No clinical benefit of ACE inhibitor, ARB suspension in mild to moderate COVID-19
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In patients hospitalized with mild or moderate COVID-19, suspending ACE inhibitors and angiotensin receptor blockers for 30 days, compared with continued treatment, did not impact the number of days alive and out of hospital.
BRACE CORONA provides the first randomized controlled trial data on continuing vs. suspending ACE inhibitors and angiotensin receptor blockers in this patient population.
“Because these data indicate that there is no clinical benefit from routinely suspending these medications in hospitalized patients with mild to moderate COVID-19, they should be generally continued for those with an indication,” Renato D. Lopes, MD, MHS, PhD, professor of medicine at Duke University School of Medicine and member of the Duke Clinical Research Institute, said while presenting results of the BRACE CORONA trial at the virtual European Society of Cardiology Congress.
Suspended vs. continued treatment
For the BRACE CORONA trial, investigators enrolled 659 patients with mild to moderate COVID-19 at 29 sites in Brazil. All patients reported chronic use of an ACE inhibitor (15%) or angiotensin receptor blocker (85%) for a median of 5 years before hospitalization. Upon admission, patients were randomly assigned to suspend their ACE inhibitor or angiotensin receptor blocker for 30 days (n = 334) or to continue treatment (n = 325).
At 30 days, the primary outcome of mean number of days alive and out of hospital was 21.9 days for patients who suspended ACE inhibitors and angiotensin receptor blockers vs. 22.9 days for those who continued their medications (mean difference, –1.1 days; 95% CI, –2.33 to 0.17). The mean ratio for days alive and out of hospital between the suspended and continued groups was 0.95 (95% CI, 0.9-1.01; P = .09), according to the results.
The proportion of patients alive and out of hospital by the end of 30 days was 91.8% in the suspended group vs. 95% in the continued group. The researchers observed a similar 30-day mortality rate for patients who continued vs. suspended their ACE inhibitor or angiotensin receptor blocker (2.8% vs. 2.7%; HR = 0.97; 95% CI, 0.38-2.52). Nine patients died in each group during the study.
BRACE CORONA was an academic-led, phase 4 randomized trial. Lopes presented these primary results roughly 5 months after the first patient underwent randomization on April 19.
Of those enrolled, 57% had mild COVID-19 at presentation, defined as blood oxygen saturation 94% and/or lung infiltrates < 50%, and 43% had moderate COVID-19, defined as blood oxygen saturation < 94% or lung infiltrates 50% and/or partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300. There were no severe cases of COVID-19, as the trial excluded patients who were hemodynamically unstable at presentation, as well as those who were using more than three antihypertensive medications, or sacubitril/valsartan (Entresto, Novartis). Cough, fever and shortness of breath were the most common symptoms in this population. Median time from symptom onset to hospital presentation was 6 days.
The patients’ mean age was 56 years, 40% were women and about 52% were obese (mean BMI, 31 kg/m2). All patients had hypertension and only 1.4% had HF at presentation.
‘Evidence is urgently needed’
Given the frequent use of ACE inhibitors and angiotensin receptor blockers worldwide, “randomized clinical trial evidence is urgently needed to guide the management of patients with COVID-19,” Lopes said.
Because the virus that causes COVID-19 acts through the ACE2 receptor, there was concern that use of renin-angiotensin-aldosterone system antagonists such as ACE inhibitors and angiotensin receptor blockers, which are widely used to treat hypertension, HF and other CV conditions, might predispose people to COVID-19 or worsen its effects. But, data from observational studies — and now the BRACE CORONA randomized trial — suggest that concern is unfounded.
“Our findings constitute contemporary and high-quality randomized evidence to guide the care of patients with COVID-19,” Lopes said.
During a discussion of the BRACE CORONA trial, Gianfranco Parati, MD, professor of cardiovascular medicine at University of Milan, Italy, said this trial provides an important contribution because of its randomized design.
Parati noted the different mechanism of action of ACE inhibitors and angiotensin receptor blockers, and said it will be interesting to determine whether there is a different effect between the two medications, as BRACE CORONA predominantly included patients treated with angiotensin receptor blockers.
Lopes said the trial aimed to test the whole renin-angiotensin system, which is why the researchers analyzed the impact of ACE inhibitors or angiotensin receptor blockers. Subgroup analyses of BRACE CORONA showed a very consistent effect on the outcomes for ACE inhibitors and also angiotensin receptor blockers, he said.
Parati also highlighted the short-term suspension of these drugs for 30 days and said it is possible that the ACE inhibitors and angiotensin receptor blockers may have longer-lasting effects beyond 30 days.
“These results are probably not the last word and it could be difficult to translate them in daily practice without considering the combined contribution of age and comorbidities to mortality risk in COVID-19 patients,” Parati said during the discussion.
Taken together, the findings confirm recommendations released by various cardiology societies, including the ESC, American College of Cardiology, American Heart Association and the Heart Failure Society of America, that patients on RAAS antagonists should continue to take their medications.
Perspective
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B. Hadley Wilson, MD, FACC
This is an important trial because ACE inhibitors and angiotensin receptor blockers are very prevalent and effective agents for CV treatment. We know that they save lives in patients with HF and are also one of our mainstays for antihypertensive therapy, among other uses. There were early concerns and observations since the start of the pandemic that people on ACE inhibitors and angiotensin receptor blockers might be more susceptible to SARS-CoV-2 and to worse outcomes. There are millions of people on ACE inhibitors and angiotensin receptor blockers; to think about having to stop them is a very serious concern.
The BRACE CORONA trial demonstrates that continuing ACE inhibitors and angiotensin receptor blockers does not worsen outcomes in patients with mild or moderate COVID-19. It is very reaffirming that we now have a randomized trial that corroborates the fact that we may continue our patients safely on these essential medications.
The investigators did an outstanding job mobilizing this trial and enrolling patients very quickly. They got very important answers that I think will help us through this pandemic and beyond.
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Lopes R. Hot Line: BRACE CORONA. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 1, 2020 (virtual meeting).
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