Randomized trial underway to assess RAAS inhibitors in COVID-19
Many international medical societies have endorsed the continuation of renin-angiotensin-aldosterone system inhibitors such as ACE inhibitors and angiotensin II receptor antagonists to control BP in patients during the COVID-19 pandemic despite concerns about the drugs’ relationship to ACE2, the receptor that helps the virus bind to cells. Researchers at the University of Pennsylvania Perelman School of Medicine recently started the REPLACE COVID trial to provide more information about the effects of these medications in patients hospitalized with COVID-19.
The REPLACE COVID trial recently started enrollment, and researchers aim to enroll 152 patients hospitalized for COVID-19 who will be assigned continuation or discontinuation of ACE inhibitors or angiotensin II receptor antagonists.
According to the trial listing on ClinicalTrials.gov, the primary outcome is a global rank score that will assess outcomes including number of days on invasive mechanical ventilation or extracorporeal membrane oxygenation, time to death, modified Sequential Organ Failure Assessment (SOFA) score and the number of days on pressor/inotropic therapy or renal replacement therapy. Secondary outcomes include length of hospital stay, all-cause death, area under the curve of the modified SOFA score and length of ICU stay. All outcomes will be analyzed for up to 28 days.
Healio spoke with co-principal investigators Julio A. Chirinos, MD, PhD, associate professor of cardiovascular medicine, and Jordana B. Cohen, MD, MSCE, assistant professor in the division of renal-electrolyte and hypertension and the department of biostatistics, epidemiology and informatics, both at the Hospital of the University of Pennsylvania, to learn more about the REPLACE COVID trial.
Question: Why did you decide to undertake this trial?
Cohen: This all started because there was a large amount of media coverage surrounding letters to the editors in The BMJ (Sommerstein R, et al. BMJ. 2020;doi:10.1136/bmj.m810) and The Lancet (Fang L, et al. Lancet. 2020;doi:10.1016/S2213-2600(20)30116-8) describing theoretical concern for the risk for ACE inhibitors and angiotensin II receptor antagonists, which are two very common antihypertensive medications, to increase ACE2 expression.
ACE2 is responsible for intracellular entry of COVID-19 into the lung cells. The theoretical concern was that if ACE inhibitors and angiotensin II receptor antagonists increase ACE2 expression, that may increase the risk for both infection with COVID-19 and disease severity among those people who have COVID-19. This concern was based on animal studies, with only limited and inconclusive human data available, so these are purely theoretical concerns. This is not something that has been demonstrated to truly be a risk.
It is very concerning to us that many people, as a result of media coverage, were recommending that patients stop their medications or patients themselves are making the decision to stop these important medications, which are often critical for people who have CVD, chronic kidney disease, hypertension and diabetes. A rash decision to stop treatment could be quite dangerous.
Alternatively, there has been a swing in the other direction where there has been a response with multiple international societies recommending that people not stop these medications, but continue them. Some people are actually starting them de novo due to some other theories based off of, again, not necessarily substantiated data yet, that these medicines might be helpful in COVID-19 due to similar mechanisms. Because these treatments might reduce inflammation related to that ACE2 pathway, they have been demonstrated to be helpful in other types of viral diseases.
It is quite possible that it can go in either direction. We consider there to be true equipoise regarding the potential benefit or harm of these medications. We think the only way to truly answer this well and adequately is through very rapid randomized controlled trials.
There have been several attempts at retrospective studies that have come out now, either published or in pre-print, that show results in either direction depending on how the study is designed and in what population in terms of whether these medicines are helpful or harmful. We need a well-designed randomized controlled trial to answer that question.
Chirinos: It is a valid point that there are potential mechanisms for interactions between these medications and SARS-CoV-2. What we do not know is the nature of those interactions and whether they are clinically relevant. The reason for suspecting that there may be interactions is that ACE2 is a cellular receptor for the virus, and ACE2 is part of the RAAS system that is impacted by ACE inhibitors and angiotensin receptor blockers.
Now whether these medications lead to upregulation of ACE2, which may favor viral infection, or lead to anti-inflammatory effects and protection of organs such as the heart and the kidneys, is a matter of debate. We frankly have no evidence in either direction from experimental trials, which is what we really need to do.
Observational studies are plagued with problems in this particular scenario because there are many reasons by which a clinician may decide to initiate or stop these medications in patients who have COVID-19. If we only look at the association between the use of these medications and outcomes in an observational study where clinicians made that decision based on multiple factors that we cannot capture in observational studies, we may arrive at the entirely wrong conclusion.
In the meantime, I fully agree with the societies’ recommendations that for patients who have established indications for these medications, we should continue to use them unless new randomized controlled trial evidence suggests otherwise.
Q: How long will this study take to complete, and what do you hope to learn from it?
Chirinos: We hope that it will be done in less than 3 months.
Cohen: We are hoping to understand if these medicines should be continued or withheld in patients who are hospitalized with COVID-19 who are already on these medications. As Dr. Chirinos mentioned, we really do not think that there is any other way to determine the best course forward without randomly assigning patients and determining the answer to that question with a randomized trial.
Chirinos: I fully agree. I would also echo what Dr. Cohen said before about equipoise, which is where we are right now. We are in a situation where we do not know what to do in patients who are already taking these medications and fall ill with COVID-19 to the point where they need to be in the hospital. Again, the only way to solve it is through a randomized trial, and we hope to learn the definitive answer to that particular clinical question, which is going to be increasingly common as more people fall ill with this disease.
Q: How might the potential success of this trial impact the system of care for COVID-19?
Cohen: It will answer important questions that many providers are struggling with right now about whether or not to continue or stop these medicines. Normally, it is already a debate as to whether or not to stop these medicines in people who are hospitalized. This will help provide critical information for providers on what to do when people come in with COVID-19 who are already on these medicines.
Q: You and your team are pursuing several funding mechanisms for this trial including a social fundraising campaign . How has that been so far?
Chirinos: It has been partially successful, but let me clarify this first. We are doing this trial no matter what. In fact, we have already started successfully enrolling. The reason we are able to do this trial is because Penn, thankfully, provides great infrastructure to execute the data coordinating center and enrollment in the trial across Penn Medicine hospitals, but also due to several established investigators at other institutions who have jumped and said we want to help and we want to be part of this effort, even though we don’t necessarily have funding for these other sites.
They have established their own or have applied for their own local funding or used their existing infrastructure and manpower within their established research operations that are generally purposed for something entirely different, but that in this time of crisis are being repurposed for addressing the COVID-19 crisis. We found very positive reception by established investigators in several countries, particularly the U.S., that are willing to help and bring in their expertise, infrastructure, their ability to recruit patients, their collaboration and their funding. We have found ourselves in a very fortunate situation of collaborating with all of these amazing investigators around the world.
Having said that, adding more sites will give us the opportunity to answer the question more quickly. This is a situation where every day counts, so we are working nights and weekends. Our coordinators are working through weekends and enrolling at any time of the day. If we get a successful fundraising campaign, we are going to be able to add sites that otherwise would not be able to be added because they do not have that funding. – by Darlene Dobkowski
For the latest news on COVID-19 including case counts, information about the global public health response and emerging research, please visit the COVID-19 Resource Center on Healio.
For more information:
Julio A. Chirinos, MD, PhD, can be reached at firstname.lastname@example.org; Twitter: @juliochirinosmd.
Jordana B. Cohen, MD, MSCE, can be reached at email@example.com; Twitter: @jordy_bc.
Disclosures: Chirinos reports he received honoraria from Akros Pharma, Bayer, Bristol-Myers Squibb, Edwards Lifesciences, Fukuda-Denshi, Ironwood Pharmaceuticals, Johnson & Johnson, Merck, Microsoft, OPKO Healthcare, Pfizer and Sanofi and research grants from Bristol-Myers Squibb, Fukuda-Denshi and Microsoft. Cohen reports no relevant financial disclosures.