Apixaban Treatment for Acute VTE

A fixed-dose regimen of apixaban, an oral factor Xa inhibitor, to treat venous thromboembolism (VTE) demonstrated noninferiority to conventional therapy with enoxaparin and warfarin, according to findings from the AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) trial published online in the New England Journal of Medicine [doi:10.1056/NEJMoa1302507].

Apixaban has demonstrated a rapid onset of action and predictable pharmacokinetics that allow a fixed-dose regimen. The agent has been proven effective for the prevention of acute VTE in patients who have completed 6 to 12 months of anticoagulation therapy.

AMPLIFY was a randomized, double-blind, multicenter study that compared the efficacy and safety of apixaban with conventional therapy in patients with VTE, pulmonary embolism (PE), or both. The study enrolled 5395 patients with objectively confirmed, symptomatic proximal deep vein thrombosis (DVT) or PE from 358 centers in 28 countries from August 2008 through August 2012. Exclusion criteria included patients who had active bleeding, a high risk of bleeding, or other contraindications to treatment with enoxaparin and warfarin.

Patients were randomly assigned to apixaban 10 mg twice daily for the first 7 days, followed by 5 mg twice daily for 6 months (n=2691) or subcutaneous enoxaparin (1 mg/kg of body weight every 12 hours) for at least 5 days plus warfarin for 6 months (n=2704). The warfarin dose was adjusted to maintain the international normalized ratio (INR) between 2.0 and 3.0. Enoxaparin or placebo was discontinued when a blinded INR of 2.0 or more was achieved.

The primary outcome measure was the composite of recurrent symptomatic VTE or death related to VTE. Secondary outcome measures included each component of the primary composite, as well as death from cardiovascular causes and all-cause mortality. The primary safety outcome measure was major bleeding and the secondary safety outcome measure was the composite of major bleeding and clinically relevant nonmajor bleeding.

Data showed that treatment with apixaban led to a recurrent VTE rate of 2.3% (n=59) at 6 months compared with 2.7% (n=71) with conventional treatment (relative risk [RR], 0.84; 95% confidence interval [CI], 0.60 to 1.18). The difference in risk (apixaban minus conventional therapy) was -0.4% (95% CI, -1.3-0.4). Apixaban was noninferior to conventional therapy (P<.001) for predefined upper limits of 95% CIs for RR (<1.80) and the difference in risk (<3.5%).

Major bleeding occurred in 0.6% of patients in the apixaban group and 1.8% of patients in the conventional therapy group (RR, 0.31; 95% CI, 0.17 to 0.55; P<.001 for superiority). Analysis of the composite secondary safety outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the apixaban arm compared with 9.7% of those in the conventional therapy arm (RR, 0.44; 95% CI, 0.36-0.55; P<.001). During the 30-day follow-up period, recurrent VTE occurred in 6 patients (0.2%) who had received apixaban and in 9 patients (0.3%) who had received conventional therapy. The rates of adverse events were similar in the 2 treatment groups.

The researchers said that results are likely to be generalizable to the VTE population. They recruited a wide spectrum of patients, a majority of whom had unprovoked VTE, and the rate of major bleeding and clinically relevant nonmajor bleeding with warfarin were similar to those reported in other studies. They noted that additional information is needed about the safety and efficacy of apixaban in patients with cancer, low body weight, or a creatinine clearance <50 mL per minute.

The results of this study, along with those of the Efficacy and Safety Study of Apixaban for the Extended Treatment of Deep Vein Thrombosis or Pulmonary Embolism, demonstrated that “Apixaban provided a simple, effective, and safe regimen for the initial and long-term treatment of venous thromboembolism,” the researchers concluded.