April 08, 2014

Apixaban for Treatment of Venous Thromboembolism: The Holy Grail?

Dr. Bharat Awsare, Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine at Thomas Jefferson University Hospital reviews the results published in the New England Journal of Medicine August 29, 2013 (Agnelli et al. “Oral Apixaban for the Acute Treatment of Venous Thromboembolism.” NEJM 369(9): 799-808).

Warfarin is the most widely used anticoagulant in the world; yet sixty years after it was first approved for human use in the 1950’s, there continues to be a quest for the Holy Grail of anticoagulants: one that is easy to administer, requires no laboratory monitoring, has no drug-drug interactions, and is associated with minimal bleeding risks. 

Non-warfarin oral anticoagulants offer such a promise.  The newest oral anticoagulant is apixaban, a direct Factor Xa inhibitor, which requires no laboratory monitoring and can be given at a fixed dose.  The AMPLIFY trial sought to compare apixaban to conventional therapy for the acute treatment of venous thromboembolism.  Results were published in the New England Journal of Medicine August 29, 2013 (Agnelli et al. “Oral Apixaban for the Acute Treatment of Venous Thromboembolism.” NEJM 369(9): 799-808).

Hypothesis:  Apixaban in non-inferior to conventional therapy for the acute treatment of venous thromboembolism (VTE).

Study design:  Patients were randomized to therapy with fixed dose apixaban (10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months) versus conventional therapy (enoxaparin as a bridge to warfarin for 6 month duration of therapy).  The primary endpoint was symptomatic recurrent VTE or VTE-associated mortality.

Results:  A total of 5395 patients were enrolled.  The primary endpoint of symptomatic VTE occurred in 59 of 2609 (2.3%) in the apixaban group and 71/2635 (2.7%) in the conventional group.  Statistical analysis showed that apixaban was non-inferior to conventional therapy (p<0.001).  However, apixaban was superior to conventional therapy for risk of major bleeding (0.6% vs. 1.8%, relative risk 0.31, p<0.001).  There was also a reduction in all bleeding (4.3% vs. 9.7%, relative risk 0.44, p<0.001).

This study gives a potentially promising therapeutic option for acute treatment of VTE—one that is orally administered, efficacious, requires no laboratory monitoring, and has a low bleeding risk.  So, is this the Holy Grail?  Some caution should probably be exercised for several reasons.

Firstly, there is a lifetime of “real-life” experience with warfarin regarding efficacy, bleeding risk, and drug-drug interactions compared with apixaban.  Although this study showed superiority of apixaban for bleeding risk, the matriculation of its use outside the relatively safe confinements of a clinical study with exclusion criteria requires pause.  There is also experience regarding management of bleeding complications with warfarin compared to the newer agents.

In addition, certain groups were excluded from the study and therefore results may not be generalizable to these groups:  massive pulmonary embolism, renal insufficiency with creatinine clearance less than 25 ml/min, malignancy, and thrombocytopenia are some of these groups.

Lastly, one-third of patients had no qualifying diagnosis of pulmonary embolism.  Nevertheless, despite massive pulmonary being excluded, 37% had “extensive” clot burden identified by imaging.

In totality, apixaban appears to be an effective and attractive option for the treatment of VTE.  In addition, the ease of administration and low bleeding risk make it a potentially superior option for long term anticoagulant therapy.  Of course, phase IV trials as well as pharmacoeconomic data will need to be analyzed in the future to confirm the cost-benefit improvements.

 

Jefferson