Negative Data for Apixaban in Extended VTE Prevention

November 13, 2011

Updated November 13, 2011 (Orlando, Florida) – Prolonging prophylaxis for venous thromboembolism (VTE) in medically ill patients with a 30-day course of the new oral anticoagulant apixaban (Bristol-Myers Squibb/Pfizer) was not superior to a shorter six- to 14-day course of subcutaneous enoxaparin--designed to represent standard in-hospital VTE prevention--results of the Apixaban Dosing to Optimize Protection from Thrombosis (ADOPT) trial demonstrate [1].

The findings were reported today in a late-breaking clinical-trial session at the American Heart Association 2011 Scientific Sessions by Dr Samuel Z Goldhaber (Brigham and Women's Hospital, Boston, MA) and published simultaneously in the New England Journal of Medicine.

"The ADOPT trial does not provide evidence to justify a policy of extended prophylaxis in a broad population of medically ill patients after hospital discharge," said Goldhaber in a press conference at the AHA meeting.

However, the ADOPT findings, together with those from similar studies--such as the MAGELLAN trial with rivaroxaban (Xarelto, Bayer/Johnson & Johnson) and EXCLAIM with enoxaparin--show that "it is clear that the risk of VTE increases beyond the time of hospital discharge" in this patient population, they note.

Thus, more precise risk-stratification methods are needed to drill down and "identify a narrower spectrum of medically ill patients who may benefit from extended prophylaxis."

Discussant of the ADOPT trial, Dr Mary Cushman (University of Vermont, Burlington), concurs. "This is an important public-health problem we need to address," she stated. One-half of all VTE events in medically ill patients occur after discharge from the hospital, with an increased risk of VTE remaining for a duration of around three months, she noted, "but we don't understand which patients are at highest risk."

Asked by heartwire if he was disappointed by the results of ADOPT, Goldhaber said no. "I was very proud that the trial investigated the toughest area that remains in VTE prophylaxis. It's clear to me that ADOPT is going to serve the medical community as a turning point on how future trials of extended-duration VTE prophylaxis [in the medically ill] should be designed. It's going to be much simpler."

Most VTE Events Occur in the Medically Ill

While extended-duration anticoagulant prophylaxis for VTE after leaving the hospital is recommended for surgical patients, there is no such advice for acutely ill medical patients, who, at the very most, receive VTE prophylaxis only during their hospital stay, say Goldhaber and colleagues. Yet the majority of VTE events occur in the medically ill.

The ADOPT trial does not provide evidence to justify a policy of extended prophylaxis in a broad population of medically ill patients after hospital discharge.

And Goldhaber noted that the most serious sequela of VTE, pulmonary embolism (PE), is the third most common cardiovascular disease after MI and stroke. "While we have come a long way in reducing the death rate in hospitalized patients," there is still the question of what to do with the medically ill after they leave the hospital. And with patients being discharged earlier and earlier, many of them remain at high risk of VTE events, he stressed.

Only a couple of trials have examined this issue previously, he noted. The first study, EXCLAIM, reported in 2007, found lower rates of VTE with extended prophylaxis with subcutaneous enoxaparin for an average period of 28 days compared with placebo. However, this benefit was offset by a significant increase in major bleeding in the enoxaparin group.

Similarly, the MAGELLAN trial examined extended prophylaxis with 10 mg once daily of the factor Xa inhibitor rivaroxaban compared with short-term prophylaxis with enoxaparin (10 days, 40 mg per day) followed by placebo. Again, lower rates of VTE in the rivaroxaban group were offset by more major bleeding events.

Bleeding More Likely With Apixaban, But Similar to Aspirin

ADOPT is akin to MAGELLAN and examines another new oral factor Xa inhibitor, apixaban, in the medically ill. In the study, 6528 patients who were acutely ill with congestive heart failure, respiratory failure, or other medical disorder and at least one additional risk factor for VTE were randomized to enoxaparin 40 mg subcutaneously once daily for six to 14 days or apixaban 2.5 mg orally, twice daily, for 30 days The trial was a double-dummy design, so those who received enoxaparin also got an oral placebo twice daily and those who were taking apixaban had daily placebo subcutaneous injections in place of enoxaparin.

The primary efficacy outcome was a 30-day composite of VTE-related death, PE, symptomatic deep vein thrombosis (DVT), or asymptomatic proximal-leg DVT, as detected by ultrasound on day 30. The primary safety outcome was bleeding.

Of 4495 evaluable patients, 60 (2.71%) in the apixaban group (n=2211) met the criteria for the primary end point, compared with 70 (3.06%) (patients in the enoxaparin group (n=2284) (relative risk with apixaban 0.87; p=0.44).

Major bleeding was two and a half times more likely in the apixaban group, occurring in 0.47% of patients, compared with 0.19% of those in the enoxaparin group (relative risk 2.58; p=0.04) by day 30. But Goldhaber told heartwire this magnitude of bleeding with apixaban was still pretty low, "the equivalent of what would be expected with aspirin,"

Extended Prophylaxis With Apixaban Still "May Have Promise"

Goldhaber says there are some important factors to take into consideration when interpreting the results of ADOPT. First, "the trial was designed six years ago, when the average hospital stay was much longer--10 days was not that unusual--so it did not seem to us to be a major issue that we were prescribing six to 14 days of enoxaparin," he observed.

ADOPT is going to serve the medical community as a turning point on how future trials of extended-duration VTE prophylaxis should be designed. It's going to be much simpler.

If the analysis is limited to the period after enoxaparin was stopped, only 18 of those receiving extended treatment with apixaban had a primary end point, compared with 31 patients in the enoxaparin group (relative risk with apixaban 0.59), he said.

Second, many patients were lost to follow-up (around 1000 in each group by day 30), because of missing or unevaluable ultrasounds, so the trial "was underpowered."

In the future, he says, "Patients will be enrolled and randomized within a day or two of hospital discharge, and they will be assigned either to the anticoagulant drug or to its placebo; the end point will be symptomatic DVT and PE without assessment for asymptomatic disease on ultrasound.

"That way, the noise of the unevaluable ultrasounds disappears, and we don't artificially distort the two groups by giving the comparator group much more anticoagulant prophylaxis than would ordinarily be given in day-to-day practice.

"Even though our trial was negative, the strategy of extended prophylaxis with apixaban may have promise," the authors conclude in the paper.

Goldhaber reports receiving consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, EKOS, Medscape, Merck, Portola, and Sanofi-Aventis and grant support through his institution from Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, EKOS, Johnson & Johnson and Sanofi-Aventis. He is the author of Clotblog on Disclosures for the coauthors are listed in the paper.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.