Does Enoxaparin Prophylaxis Really Help Most Hospitalized Patients?
A huge randomized trial (LIFENOX) stunned experts by showing no benefit of enoxaparin prophylaxis in preventing pulmonary embolism or all-cause mortality in acutely ill medical patients, compared to knee-length graduated compression stockings alone. Ajay Kakkar, Claudio Cimminiello, Jean-Francois Bergmann et al report their surprising results in the December 29 New England Journal of Medicine.
Investigators randomized 8,323 acutely ill medical patients to receive enoxaparin 40 mg once daily or placebo, in addition to knee-length graduated compression stockings (both groups). All got treated for 10 (+/- 4) days; patients with short stays continued to get enoxaparin at home to ensure parity. This took place at 193 sites outside the U.S. (in China, India, Korea, Mexico, the Phillipines, and Tunisia) from 2008-2011. Sanofi (makers of Lovenox) financed the LIFENOX study.
LIFENOX's findings are as simple as they are startling, especially for those of us who have been trained on the necessity of chemoprophylaxis in nearly all hospitalized patients. Enoxaparin had little detectable effect, either for health or harm, in acutely ill medical patients at 30 or 90 day follow-up:
- No difference in all-cause mortality (4.9% vs. 4.8%)
- No difference in the rate of fatal pulmonary embolism (1 patient in each group)
- No difference in the rate of major hemorrhagic events, although enoxaparin trended toward harm (0.4% vs. 0.3%), and enoxaparin caused more minor bleeding (defined as less than 2 units transfused).
Investigators reached their enrollment target of 8,300, but because the death rate was 5% rather than the expected 7% in the placebo arm, their power to detect a 20% difference in mortality between groups fell to 57%.
Comprehensive identification of the incidence of asymptomatic deep vein thrombosis or nonfatal pulmonary embolism was beyond the scope of the study. There was no difference in the rate of symptomatic deep vein thrombosis, but the very low rates suggest underreporting by participating centers.
These counterintuitive results of course need confirmation, perhaps in a higher-risk patient group (this group was generally at lower risk, being younger, mostly cancer-free, hospitalized for infection, and generally without previous history of venous thromboembolism). But they also highlight the possible pitfalls of using surrogate measures as metrics of quality of care. Thromboprophylaxis saves lives in orthopedic patients, but out of 9 trials of pharmacologic thromboprophylaxis in medical patients, only one showed a mortality benefit ... in 1982.
What do we really know about chemoprophylaxis of DVT/PE? Heparin prophylaxis prevents asymptomatic, surveillance-detected deep venous thrombosis in hospitalized medical patients. And people with untreated proximal DVTs (some of which are asymptomatic) die more often than those without it. That makes prophylaxis for all hospitalized patients logical, but (as this trial shows) any real benefits are unproven. Medical educators have managed to teach legions of physicians that deep venous thrombosis = pulmonary embolism, but the truth is far more complex.
This study's results are maybe not as surprising when examined in the wake of the EXCLAIM, MAGELLAN, and ADOPT trials -- all were attempts to extend the indication of enoxaparin and other anticoagulants in acutely medically ill patients to include continued prophylaxis after hospital discharge. None showed a meaningful risk-benefit profile after factoring in the excess hemorrhages.
Clinical Takeaway: Regardless of the power limitations of this trial, it suggests that in medically ill patients at moderate risk for DVT, the number needed to treat with enoxaparin prophylaxis to prevent one death from pulmonary embolism is very, very high. It also highlights the dearth of large studies with patient-important outcomes to support the use of current therapies and quality metrics in the U.S. As this was a non-U.S. population, it's hard to extrapolate these findings to our system and centers. The results in this low-to-moderate risk population should by no means be extended to critically ill patients, who (the best evidence suggests) have a high risk for DVT and pulmonary embolism, and should receive pharmacologic prophylaxis unless contraindicated.
Kakkar AK et al. Low-Molecular-Weight Heparin and Mortality in Acutely Ill Medical Patients. N Engl J Med 2011;365:2463-2472.