Low-Molecular-Weight Heparin and Mortality in Acutely Ill Medical Patients

Study Questions:

Is the use of low molecular weight heparin for thromboprophylaxis associated with a reduction in mortality in acutely ill medical patients?

Methods:

The authors reported the results of LIFENOX, a double-blind, placebo-controlled, randomized trial of subcutaneous enoxaparin (40 mg daily) versus placebo (during hospitalization—10 ± 4 days—for either heart failure, active cancer, or severe systemic infection, in addition to at least one of the following: chronic pulmonary disease, obesity [body mass index ≥30], history of venous thromboembolism, or age greater than 60 years). The study was conducted at 193 sites in China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia. The primary efficacy outcome was rate of death from any cause at 30 days after randomization. Rate of major bleeding up to 48 hours after treatment period was also reported.

Results:

This study randomized 8,307 patients to receive enoxaparin plus elastic compression stockings (n = 4,171) or placebo plus elastic compression stockings (n = 4,136), in the intention-to-treat population. Mortality from any cause was 4.9% versus 4.8% in the enoxaparin versus placebo groups, respectively (relative risk [RR], 1.0; 95% confidence interval [CI], 0.8-1.2; p = 0.83). Major bleeding rate was 0.4% versus 0.3% in the enoxaparin versus placebo groups, respectively (RR, 1.4; 95% CI, 0.7-3.1; p = 0.35).

Conclusions:

The authors concluded that the use of enoxaparin plus elastic compression stockings, as compared with elastic compression stockings alone, was not associated with a reduction in the rate of death from any cause among hospitalized, acutely ill medical patients.

Perspective:

Data from prior studies clearly demonstrate that risk of venous thromboembolism and pulmonary embolism are increased in patients hospitalized for acute medical illness, though not nearly so much as patients hospitalized for surgical procedures. Although the risk is lower in medical patients, because of their larger numbers, the majority of pulmonary embolism cases occur in acutely ill medical, rather than surgical, patients. Prior studies have also clearly demonstrated that rates of venous thromboembolism, as documented by objective testing, are reduced in acutely ill hospitalized medical patients through the use of low molecular weight heparin prophylaxis. Nonetheless, medical thromboprophylaxis has not been shown to reduce mortality, and, possibly as a result, continues to be significantly underused. The current study attempted to determine if medical thromboprophylaxis use is associated with a reduction in mortality, in a very large randomized trial among acutely ill hospitalized medical patients. Despite the large size of this study, no difference in mortality could be discerned. This suggests that either the mortality reduction with medical thromboprophylaxis is too small (or absent) to be detected in this large study, or the study design led to possibly erroneous findings. Although intended to be definitive, the study raises many questions. First, the mortality rate observed was very low. Furthermore, the overwhelming majority of patients were enrolled in Asian countries, where the rate of venous thromboembolism is known to be much lower than in western nations. We are therefore left with the conundrum of knowing that medical thromboprophylaxis is effective at preventing venous thromboembolism, but appears, in this study, to be associated with no reduction in mortality. Further study is clearly warranted.

Clinical Topics: Anticoagulation Management, Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Acute Heart Failure

Keywords: Risk, Neoplasms, Republic of Korea, Stockings, Compression, Pulmonary Embolism, Heparin, Venous Thromboembolism, Pressure, Mexico, Philippines, China, Body Mass Index, Malaysia, Enoxaparin, Cardiology, Heart Failure, India, Cardiovascular Diseases, Tunisia, Obesity, Confidence Intervals, Hemorrhage, Lung Diseases


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