Speaker
John Alexander, MD, MHS
Professor of Medicine/Cardiology
DCRI/Duke University
Keywords
PROACT Xa, Aortic Valve Replacement, Warfarin, Apixaban, Pragmatic Clinical Trial
Key Points
- In the PROACT Xa trial, researchers wanted to learn if patients with an On-X mech valve implanted in the aortic position can be maintained on a factor Xa inhibitor (Apixaban) with a safe level of thromboembolic events compared to standard warfarin.
- The trial was designed to randomize 1,000 patients who had an On-X aortic valve replacement at least 3 months prior to randomization with either a standard dose of Apixaban (5mg) or continued warfarin (the standard of care). The primary endpoint was composite of valve thrombosis or valve-related thromboembolism, and the primary safety endpoint was major bleeding. The drugs were administered open label and all patients were given a low dose of aspirin. The trial took place at 64 sites, and randomized 863 patients.
- Sites were selected based on their On-X AVR volume, and the study leveraged the surgeon/patient relationship for recruitment. The study used remote enrollment, and there was also a centralized outreach to patients with On-X AVR by mail to all U.S. patients with a link to clinicaltrials.gov to learn more about the study. Several sites could enroll patients from outside of their system, based on regional or state requirements from local IRBs.
- The study drug was mailed directly to participants, and at the end of the trial participants were instructed to destroy the drug. The price for Apixaban was $600 per bottle/$6M, and the price for warfarin was $50K. Follow up was conducted with a standardized script to ascertain events, and medical records were collected for event adjudication.
- On Sept. 21, 2022, the PROACT Xa DSMB recommended stopping enrollment and transitioning patients off of the study drug due to an observed excess in thromboembolic events in the Apixaban arm compared to the warfarin arm. Enrollment was stopped and all enrolled patients were contact to transition off of the study drug and back onto standard of care warfarin.
- Of the total 863 enrolled patients, 20 on Apixaban had a valve thrombosis or valve-related thromboembolism event, compared to 6 events in the warfarin arm. The study determined that Apixaban was not non-inferior to warfarin for the prevention of valve thrombosis or valve-related thromboembolism and resulted in more thromboembolic events than warfarin in patients with an On-X mechanical aortic valve.
Learn more
Read about the PROACT Xa study.
Discussion Themes
-What was your impression of the challenges imposed for doing this trial? Tracy Wang: It is safe to say that none of us predicted COVID, and it hit pretty soon after we started enrollment. We never had to make too many procedural operations because everything was set up as much as possible for remote recruitment. The pragmatic elements were already in place so when COVID happened the main thing that had the biggest impact on our study was the shortage of study coordinators that effected every trial, and a few of our study sites went under due to difficulty of staffing and sustaining a research enterprise. We never had an amendment to the protocol.
-How are you taking it forward now that you are at PCORI? Tracy Wang: What lessons learned are your taking forward at PCORI? There are several things that are going to be in the PCORI rubric. We have a strong focus on comparative effectiveness and looking at critical health decisions. We are trying to do more of that and ask the more impactful questions to help patients and stakeholders make critical decisions in their care. From a funder’s perspective, trials of this size and impact can be done for prices that are not in the $200-300 million range. A lot of this has to do with the infrastructure, PROACT tapped into a unique device infrastructure.
-Since you demonstrated that a couple sites were able to care for subjects in any location, would you say more about the value that the additional separate clinical sites provided? John Alexander: One of the things we did in PROACT X-a is we allowed flexibility. There were sites that did no remote consent or enrollment. We said that was fine. Then others did remote. At times they changed their mind, based on other people doing it. There were some sites that allowed remote within a specific region. There were 2 sites that would take patients from anywhere in the U.S. It was very individualized. Tracy Wang: Until there is more widespread experience in supporting decentralized trials, I do think there’s still value to the “local” clinical sites and certainly more patient familiarity and comfort.
Tags
#pctGR, @Collaboratory1