REPLACE COVID Bolsters Advice to Continue RAAS Inhibitors in COVID-19 Patients

Along with BRACE CORONA, there are now two RCTs showing no impact on outcomes when maintaining ACE inhibitors and ARBs.

REPLACE COVID Bolsters Advice to Continue RAAS Inhibitors in COVID-19 Patients

Another randomized trial, REPLACE COVID, indicates that patients already taking ACE inhibitors and ARBs when they’re hospitalized for COVID-19 should continue to do so, supporting recommendations from international CV societies.

When it came to outcomes including all-cause death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during hospitalization, there were no differences between patients who continued versus discontinued their renin-angiotensin-aldosterone-system (RAAS) inhibitors after they were admitted, researchers report in a study published online last week in the Lancet Respiratory Medicine.

More of TCTMD's coverage on our COVID-19 hub.
More of TCTMD's coverage on our COVID-19 hub.

Considering these findings and those from the BRACE CORONA trial, presented last year at the virtual European Society of Cardiology Congress, the message is simple, according to senior author Julio Chirinos, MD, PhD (University of Pennsylvania, Philadelphia). “In people who fall ill with COVID-19 requiring hospital admission, continuing these medications for established indications should be considered safe.”

Early after SARS-CoV-2 started circulating around the world, there were concerns that use of RAAS inhibitors might worsen the severity of COVID-19. That’s because there was some evidence that the agents increase the expression of ACE2, which has been shown to facilitate entry of the novel coronavirus into host cells.

International CV societies came out in favor of continuing ACE inhibitors and ARBs in patients hospitalized with COVID-19 while acknowledging the need for better data exploring the issue. Subsequent observational studies mostly suggested that there was no relationship between outpatient use of RAAS inhibitors and risk of COVID-19 hospitalizations or mortality, but randomized trials were launched to provide more-definitive insights.


REPLACE COVID, co-led by Chirinos and Jordana Cohen, MD (University of Pennsylvania), was a randomized, open-label trial conducted at 20 hospitals in the United States, Canada, Mexico, Sweden, Peru, Bolivia, and Argentina. It included 152 hypertensive patients (mean age 62 years; 45% women) randomized to continue or discontinue their ACE inhibitors and ARBs.

The primary outcome consisted of a global rank score that incorporated time to death; duration of mechanical ventilation or extracorporeal membrane oxygenation; time on renal replacement or inotropic or vasopressor therapy; and multiorgan dysfunction during hospitalization, assessed with the modified Sequential Organ Failure Assessment (SOFA) score. The global rank score did not significantly differ between the continuation and discontinuation arms (median 73 vs 81; P = 0.61).

There were also no differences in any of the secondary outcomes, including all-cause death (15% vs 13%; P = 0.99) and median length of the hospital stay (6 vs 5 days; P = 0.56).

Adverse events occurred in 39% of patients who continued their RAAS inhibitors and 36% of those who stopped taking them (P = 0.77). Blood pressure and serum levels of potassium and creatinine during follow-up were similar in the two trial arms.

“Our findings, derived from a prospective, multicenter, randomized, controlled design, are consistent with previously published observational studies and unpublished trial evidence, which have generally shown no difference in the risk of SARS-CoV-2 infection and COVID-19 severity among patients who are treated with ACE inhibitors or ARBs compared with those who are not,” the authors conclude.

Message From Two Trials

The unpublished trial evidence to which they refer comes from BRACE CORONA, a 659-patient trial conducted across 29 centers in Brazil. There was no difference between the continuation and discontinuation groups in terms of days alive and out of the hospital at 30 days or risk of death.

REPLACE COVID’s investigators note that the patient population in BRACE CORONA was younger (mean age 55) and had a lower comorbidity burden compared with their own; in addition, the mortality rate was lower in BRACE CORONA.

“Thus, the participants in the BRACE CORONA trial might not be fully generalizable to patients typically admitted to hospital with COVID-19 and hypertension globally,” they say. “Additionally, 11% of participants enrolled in the BRACE CORONA trial were excluded after randomization due to protocol deviations, absence of informed consent, or Good Clinical Practice violation.”

Renato Lopes, MD, PhD (Duke University, Durham, NC), principal investigator of BRACE CORONA, said REPLACE COVID has some has some limitations of its own, primarily its small size.

Nonetheless, he commented to TCTMD, “I’d rather have these small studies that are randomized than large observational studies, where despite being large you can never correct for the systematic error and therefore you just might be magnifying a certain bias or certain confounder that cannot be [adjusted for] if you don’t have the randomization.”

On its own, REPLACE COVID would not be definitive, but considering that the findings are consistent with those from BRACE CORONA, “I think then it gives even more reassurance for this topic,” said Lopes, who noted that the full BRACE CORONA results will be published in a major journal next week.

With the two trials together, “I think that now we have enough to say that we should not stop these drugs, because it doesn’t make sense and we might be potentially even causing harm,” he concluded.

In an accompanying editorial, Bryan Williams, MD (University College London, England), agrees with the thrust of Lopes’ assessment. He notes, however, that the patient populations of both REPLACE COVID and BRACE CORONA are younger on average compared with the severely ill COVID-19 patients typically seen in many hospitals.

“Indeed, the impact of age and comorbidity on outcomes in COVID-19 is clearly evident from the fact that many fewer people died or had intensive care dependency in the larger but younger study population of the BRACE CORONA trial than the smaller but older study population of the REPLACE COVID trial,” Williams writes. “An important caveat for both studies is that the data most reliably apply to patients previously receiving ACE inhibitors or ARB treatment for hypertension and associated conditions, other than for heart failure, which was an important exclusion [criterion] for both studies because of the higher perceived risk of withdrawing the benefits of renin-angiotensin system inhibition in patients with heart failure.”

Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • The trial was sponsored by the investigators from the various enrollment centers; the REPLACE COVID Trial Social Fundraising Campaign supported a portion of enrollment at the University of Pennsylvania; and FastGrants supported enrollment at the University of Michigan. Several US investigators have National Institutes of Health (NIH) funding for research efforts outside of this work.
  • Cohen reports receiving consulting honoraria from Sanifit, Bristol Myers Squibb, Edwards Lifesciences, Bayer, and Johnson & Johnson; research grants from the NIH, Microsoft, Fukuda-Denshi, and Bristol Myers Squibb; compensation from the American Heart Association and the American College of Cardiology for editorial roles; and visiting speaker honoraria from Washington University and the University of Utah, all outside of the submitted work.
  • Williams reports honoraria from Pfizer, Daiichi Sankyo, Boehringer Ingelheim, Menarini, and Servier for lectures on hypertension; and support from the NIHR University College London Biomedical Research Centre.