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The BRACE-CORONA trial ― the first randomized trial to address the question of whether patients with COVID-19 should continue to take angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) ― has now been published.
The study, which was conducted in patients hospitalized with COVID-19 who were taking ACEIs or ARBs before hospitalization, showed no significant difference in the mean number of days alive and out of the hospital for those assigned to discontinue vs those assigned to continue these medications.
There were, however, hints that continuing to take ACEIs or ARBs may be beneficial for patients with more severe COVID-19.
The study was first presented at last year’s European Society of Cardiology (ESC) Congress 2020 and was reported by theheart.org | Medscape Cardiology at that time. The study was published online in JAMA on January 19, 2021.
“These findings do not support routinely discontinuing ACEIs or ARBs among patients hospitalized with mild to moderate COVID-19 if there is an indication for treatment,” the authors conclude.
Led by Renato D. Lopes, MD, Duke Clinical Research Institute, Durham, North Carolina, the researchers explain that there has been conflicting speculation about the effect of renin-angiotensin-aldosterone system (RAAS) inhibitors on the course of COVID-19.
On the one hand, observations from animal models suggest that ACEIs and ARBs upregulate the expression of ACE2, a receptor involved in SARS-CoV-2 infection of host target cells. This led to suggestions that these medications may enhance viral binding and cell entry. Conversely, RAAS inhibitors could benefit patients with COVID-19 through effects on angiotensin II expression and subsequent increases in angiotensin 1–7 and 1–9, which have vasodilatory and anti-inflammatory effects that might attenuate lung injury.
The BRACE-CORONA trial included 659 patients hospitalized in Brazil with mild to moderate COVID-19 who were taking ACEIs or ARBs prior to hospitalization. The median age of the patients was 55 years. Of these patients, 57.1% were considered to have mild cases at hospital admission, and 42.9% were considered to have moderate cases.
Results showed no significant difference in the number of days alive and out of the hospital for patients in the discontinuation group (mean, 21.9 days) in comparison with patients in the continuation group (mean 22.9 days). The mean ratio was 0.95 (95% CI, 0.90 – 1.01).
There also was no statistically significant difference in deaths (2.7% of the discontinuation group vs 2.8% for the continuation group); cardiovascular death (0.6% vs 0.3%), or COVID-19 progression (38.3% vs 32.3%).
The most common adverse events were respiratory failure requiring invasive mechanical ventilation (9.6% in the discontinuation group vs 7.7% in the continuation group), shock requiring vasopressors (8.4% vs 7.1%), acute myocardial infarction (7.5% vs 4.6%), new or worsening heart failure (4.2% vs 4.9%), and acute kidney failure requiring hemodialysis (3.3% vs 2.8%).
The authors note that hypertension is an important comorbidity in patients with COVID-19. Recent data suggest that immune dysfunction may contribute to poor outcomes among patients who have COVID-19 and hypertension.
It has been shown that when use of long-term medications is discontinued during hospitalization, the use of those medications is often not resumed, owing to clinical inertia. Long-term outcomes worsen as a result, the authors report. In the current study, all patients had hypertension, and more than 50% were obese; both of these comorbidities increase the risk for poor outcomes with COVID-19, they add.
They point out that a sensitivity analysis in which site was regarded as a random effect showed a statistically significant finding in favor of the group that continued ACEIs or ARBs. This finding was similar to that of the on-treatment analysis. There were also statistically significant interactions between treatment effect and some subgroups, such as patients with lower oxygen saturation and greater disease severity at hospital admission. For these patients, continuing ACEIs or ARBs may be beneficial.
“The primary analyses with the null results but wide 95% confidence intervals suggest that the study might have been underpowered to detect a statistically significant benefit of continuing ACEIs or ARBs,” they say.
Lopes has received grant support from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Sanofi, and Pfizer and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Sanofi, and Portola.
JAMA. Published online January 19, 2021. Full text