Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.
Writing Committee for the REMAP-CAP Investigators None., Lawler PR., Derde LPG., van de Veerdonk FL., McVerry BJ., Huang DT., Berry LR., Lorenzi E., van Kimmenade R., Gommans F., Vaduganathan M., Leaf DE., Baron RM., Kim EY., Frankfurter C., Epelman S., Kwan Y., Grieve R., O'Neill S., Sadique Z., Puskarich M., Marshall JC., Higgins AM., Mouncey PR., Rowan KM., Al-Beidh F., Annane D., Arabi YM., Au C., Beane A., van Bentum-Puijk W., Bonten MJM., Bradbury CA., Brunkhorst FM., Burrell A., Buzgau A., Buxton M., Cecconi M., Cheng AC., Cove M., Detry MA., Estcourt LJ., Ezekowitz J., Fitzgerald M., Gattas D., Godoy LC., Goossens H., Haniffa R., Harrison DA., Hills T., Horvat CM., Ichihara N., Lamontagne F., Linstrum KM., McAuley DF., McGlothlin A., McGuinness SP., McQuilten Z., Murthy S., Nichol AD., Owen DRJ., Parke RL., Parker JC., Pollock KM., Reyes LF., Saito H., Santos MS., Saunders CT., Seymour CW., Shankar-Hari M., Singh V., Turgeon AF., Turner AM., Zarychanski R., Green C., Lewis RJ., Angus DC., Berry S., Gordon AC., McArthur CJ., Webb SA.
IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. OBJECTIVE: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.