麻豆传媒

Stopping an ACE inhibitor or angiotensin receptor blocker (ARB) at admission for COVID-19 doesn't help outcomes, even for high-risk groups, the BRACE CORONA randomized trial showed.

Continuing these drugs for patients on them before admission if anything yielded numerically more days alive and out of the hospital at 30 days compared with temporarily suspending use (mean 22.9 vs 21.9, P=0.09).

Proportion of patients alive and out of the hospital at day 30 came out similar as well (95.0% continuing vs 91.8%), reported Renato Lopes, MD, PhD, of Duke Clinical Research Institute in Durham, North Carolina, at the European Cardiology Society (ESC) virtual meeting.

All-cause mortality at 30 days was 2.8% with continued use vs 2.7% with temporary stopping the drugs (HR 0.97, 95% CI 0.38-2.52).

"Our results endorse now with more reliable and definitive data what the societies have recommended," which was an expert consensus based on observational data that patients should not stop ACE/ARB drugs over COVID-19 concerns, Lopes told 麻豆传媒 at a press briefing for the ESC hot-line session.

Observational data had supported that recommendation, but there was theoretical risk that ACE inhibitors and ARBs could increase expression of the ACE2 receptors that the SARS-CoV-2 virus binds to and enhances its entry into cells, leading to worse outcomes.

Hadley Wilson, MD, of Sanger Heart & Vascular Institute in Charlotte, North Carolina, called the results "very reassuring" for safety.

"We certainly don't want to have to discontinue these drugs unless they're harmful," and if anything there was a weak trend for benefit that could have become significant with longer follow-up or larger numbers, he said. "This is a large enough randomized trial that I can say with some certainty that this issue is settled."

However, ESC session study discussant Gianfranco Parati, MD, of the University of Milano-Bicocca in Italy, said the "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."

The trial included 695 adults hospitalized in Brazil with confirmed COVID-19 who were chronic (median 5 years) users of ACE inhibitors (17%) or ARBs (83%). They were randomized to temporarily suspend those drugs for 30 days or continue use.

All the patients had hypertension; only 1% had heart failure. About 40% were women, mean age was 56, and 52% were obese. COVID-19 severity in the first 24 hours after presentation was mild for 57% and moderate for 43%. Severe cases were excluded because "those patients are usually in shock," Lopes said. "Obviously, all the antihypertensive drugs need to be dropped."

Patients were excluded if they had a hospitalization due to decompensated heart failure in the prior 12 months, use of more than three antihypertensives, use of sacubitril/valsartan (Entresto), or hemodynamic instability in the first 24 hours until confirmation of COVID-19 diagnosis.

Secondary outcomes showing no difference between treatment groups included:

• COVID-19 disease progression (worsening on chest imaging or need for intubation, mechanical ventilation, or vasoactive drugs)
• Myocardial infarction
• Stroke
• Thromboembolic events
• Cause of death
• Myocarditis or pericarditis
• Arrhythmia requiring treatment
• Hypertensive crisis

Subgroup analyses likewise showed no difference by age, obesity, oxygen saturation at presentation, duration from symptom onset to randomization, degree of lung involvement, and COVID-19 severity at presentation.

Notably, about a quarter of the patients were age 65 and older. Parati said his group's experience has been that there is a difference in outcomes for older but not younger patients. However, Lopes noted that formal interaction analysis didn't turn up a significant difference by age, although numerically there was a greater benefit to continuing these drugs in the older group. The same was true for sicker patients and those with more comorbidities, he said.

"The message is pretty clear," Wilson concluded. He noted that this is one of the first randomized trials to be completed in the cardiovascular field dealing with SARS-CoV-2.

"The investigators should be congratulated on the speed with which they were able to enroll a large number of patients and get results," he told 麻豆传媒. "Their timeline was quite impressive, starting some of the first patients as early as April."

Whereas some trialists have reported struggling to clear the bureaucratic hurdles to enrolling patients for antithrombotic trials, for example, in COVID-19 hospitalized patients, Wilson noted that the design of this trial in stopping rather than starting a treatment gave the researchers a logistical headstart.

Parati noted that patients were not stratified by ACE inhibitor versus ARB use in randomization -- a limitation since those drugs have different mechanisms of action. Also, he acknowledged the difficulty in assessing mortality risk over such a short follow-up period in a moderate-risk, relatively young cohort. As well, data were lacking on the drugs used for COVID-19 treatment in the cohort.

In addition, Parati argued, short-term suspension of ACE inhibitors and ARBs can't be considered equivalent to never taking them, since they have long-lasting effects that persist due to structural and not only functional changes with chronic use.

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