Physicians' Academy for Cardiovascular Education

AMPLIFY-EXT: apixaban for prevention of venous thromboembolism

Literature - Agnelli G, Buller HR, Cohen A, et al. - N Engl J Med 2013;368:699-708


Apixaban for Extended Treatment of Venous Thromboembolism


Agnelli G, Buller HR, Cohen A, et al.
N Engl J Med 2013;368:699-708


Background

Venous thrombo-embolism is the third most common cause of vascular disease-related deaths [1]. The mainstay of treatment is anticoagulation; guidelines recommend therapy for 3 months or longer [2,3]. Although warfarin is effective for the prevention of recurrent venous thromboembolism, the concerns about bleeding, coupled with the inconvenience of laboratory monitoring and dose adjustments, are difficult for long-term treatment.
Apixaban is an oral factor Xa inhibitor administered in fixed doses without the need for laboratory monitoring and dose adjustments. At a dose of 5 mg twice daily, apixaban has  been shown to be effective for the prevention of stroke in patients with atrial fibrillation, and at a dose of 2.5 mg twice daily, it has been shown to be effective for thromboprophylaxis after major orthopedic surgery ‘5-7].
In the AMPLIFY-EXT  study,  2,486 VTE patients were randomized to either  placebo or apixaban (2,5 or 5 mg twice daily) for an additional 12 months after completing an initial standard anticoagulation regimen for 6-12 months.


Main results:

At both doses, apixaban treatment was associated with a large reduction in clinical events and no increase in major bleeding events.

Recurrent VTE (fig. 1):
  • 1.7% for low-dose apixaban versus 1.7% for high-dose apixaban versus 8.8% for placebo, RR 0.19 (0.11-0.33) for low-dose apixaban and 0.20 (0.11-0.34) for high-dose apixaban

Major or clinically relevant bleeding (fig. 2):
  • 3.2% for low-dose apixaban versus 4.3% for high-dose apixaban versus 2.7% for placebo, RR 1. 20 (0.69-2.10) for low-dose placebo and 1.62 (0.96-2.73) for high-dose apixaban


Conclusion:

Both the 2.5-mg dose and the 5-mg dose of apixaban reduced the risk of recurrent venous thromboembolism (fatal or nonfatal). These benefits were observed with rates of major bleeding that were low and similar to those in the placebo group.


Editorial comment [7]:

” For patients at higher risk for recurrent VTE, the new targeted anticoagulants are attractive alternatives to warfarin. The finding that a low prophylactic dose of apixaban has the same efficacy as the full therapeutic dose, with no increased risk of major bleeding, may tip the risk-to-benefit ratio in favor of extended treatment for this patient population. The wide therapeutic window of this agent enables use of a lower dose that retains great efficacy with no or only a minimal increase in bleeding.”
 

Figure 1. Kaplan–Meier Cumulative Event Rates.

Kaplan–Meier cumulative event rates are shown for the composite secondary efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death

Figurer 2. Kaplan–Meier Cumulative Event Rates.

Kaplan–Meier cumulative event rates are shown for the secondary safety outcome of the composite of major or clinically relevant nonmajor bleeding

Link full article

http://www.nejm.org/doi/full/10.1056/NEJMoa1207541



References:

1. Goldhaber SZ, Bounameaux H. Pulmonary embolism and deep vein thrombosis. Lancet 2012;379:1835-46.
2. Torbicki A, Perrier A, Konstantinides S, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008;29:2276-315.
3. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:Suppl:e419S-e494S.
4. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
5. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17.
6. Raskob GE, Gallus AS, Pineo GF, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip or knee replacement: pooled analysis of major venous thromboembolism and bleeding in 8464 patients from the ADVANCE-2 and ADVANCE-3 trials. J Bone Joint Surg Br 2012;94:257-64.
7. Connors JM. Extended Treatment of Venous Thromboembolism N Engl J Med 2013; 368:767-769


Abstract

Background:
Apixaban, an oral factor Xa inhibitor that can be administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism.

Methods:
In this randomized, double-blind study, we compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy. The study drugs were administered for 12 months.

Results:
A total of 2486 patients underwent randomization, of whom 2482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval [CI], 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P<0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group.

Conclusions:
Extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding.

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