RAS inhibition and COVID-19: more questions than answers?

Since the beginning of the COVID-19 pandemic and the first reports of an increased mortality among patients with COVID-19 treated for hypertension, the potential role of renin–angiotensin system (RAS) blockers on the severity of the disease has been questioned.1, 2 Although RAS blockers have been associated with better outcomes in pneumonia models, they might also upregulate the expression of angiotensin-converting enzyme 2 (ACE2) receptor, which acts as a co-receptor for human cell infection by SARS-CoV-2 through the binding with the spike protein.3, 4, 5 Following neutral and reassuring large observational studies and meta-analyses, two randomised trials have been done and published: the BRACE CORONA and the REPLACE COVID trials.6, 7 Both studies concluded an absence of effect of chronic RAS blockade on the course of COVID-19, as previously observed in observational studies.

The Stopping ACE-inhibitors in COVID-19 (ACEI-COVID19) trial by Bauer and colleagues, published in the Lancet Respiratory Medicine, is the third randomised study evaluating the risk and benefit of RAS blockers discontinuation on the severity of COVID-19. This trial is specific in its inclusion of an older population who have comorbidities such as overweight, chronic obstructive pulmonary disease, hypertension, and heart failure. This was not intended by the design, but it rather reflects the characteristics of the patients admitted to hospital during the first waves of the disease in Europe. The raw results on the primary endpoint of this well-conducted study confirm the two previous trials: there is no effect of RAS blockers on the severity and evolution of the disease up to 30 days. In this high-risk population, exposed to a high mortality rate (one of ten patients died during the study period), there was no difference in mortality between the two groups. However, it would be overly simplistic to label this trial as negative or neutral on the basis of only the primary endpoint analysis. Bauer and colleagues underline that, after its peak, the mean sequential organ failure assessment scores in the discontinuation group decreased more rapidly and reached lower values than in the continuation group. They, therefore, suggest that discontinuation might lead to a faster and better recovery among these older, high-risk patients with COVID-19.

This conclusion should be interpreted with great caution, considering that it derives from secondary analyses in a study that did not meet its primary endpoint. Are these findings falsely positive? This is not the first time that a negative study has revealed positive findings in secondary outcomes or analyses. The ASCOT-BPLA trial (amlodipine-based regimen vs atenolol-based regimen for the treatment of hypertension), is a famous example of such discrepancies. In the ASCOT-BPLA trial, the primary composite outcome (non-fatal myocardial infarction and coronary heart disease related death) did not reach significance, but almost all secondary outcomes, including all cause death, and non-fatal and fatal stroke, were significantly reduced by amlodipine. The results of these secondary endpoints were considered as plausible, consistent within the study and across previous trials, and to be based on a strong rationale.

However, the same considerations cannot fully apply to the results of the ACEI-COVID trial: first, the secondary endpoints did not confirm any previous data from other non-randomised or randomised studies; second there is slender plausibility and no clear explanation for these results; third they derive from a small sample size study with insufficient power and inflation of the risk alpha. Thus, they should be considered for what they are: hypothesis generating, requiring confirmation and, should not be used to guide a clinical decision of RAS blockers discontinuation without more evidence. Although there is no safety signal in the discontinuation group, the risk of RAS blockers discontinuation is well known and the follow-up was probably too short to detect any difference in the adverse events rate between the two groups.11, 12

Nevertheless, the ACEI-COVID study raises several key questions. Why might older patients have a benefit of discontinuation that younger patients do not have? Is it related to the kidney function or blood pressure control, or to the severity of lung damage, or to the expression ACE2 in this population? Is there a protective effect of calcium channel blockers (which have been used as a replacement therapy) on COVID-19? Why do the patients with COPD have a particular benefit from ACE discontinuation, when the use of RAS blockers in patients with COPD was associated with improved outcomes in observational studies before the COVID-19 era?

The ACEI-COVID study adds more data to the existing evidence showing that RAS blockers should not be systematically discontinued in patients with COVID-19, but it leaves us also with more questions than answers.

MK has received consulting fees from Sanofi, Bayer, and Kiniksa, and research grants from Federation Francaise de Cardiologie and the French Ministry of Health. GM has received grants from Abbott, Amgen, AstraZeneca, Boston Scientific, Bristol-Myers Squibb, Idorsia, Servier, Medtronic, Pfizer, and Quantum Genomics, and consulting fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Idorsia, Medtronic, and MSD.