Thalia Field, MD, FRCPC, MHSc, University of British Columbia in Vancouver, Canada, shares the compelling findings of the Phase II SECRET trial (NCT03178864) presented at the ESOC 2023 conference. The primary objective of the SECRET trial was to address the existing uncertainties surrounding cerebral venous thrombosis (CVT) management by comparing the safety and efficacy of rivaroxaban to the standard treatment of warfarin or low molecular-weight heparin for 180 days. Despite direct oral anticoagulants (DOACs) demonstrating safety and efficacy in other types of venous thromboembolism, there was hesitance in their adoption for CVT due to the lack of specific evidence and concerns regarding intracranial hemorrhage. Dr. Field and her team designed the SECRET trial as a pilot safety study to assess the safety and potential benefits of DOACs, as well investigating the feasibility of recruitment in this patient population. The trial also aimed to identify alternative meaningful endpoints for future CVT studies, as conventional endpoints may not capture the nuances of this rare disease. During the course of the trial, over 50 patients were successfully recruited from multiple sites across Canada. Bleeding rates were numerically higher in the rivaroxaban arm compared to standard of care, but rates were low overall. The trial also explored secondary outcomes such as functional independence, quality of life, mood, fatigue, and cognitive performance, which were all markedly improved by day 180. The SECRET trial has yielded valuable insights for the future management of CVT and holds the potential to influence upcoming guideline updates.
These works are owned by Magdalen Medical Publishing (MMP) and are protected by copyright laws and treaties around the world. All rights are reserved.
Transcript (edited for clarity)
When we got the trial ready several years ago, at the time, the standard of practice was still using warfarin after a period of parenteral anticoagulation. At that time I think there was a lot more hesitancy in using DOACs even though their safety and efficacy had been demonstrated in other types of venous thromboembolism. But I think people were still feeling very shy because of the lack of evidence specifically in cerebral venous thrombosis and concerns about intracranial hemorrhage because about 40% of patients with CVT have some degree of bleeding on their initial scans...
When we got the trial ready several years ago, at the time, the standard of practice was still using warfarin after a period of parenteral anticoagulation. At that time I think there was a lot more hesitancy in using DOACs even though their safety and efficacy had been demonstrated in other types of venous thromboembolism. But I think people were still feeling very shy because of the lack of evidence specifically in cerebral venous thrombosis and concerns about intracranial hemorrhage because about 40% of patients with CVT have some degree of bleeding on their initial scans. So, when we were developing the trial, our goal was to see if there was acceptable safety for use of DOACs prior to conducting a fully powered clinical trial comparing the standard against warfarin. That shifted over time. The guidelines have not yet changed to reflect the small studies that have demonstrated acceptable safety for DOACs in lower risk populations. But I think those guideline updates are coming from the AHA, from the European Stroke Organisation, and also from the Canadian Stroke Consortium. All of us are developing guidelines and I suspect some comments about DOACs will be there in the future. But the published standard of practice remains vitamin K antagonists.
So the other thing I would say is that, you know, with these other studies that have come up over time, I think people have felt a lot more comfortable integrating use of DOACs into their practice in many cases, even though there remain no fully powered comparative trials.
So SECRET was a feasibility trial. Cerebral venous thrombosis is a rare cause of stroke and what we were trying to do, I think, is determine the best foundation to conduct the most efficient and meaningful trial in the future about treatments for cerebral venous thrombosis. So we had a couple of specific objectives. One is that we wanted to get a sense of what recruitment targets were going to be like, not just because cerebral venous thrombosis is a rare disease, but also because not all patients would be able to qualify for the trial given particular inclusion and exclusion criteria, including contraindications to DOACs like being pregnant or breastfeeding. And also just because we know that not everybody who’s a candidate for a clinical trial would like to give informed consent. So we had the randomized trial and we also had a parallel registry through which we could continue to prospectively collect data. The second thing we wanted to do is do a pilot safety trial looking for any signals that would suggest that DOACs were unacceptably safe for further testing in fully randomized, fully powered randomized trials. And the third thing we wanted to do is to look at alternative considerations for outcomes that would be meaningful to patients and would be more common endpoints to consider for future trials for cerebral venous thrombosis. As a rare disease, you’re going to have smaller numbers to begin with and conventional endpoints that would you would usually find in an anticoagulation trial like major bleeding or recurrence of venous thromboembolism in this patient population tend to be rare. So we were also looking at endpoints that are commonly experienced, things like headache or mood or fatigue and things like that that might be acceptable to include as outcomes for future trials, to power trials in the future.
We were able to recruit our target of over 50 patients for the feasibility trial. We needed to engage several sites across Canada. We had 12 sites that recruited on average two patients per site per year for a total of 21 patients per year between 2019 and 2021. We found that overall the rate of bleeding in the standard of care arm, so mostly patients on warfarin with a few patients that remained on low molecular weight heparin throughout the trial, that the bleeding rates were actually lower than expected. We had no bleeding or recurrent venous thromboembolism or death or major extracranial hemorrhage within the first 180 days in the standard of care group. In the rivaroxaban group, we had one major intracranial bleed, a spontaneous subdural after about four months of therapy and two clinically relevant non-major bleeding events both related to gynecological bleeding. On extended follow up between day 180 and day 365, we had one additional major hemorrhage in the patients in the warfarin group and that the one patient that experienced that endpoint later died. So overall, the rates of serious events were low overall, but there were numerically more bleeding events, particularly within that first 180 days in the rivaroxaban group. Still, those rates of bleeding were not out of keeping with what had been seen in previous studies of DOACs for CVT.
So the secondary outcomes with respect to patient centered prognosis, we found that most patients were actually functionally independent even at baseline. So you know, as a conventional outcome, that’s not a very good starting place to begin with if you’re going to look at change over time. What we did find is that people had really impaired quality of life, low mood fatigue, poor cognitive performance at baseline in both groups. But what was very encouraging is that we saw substantial improvements over time, even as early as the six-month mark and then with further incremental gains up until the 12-month point.