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ATLANTA -- Apixaban taken for an additional year after a standard course of treatment for venous thromboembolism (VTE) reduced recurrent events in a placebo-controlled trial, researchers said.

The extended treatment with apixaban, an oral inhibitor of factor Xa, was associated with death or recurrent VTE in about 4% of patients receiving either of two doses, compared with 12% in patients assigned to placebo (P<0.001), according to Giancarlo Agnelli, MD, of the University of Perugia in Italy, and colleagues.

Results of the 2,842-patient Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy–Extended Treatment (AMPLIFY-EXT) trial were presented here at the American Society of Hematology (ASH) annual meeting and published simultaneously online in the New England Journal of Medicine.

The study also found that rates of major bleeding were lower with apixaban than placebo, although clinically relevant but nonmajor bleeding events were somewhat more common in patients taking the active drug.

Apixaban remains investigational in the U.S., but has been approved in Europe and Canada for preventing stroke and systemic embolism in patients with atrial fibrillation and also for VTE prevention following joint surgery. The FDA is to decide on U.S. approval for the former indication by March 2013.

The drug has had something of a checkered history in clinical trials, failing to show a benefit over a standard anticoagulant drug in one study and apparently increasing bleeding risk in two others.

But it has shown enough efficacy in other trials for indications currently treated with warfarin or heparin analogues so that eventual U.S. approval is expected. Like the other new oral anticoagulants, rivaroxaban (Xarelto) and dabigatran (Pradaxa), apixaban can be given at a fixed dose without the need for regular monitoring of blood coagulation.

The current study involved patients with an initial episode of VTE who had completed 6 to 12 months of anticoagulant treatment without experiencing a second episode.

At that point, Agnelli and colleagues identified those for whom there was no compelling indication for continuing versus stopping anticoagulant therapy.

These 2,482 patients were randomized in a 1:1:1 ratio to receive placebo, apixaban at 2.5 mg twice daily (the prophylactic dose), or apixaban at 5 mg twice daily (the dose for treating a VTE episode) for 1 year.

The primary endpoint was a composite of symptomatic recurrent VTE (deep vein thrombosis or pulmonary embolism) and all-cause death.

Rates of the primary endpoint were 3.8% with low-dose apixaban, 4.2% with the higher dose, and 11.6% with placebo.

Relative to the placebo group, relative risks for the primary endpoint for the low and high apixaban doses were 0.33 (95% CI 0.22 to 0.48) and 0.36 (95% CI 0.25 to 0.53), respectively.

Recurrent VTE episodes drove the primary outcome, as only about 10% of the endpoint events were deaths. These included one in the low-dose apixaban group, four in the high-dose arm, and nine in the placebo group.

Other efficacy outcomes, such as a composite of all cardiovascular events including major bleeds, clearly favored apixaban at both doses with no difference between them.

Subgroup analysis using another secondary outcome measure, a composite of VTE recurrence and VTE-related death, found no significant differences in efficacy among patients stratified by age, gender, renal impairment, body weight, or type of index event.

Major and clinically relevant nonmajor bleeding events were distributed as follows, as percentages of the study arm affected:

• 2.5 mg apixaban: 0.2% major, 3% nonmajor
• 5 mg apixaban: 0.1% major, 4.2% nonmajor
• Placebo: 0.5% major, 2.3% nonmajor

For the clinically relevant nonmajor events, rates with the 5-mg dose were significantly higher than for placebo (RR 1.82, 95% CI 1.05 to 3.18).

The very small numbers of major bleeding events ( seven overall) meant that the differences between arms were not statistically significant.

Agnelli and colleagues also looked at events occurring during the 30 days after the trial ended and patients had stopped the study drugs. They found recurrent VTE during this period in two patients in the placebo group, three in the low-dose apixaban group, and five in the high-dose group.

At an ASH press briefing, Agnelli said the balance of efficacy and safety was most easily appreciated by comparing numbers needed to treat with the corresponding number needed to harm.

He estimated that treating 14 patients with extended apixaban would prevent one episode of fatal or nonfatal VTE. In contrast, 200 patients would have to be treated to cause one episode of major or clinically relevant nonmajor bleeding, Agnelli said.

He also indicated that, clinically, the lower dose would be preferable. "The 5-mg dose had no advantage," he said.

ASH press briefing moderator Agnes Lee, MD, of the University of British Columbia in Vancouver, B.C., who was not involved in the study, said it "proves that apixaban is highly effective [and] highly safe for patients with venous thromboembolism."

She added that it may be especially attractive in patients with renal impairment. Compared with rivaroxaban and dabigatran, "apixaban is least dependent on renal clearance," Lee said, making it potentially a better option in patients with impaired kidney function.

From the American Heart Association:

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