AHA: VTE study suggests need to ADOPT better trial design for these patients

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ORLANDO, Fla.—In medically ill patients with venous thromboembolism (VTE), an extended course of thromboprophylaxis with apixaban (Eliquis, Bristol-Myers Squibb) was not found to be a superior course with enoxaparin (Lovenox, Sanofi-Aventis) and led to more bleeding in the ADOPT trial, presented Nov. 13 as a late-breaker at the 2011 American Heart Association (AHA) conference. However, the study was ultimately underpowered because one-third of the patients were not included in the final results.

“Pulmonary embolism [PE] is the third most common cardiovascular disease, after MI and stroke. The condition causes between 100,000 and 180,000 deaths per year in the U.S. alone,” said the study’s principal investigator Samuel Z. Goldhaber, MD, of Brigham and Women’s Hospital in Boston, during the press conference. “We’ve come a long way in decreasing the death rate from PE among hospitalized patients. However, the challenge for us remains the discharged patient, as patients are at higher risk of PE after they leave the hospital.” 

The efficacy and safety of prolonging VTE prophylaxis beyond hospital discharge in medically ill patients remains uncertain. The researchers hypothesized that extended use of apixaban would be more effective than short-term use of exonaparin.

The double-blind, double-dummy, placebo-controlled trial featured acutely ill patients with congestive heart failure, respiratory failure or other medical disorders and at least one additional risk factor for VTE. Patients, who were hospitalized with an expected stay of at least three days, were randomly selected to receive apixaban, administered orally at a dose of 2.5 mg twice daily for 30 days, or exonaparin, administered subcutaneously at a dose of 40 mg once-daily for six to 14 days.

The primary efficacy outcome was the 30-day composite of death related to VTE, PE, symptomatic deep vein thrombosis (DVT) or asymptomatic proximal-leg DVT, as detected with the use of systematic bilateral compression ultrasonography at 30 days. The primary safety outcome was bleeding. 

Goldhaber and colleagues enrolled a total of 6,528 subjects who underwent randomization, 4,495 of whom could be evaluated for the primary efficacy outcome—2,211 in the apixaban group and 2,284 in the enoxaparin group. Among the patients who could be evaluated, 2.71 percent in the apixaban group and 3.06 percent in the enoxaparin group met the criteria for the primary efficacy outcome.

By day 30, major bleeding had occurred in 0.47 percent of the patients in the apixaban group and in 0.19 percent of the patients in the enoxaparin group. 

During his presentation, Goldhaber acknowledged that the study was underpowered, primarily because one-third of the ultrasounds were not “evaluable or obtained.” Another limitation of the trial was the fact that enoxaparin was administered at six days or more, even if patients were discharged sooner, which “is not the standard of care,” Goldhaber said. These patients favored better efficacy with enoxaparin than would be expected with ordinary care. Also, ultrasounds obtained at day 10, which also is “not the standard of care, altered the natural history of VTE because ‘silent DVTs’ were identified and treated."

In the New England Journal of Medicine, where the trial was simultaneously published, the ADOPT researchers wrote that the trial “does not provide evidence to justify a policy of extended prophylaxis in a broad population of medically ill patients after hospital discharge. However, with event rates of venous thromboembolism at 30 days … it is clear that the risk of venous thromboembolism increases beyond the time of hospital discharge. More precise risk-stratification methods are needed to identify a narrower spectrum of medically ill patients who may benefit from extended prophylaxis.”

Goldhaber added that it might be beneficial to identify high-risk subgroups that might benefit from extended VTE prophylaxis.

In her review of the ADOPT trial, Mary Cushman, MD, from the University of Vermont in Burlington, concurred with the findings of the ADOPT researchers. She also recommended that future trials develop validated risk models to include only high-risk patients in trials, use treatment with the lowest bleed risk and continue follow-up after treatment.

The study was funded by Bristol-Myers Squibb and Pfizer.