First Randomized Trial Reassures on ACEIs, ARBs in COVID-19

September 01, 2020

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The first randomized study to compare continuing vs stopping angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for patients with COVID-19 has shown no difference in key outcomes between the two approaches.

The BRACE CORONA trial ― conducted in patients had been taking an ACE inhibitor or an ARB on a long-term basis and who were subsequently hospitalized with COVID-19 ― showed no difference in the primary endpoint of number of days alive and out of hospital among those whose medication was suspended for 30 days and those who continued undergoing treatment with these agents.

Dr Renato Lopes

"Because these data indicate that there is no clinical benefit from routinely interrupting these medications in hospitalized patients with mild to moderate COVID-19, they should generally be continued for those with an indication," principal investigator Renato Lopes, MD, of Duke Clinical Research Institute, Durham, North Carolina, concluded.

The BRACE CORONA trial was presented at the European Society of Cardiology (ESC) Congress 2020 on September 1.

Lopes explained that there are two conflicting hypotheses about the role of ACE inhibitors and ARBs in COVID-19.

One hypothesis suggests that use of these drugs could be harmful by increasing the expression of ACE2 receptors (which the SARS-CoV-2 virus uses to gain entry into cells), thus potentially enhancing viral binding and viral entry.

The other suggests that ACE inhibitors and ARBs could be protective by reducing production of angiotensin II and enhancing the generation of angiotensin 1–7, which attenuates inflammation and fibrosis and therefore could attenuate lung injury.

The BRACE CORONA trial was an academic-led randomized study that tested two strategies: temporarily stopping the ACE inhibitor/ARB for 30 days, or continuing these drugs for patients who had been taking these medications on a long-term basis and were hospitalized with a confirmed diagnosis of COVID-19.

The primary outcome was the number of days alive and out of hospital at 30 days. Patients who were using more than three antihypertensive drugs or sacubitril/valsartan or who were hemodynamically unstable at presentation were excluded from the study.

The trial enrolled 659 patients from 29 sites in Brazil. The mean age of patients was 56 years, 40% were women, and 52% were obese. ACE inhibitors were being taken by 15% of the trial participants; ARBs were being taken by 85%. The median duration of ACE inhibitor/ARB treatment was 5 years.

Patients were a median of 6 days from COVID symptom onset. For 30% of the patients, oxygen saturation was below 94% at entry. In terms of COVID symptoms, 57% were classified as mild, and 43% as moderate.

Those with severe COVID symptoms who needed intubation or vasoactive drugs were excluded. Antihypertensive therapy would generally be discontinued in these patients anyway, Lopes said.

Results showed that the average number of days alive and out of hospital was 21.9 days for patients who stopped taking ACE inhibitors/ARBs and 22.9 days for patients who continued taking these medications. The average difference between groups was –1.1 days.

The average ratio of days alive and out of hospital between the suspending and continuing groups was 0.95 (95% CI, 0.90 – 1.01; P = .09).

The proportion of patients alive and out of hospital by the end of 30 days in the suspending ACE inhibitor/ARB group was 91.8%, vs 95% in the continuing group.

A similar 30-day mortality rate was seen for patients who continued and those who suspended ACE inhibitor/ARB therapy, at 2.8% and 2.7%, respectively (hazard ratio, 0.97).

The median number of days that patients were alive and out of hospital was 25 in both groups.

Lopes said that there was no difference between the two groups with regard to many other secondary outcomes. These included COVID-19 disease progression (need for intubation, ventilation, need for vasoactive drugs, imaging results) and cardiovascular endpoints (myocardial infarction, stroke, thromboembolic events, worsening heart failure, myocarditis, hypertensive crisis).

"Our results endorse with reliable and more definitive data what most medical and cardiovascular societies are recommending ― that patients do not stop ACE inhibitor or ARB medication. This has been based on observational data so far, but BRACE CORONA now provides randomized data to support this recommendation," Lopes concluded.

Lopes noted that several subgroups had been prespecified for analysis. Factors included age, obesity, difference between ACE inhibitors/ARBs, difference in oxygen saturation at presentation, time since COVID-19 symptom onset, degree of lung involvement on CT, and symptom severity on presentation.

"We saw very consistent effects of our main findings across all these subgroups, and we plan to report more details of these in the near future," he said.

Protective for Older Patients?

The discussant of the study at the ESC Hotline session, Gianfranco Parati, MD, University of Milan-Bicocca and San Luca Hospital, Milan, Italy, congratulated Lopes and his team for conducting this important trial at such a difficult time.

He pointed out that patients in the BRACE CORONA trial were quite young (average age, 56 years) and that observational data so far suggest that ACE inhibitors and ARBs have a stronger protective effect in older COVID patients.

He also noted that the percentage of patients alive and out of hospital at 30 days was higher for the patients who continued on treatment in this study (95% vs 91.8%), which suggested an advantage in maintaining the medication.

Lopes replied that one quarter of the population in the BRACE CORONA trial was older than 65 years, which he said was a "reasonable number."

"Subgroup analysis by age did not show a significant interaction, but the effect of continuing treatment does seem to be more favorable in older patients and also in those who were sicker and had more comorbidities," he added.

Parati also suggested that it would have been difficult to discern differences between ACE inhibitors and ARBs in the BRACE CORONA trial, because so few patents were taking ACE inhibitors; the follow-up period of 30 days was relatively short, inasmuch as these drugs may have long-term effects; and it would have been difficult to show differences in the main outcomes used in the study ― mortality and time out of hospital ― in these patients with mild to moderate disease.

Commenting for | Medscape Cardiology, Franz H. Messerli, MD, and Christoph Gräni, University of Bern, Switzerland, said in a joint statement: "The BRACE CORONA trial provides answers to what we know from retrospective studies: if you have already COVID, don't stop renin-angiotensin system blocker medication."

But they added that the study does not answer the question about the risk/benefit of ACE inhibitors or ARBs with regard to possible enhanced viral entry through the ACE2 receptor. "What about all those on these drugs who are not infected with COVID? Do they need to stop them? We simply don't know yet," they said.

Messerli and Gräni added that they would like to see a study that compared patients before SARS-CoV-2 infection who were without hypertension, patients with hypertension who were taking ACE inhibitors or ARBs, and patients with hypertension taking other antihypertensive drugs.

The BRACE CORONA trial was sponsored by D'Or Institute for Research and Education and the Brazilian Clinical Research Institute. Lopes has disclosed no relevant financial relationships.

European Society of Cardiology (ESC) Congress 2020: Presented September 1, 2020.

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