Amsterdam, the Netherlands - The oral factor Xa inhibitor apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) was as effective as standard enoxaparin plus warfarin in treating acute venous thromboembolism (VTE) in a large randomized trial, one in which treatment with apixaban also led to a 69% drop in risk of major bleeding complications [1].
"The efficacy of apixaban in the patients with pulmonary embolism was similar to that in patients with deep vein thrombosis [DVT], and the relative effect was maintained in the approximately 40% of patients who presented with extensive disease," write Dr Giancarlo Agnelli (University of Perugia, Italy) and associates, in the New England Journal of Medicine.
Their report on the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial, conducted at 358 centers in 28 countries, was slated for publication July 1, 2013 in conjunction with the study"s scheduled presentation here at the 2013 Congress of the International Society on Thrombosis and Haemostasis. The New England Journal of Medicine lifted its embargo on AMPLIFY coverage on June 30, following, it said, an embargo break by Reuters.
"After 60 years of warfarin, it is an exciting time in thrombosis care," writes Dr Mary Cushman (University of Vermont, Burlington) in an accompanying editorial [2]. However, "shifting with care to new treatments is essential to safe and effective practice." She cautions that "new anticoagulants are not for every patient" and notes developments that have helped make warfarin management less burdensome, including the advent of prothrombin-time self-testing, anticoagulation clinics, and reduced monitoring frequency for some patients.
Also, she notes, a lot remains to be learned about the new oral agents, apixaban along with dabigatran (Pradaxa, Boehringer Ingelheim) and rivaroxaban (Xarelto, Bayer/Johnson & Johnson), including reversal strategies, monitoring (eg, in the presence of interacting drugs, extremes of patient weight, or bleeding or thrombosis complications), [and] approaches to treatment failure."
The trial randomized 5395 patients with acute, symptomatic proximal VTE and/or pulmonary embolism (PE) to receive, with double blinding, either apixaban (n=2691) or subcutaneous enoxaparin followed by warfarin (n=2704). The factor Xa inhibitor was given as 10 mg twice daily for seven days followed by 5 mg twice daily for six months; enoxaparin was given for at least five days (median 6.5 days), with warfarin continued for six months.
The primary efficacy outcome was seen in 2.3% of patients taking apixaban and 2.7% of those on conventional therapy, which handily met the prespecified criteria for apixaban noninferiority (p < 0.001). The results were nearly identical in each of the two VTE subgroups: those who entered with DVT and those who had PE.
Major bleeding occurred in 0.6% of the apixaban and 1.8% of the conventional-therapy groups, for a 69% drop in relative risk with the factor Xa inhibitor (p < 0.001 for superiority). The composite of major bleeding or clinically relevant nonmajor bleeding fell by 56% (p < 0.001 for superiority). VTE recurred within 30 days in 0.2% and 0.3%, respectively.
Relative risk (95% CI) for outcomes apixaban vs conventional therapy
| End points | RR (95% CI) | ||
| First recurrent VTE or VTE-related death* | 0.84 (0.60-1.18) | ||
| Major bleeding | 0.31 (0.17-0.55) | ||
| Major or clinically relevant nonmajor bleeding | 0.44 (0.36-0.55) | ||
| Death during treatment period | 0.79 (0.53-1.19) | ||
| VTE or CV death | 0.80 (0.57-1.11) | ||
| VTE, VTE-related death, or major bleeding | 0.62 (0.47-0.83) | ||
| ---------------------------------- *Primary efficacy outcome |
"The efficacy and safety of apixaban were consistent across a broad range of subgroups, including those based on clinically important features such as an age of more than 75 years, a body weight of more than 100 kg, use of parenteral anticoagulant treatment before randomization, and the duration of such treatment," suggesting that the findings are likely generalizable across a broad spectrum of patients, according to the group. The findings at participating centers where warfarin-treated patients were more often maintained in a therapeutic INR range were also consistent with trial"s overall results, they write.
"On the basis of the results of this trial, together with those of the [AMPLIFY-EXT] trial, apixaban provided a simple, effective, and safe regimen for the initial and long-term treatment of venous thromboembolism."
In AMPLIFY-EXT, as heartwire reported late last year, the risk of recurrent VTE or death was significantly reduced among patients who completed a full six-month course of anticoagulation for VTE and then stayed on apixaban another six to 12 months, so-called extended therapy for VTE, compared with anticoagulated patients who were then given placebo.
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