When a patient in need of anti-coagulation therapy asks about newer, non-warfarin options, physicians often pause. There is a lot to think about here: recent studies on several different novel anticoagulant drugs, nuances of each trial, and FDA-approved indications for each drug. For better or for worse, the pause we take to consider anticoagulation options may be about to get a little longer.
In this week’s NEJM, Agnelli et al. examine the use of apixaban, a Factor Xa inhibitor, for acute venous thromboembolism (VTE) and conclude similar effectiveness and improved safety compared to warfarin therapy.
Titled AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy), this trial enrolled over 5,000 patients with acute VTE. Patients were randomized to receive six months of either apixaban (10mg twice daily for 7 days followed by 5mg twice daily), or conventional therapy (enoxaparin followed by warfarin). The primary efficacy outcome was a composite of recurrent symptomatic VTE or death; there was no significant difference between the two groups. In the apixaban group, 59 of 2609 patients (2.3%) experienced the primary outcome, compared to 71 of 2635 patients (2.7%) in the warfarin group (P<.001 for non-inferiority).
The primary safety outcomes were major bleeding alone and a composite of major bleeding and clinically relevant non-major bleeding. Here, there was a significant difference in safety outcomes between the two groups. The apixaban group had significantly reduced rates of each outcome (0.6% versus 1.8%; 4.3% versus 9.7%; P<.001 for superiority).
While encouraging for those who view warfarin as an outdated and inconvenient therapy, AMPLIFY does little to address the class-wide concerns regarding existing novel anticoagulants. The study population does not include a significant amount of elderly or patients with renal impairment or primary oncologic diagnoses. Given that the INR of the control arm was therapeutic only 61% of the time, one might also argue that instead of spending dollars on novel anticoagulants, we should be investing in novel methods of managing outpatient warfarin dosing and monitoring. Finally, one has to consider how to weigh the value of experience with warfarin versus our relative inexperience with using novel anticoagulants.
For those physicians considering the use of novel anticoagulants, Mary Cushman, M.D., provides an accompanying editorial with some helpful advice.
Table 1: Demographic and Clinical Characteristics of the Patients.
Cushman’s six-part protocol provides an excellent structure for thinking about the nuances of existing literature and how they might apply to an individual patient. Cushman recognizes that novel anticoagulants, despite their imperfections, are here to stay—the sooner physicians learn to make constructive use of that pause, the better.