.36-1.27)
|
|
Mortality at end of treatment
|
14/1023 (1.4)
|
11/928 (1.2)
|
1.20 (0.59-2.45)
|
|
Mortality at 3 mo.
|
46/988 (4.7)
|
55/895 (6.1)
|
0.77 (0.52-1.15)
|
|
Note: PE = Pulmonary Embolism, DVT = Deep Vein Thrombosis, VTE = Venous Thromboembolism, generally considered to include both DVT and PE
|
Table adapted from Quinlan DJ, et al. Ann Intern Med 2004; 140:175-183.
|