1+1=1? The LIFENOX Trial and the Unpredictable Math of Prevention

Posted by John Staples • December 28th, 2011

If an ounce of prevention is worth a pound of cure, what are two ounces of prevention worth? While a student of algebra might confidently answer “Two pounds of cure,” an economist might mutter something about the marginal utility of additional units of prevention. Who is correct might depend entirely on the situation under study.

For the LIFENOX trial investigators, the “two ounces of prevention” under study were a combination of physical and pharmacologic venous thromboembolism prophylaxis. They asked: Among hospitalized, acutely ill medical patients, does the combination of Graduated Elastic Stockings (GES) and pharmacologic thromboprophylaxis with a low-molecular-weight heparin prevent more fatal pulmonary emboli than the use of GES alone?

Professor Lord Ajay Kakkar (Thrombosis Research Institute and University College London, London, UK) and his LIFENOX trial colleagues hypothesized that it would. Eligible patients had to be ≥40 years of age and recruited within 48 hours of hospitalization for heart failure, active cancer, or severe systemic infection. Following enrollment, 8323 patients from 193 centers were randomized to GES-plus-enoxaparin (40mg subcutaneous daily) or to GES-plus-placebo for 10+/-4 days. The primary efficacy outcome was thirty-day all-cause mortality and the primary safety outcome was the incidence of major bleeding up to 48 hours after receiving the last dose of study drug.

As published in this week’s NEJM, the results suggest that the addition of daily subcutaneous enoxaparin to GES is not associated with an improvement in 30-day all-cause mortality (4.9% of the GES-plus-enoxaparin group died within thirty days of randomization versus 4.8% of the GES-plus-placebo group; RR 1.0; 95%CI, 0.8-1.2). There was also no difference in the incidence of major bleeding between groups.

Like the aura of disappointment that follows a sporting event that ends in a tie, so-called ‘negative’ trials are sometimes perceived as vaguely unsatisfying. But cardiologist and NEJM executive editor Dr. Gregory Curfman encourages clinicians not to despair.

“I see two important take-home points from this trial. First, it provides a clear signal that, in this setting, the addition of enoxaparin to GES does not save lives. That’s a key message with clinical relevance. Second, this large trial was conducted entirely at sites outside of the United States and Europe, with 74% of enrollees coming from India or China. I think this is an exciting illustration of the growing enthusiasm and capacity for clinical trial research in rapidly-developing economies around the globe.”

So while LIFENOX is a negative trial, these positives should be enough to make anyone smile –  whether algebraist or economist.

One Response to “1+1=1? The LIFENOX Trial and the Unpredictable Math of Prevention”

  1. PGYx says:

    But where is the evidence that GES provides clinically significant GES benefit? The recent Annals of Internal Medicine guideline paper indicates that TED stockings are not beneficial in the prevention of DVT (and in fact promote skin breakdown) and thus are no longer recommended for DVT prophylaxis purposes.