Prof Renato D Lopes (Duke University Medical Center, Durham, NC, US) joined Dr Harriette Van Spall (McMaster University, Hamilton, CA) to discuss the BRACE CORONA study and the impacts of COVID-19 on clinical research.
The BRACE CORONA study investigated the impact of the suspension of the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (BRA) on the length of hospital stay and on the mortality of patients with SARS-CoV2 infection.
Recorded remotely from Durham and Hamilton, 2020.
Recording Editors: Michael Knight and Natascha Wienand
Editor: Mirjam Boros
[Van Spall] I'm Harriette Van Spall, Associate Professor of Medicine and Cardiologist at McMaster University in Canada. And I'm delighted to invite Professor Renato Lopes, principal investigator of the BRACE CORONA trial that he presented at the ESC meeting this week to join me and discuss the results of his trial. Welcome, Professor Lopes.
[Lopes] Thank you very much for having me.
[Van Spall] So, your trial evaluated the suspension of ARB or ACE therapy among patients hospitalized with mild to moderate COVID-19 infection. Tell us about your study design, primary outcomes and results.
[Lopes] Great, so let me just start with a rationale; why we have done this study. So, as you remember, there has been conflicting observational evidence about the potential impact of ACE inhibitors and ARBs on patients with COVID-19.On one hand, RAAS inhibition could be harmful because ACE inhibitors and ARBs could increase the ACE2 receptor expression, and, thus, enhance viral binding and viral entry leading to worse outcomes in patients COVID-19. But on the other hand, RAAS inhibition could be protected. Diminishing the production of angiotensin II with an ACE inhibitor or ARB can enhance the generation of angiotensin, which attenuates inflammation and fibrosis, and therefore, attenuate lung injury. So that was the rationale really.Some studies showing maybe harmful. Some other studies showing maybe beneficial. So, we felt that we really needed to give an answer to the most robust design to do so, which is the randomized trial. So basically, that's what we did. We performed the BRACE CORONA trial, which was a multicenter, phase IV randomized trial with testing two strategies: Stopping the ACE inhibitors and ARBs for 30 days or continuing these medications in patients, who were already taking them chronically and were hospitalized with a confirmed COVID-19. Patients who, of course, were using more than three antihypertensive drugs were excluded from the trial as well as if they were unstable, hemodynamically speaking. And the primary endpoint of this study was the number of days alive and out of hospital at the end of 30 days. We chose this endpoint because we believe that that's a very pragmatic, but at the same time, center, patient-center endpoint, so patients really care about being well and out of hospital and, therefore, capturing everything that could potentially have happened during the hospital. So, it's, it's a good outcome to capture everything that might have happened in the hospital. Ended up, we cannot in a very pragmatic way. In terms of the results, basically all we showed is that there was no significant difference in the total number of days alive and out of the hospital between the two strategy groups. As a matter of fact, at the end of the study, the stopping group, we had about 91.8 percent of patients alive and out of hospital, and in the continuing group, we had 95 percent of patients alive and out of hospital. And, of course, this was not statistically significant difference. So those are our primary findings.
[Van Spall] I should probably pause and ask you to describe the characteristics of your population. So the results were very impactful. I do recall at the start of the pandemic, there was quite marked uncertainty about whether patients on chronic ACE inhibition or ARB therapy should have their therapies stopped. So your results are, are very insightful, impactful, concordant with many of the observational datasets, but nothing like a randomized control trial to prove cause and effect. Tell us about the composition of the patients in this trial, however.
[Lopes] Sure, so the baseline characteristics, as expected in every randomized trial, was very well balanced between two strategy groups, two strategy arms. Our mean age was 56 years. We had about 40 percent of female patients, which we were very happy with that because a good representation. And 100 percent of patients had hypertension and only 1.5 percent of the patients had heart failure. And the reason for that is because, as part of our exclusion criteria, we, we had patients who had a hospital, a hospitalization for heart failure in the last year, in the last 12 months. Why we chose that exclusion criteria? Because we believe that if you had a recent hospitalization, maybe there was no echo points to stop the ACE inhibitors members and ARBs. So that's why we end up with only 1.5 percent of patients with, with heart failure. Interestingly, we had about 52 percent of patients who were obese. And that's really interesting because, as you know, obesity has been linked to worse outcomes in patients with COVID-19. So we had 50 percent of that, of that characteristics.
Most patients were using ARBs, about 85 percent of patients were using ARBs. And ACE inhibitors were used in about 15 percent of the patients. And then of course, in terms of the clinical severity at admission, we had about 57 percent of patients being mild, considered mild infections, and about 43 percent of patients considered moderate. So really focusing the moderate and mild infections because the severe ones, basically when we had those patients, they were excluded for other reasons. For example, they were unstable or they were in shock and they were, then it, it doesn't make sense to really testing this hypothesis because ACE inhibitors and ARBs, they have to be suspended in those situations. So this was basically our, our study population.
[Van Spall] Right, now you excluded patients with heart failure, as you mentioned, but given the lack of difference in outcomes between both strategies, would you say that you can apply these findings to patients with heart failure? Is there any reason to believe that these findings should not be applied to patients with heart failure?
[Lopes] No, I think that if anything, the heart failure group is at even higher risk of being without these medications. So that's why we chose to exclude if you had an event in the last 12 months or a hospitalization for heart failing in the last 12 months, so we have only 1.5% percent; I know it's a small proportion, but I don't see any, any reason to not extrapolate these findings also for the heart failure. Of course, we need to be cautioned. That's not what the study tested. But I think it's very reasonable to assure, or to assume that, if we had done the trial with 30, 40 percent of heart failure, the results would be probably very similar.
[Van Spall] Right, and in terms of your secondary endpoint, you found that all-cause death at 30 days did not differ between the groups. So those who suspended ACE or ARB therapy had very similar all-cause death at 30 days as those who continued with the therapy.
[Lopes]That is correct. We had a, a, a number of secondary endpoints that were all predefined, and many of them were actually adjudicated in a blinded fashion. And that includes myocardial infarction, TIAs, stroke, new or worsening heart failure, myocarditis, pericarditis, arrhythmias requiring treatment, renal insufficiency requiring dialysis, all of those endpoints we looked at including disease progression, which we believe is an important endpoint to be assessed because one of the rationale early on to stop these drugs is that they could make the course of the infection be worse. And we actually did not see any difference between those secondary endpoints between these two strategy arms. If anything, numerically, lower rates of secondary endpoints overall for those patients who actually had their ACE inhibitors and ARB to be continued. So again, not statistically significant difference, but you know, numerically favouring the continuation of these agents and not stopping them.
[Van Spall] Remarkable work, I was stuck, I was struck, rather, by how you selected patients important outcome as your primary outcome. And I was curious whether you had any patients who were partners in this research or on your steering committee.
[Lopes] Yeah, so that's a very good question. We knew a lot of the patients that were actually in the study because we do have very pragmatic way in 29 hospitals in Brazil from our ongoing registry. And what's very interesting because we have some doctors that were actually part of the study. We had some pharmacists that were part of the study. We have some family members from hospital directors who actually participated in the study. So we had a diverse number of patients in the study that illustrate really that the everybody, the teams, on this 24, 29 hospitals joining for efforts and answering this question as much as, as quickly as possible, and I think that was one of the remarkable things of this study. From protocol development to the presentation at the ESC, which includes protocol development, approval, ethical approvals, starting randomizing, finishing randomization, follow-up on all patients, which you got 100 percent follow-up in every patient, and also locking the database and doing the analysis and presenting, all of these steps we did it in five months. So I think that's really something that we are proud of because we can then, hopefully, build on top of this platform on a pragmatic way that we have high quality research that give us reliable answers to the randomization, but without losing time in things that might not be so useful for the output, outcome, at the end.
[Van Spall] I do think that that has been one of the upside of this horrid pandemic that research and clinical trials have been conducted with marked efficiency, with a view to answering questions. Some not so methodologically rigorous, but, but many with the rigor that your work has demonstrated and has moved clinical trial methods along.
[Van Spall] So I thank you for joining me and for your important work that in your trial of 659 patients demonstrated that suspending ACE or ARB therapy in patients who are hospitalized with COVID-19 is no worse than continuing ACE or ARB therapy, and that patients who are on chronic long term ACE inhibitors or ARBs should have that therapy continued with no loss in terms of clinical outcomes to them. Is that fair?
[Lopes] Right. I think that's exactly right. I think the main answer that we give in a reliable way is that we should not use the diagnosis of COVID-19 to stop these medications. If they need to be stopped, it needs to be to other reason for, because of other, due to other reasons than the COVID-19. And to your point about pragmatic trial, it's really important that we be more efficient, which doesn't mean skip steps. So you have to do the randomization right. You have to do the monitor right. You have to collect the right amount of information. You have to adjudicate the endpoints. You look at, you have to look at the safety of the patient population. So if you're doing that in a more efficient way, I think that's the future of clinical research.
[Van Spall] I’m going to ask you one last question just because we share this passion for clinical trial design. We all learn something from each study that we lead. What do you think you learned from this particular trial, one or two things that helped you change the way you run trials or, or helped with insights that you can apply moving forward?
[Lopes] Yeah, I think maybe the, the, the main lesson, there were several lessons learned in our trial, but I think we learned that we can be efficient and gain efficiency in, in doing pandemics or, or hard moments such as the ones we, we are living now with lots of patients sometimes dying and everybody overwhelmed with the work, with the uncertainty around what's going on in terms of treatments. So doing trials on that in one hand can be really efficient because approvals from IRBs can be much faster. Everybody can do things more, in a more expedite way. But what we learned is that despite doing that, we cannot skip steps. They are critical for the research and for the clinical research. So we need to keep consenting patients in the right way. We need to keep doing the monitoring to make sure that the right patients are randomized and got the treatment assignments that they were randomized to. We need to, as much as possible, adjudicate in a blinded fashion without any ascertainment bias with predefined definitions, because if we skip those steps in the middle of a pandemic that people are afraid and with fear, with uncertainty, is when human errors might increase.
[Van Spall] Right, well, thank you so much for joining me today. It was such a delight to talk to you before the meeting and during our discussion. I do hope we can stay in touch and collaborate in the future. And I appreciate the investment of this time of yours. Thank you so much.
[Lopes] Absolutely; thank you very much for having me here.