Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial

Abstract

Importance: It is unknown whether angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have a positive, neutral, or negative effect on clinical outcomes in patients with coronavirus disease 2019 (COVID-19).

Objective: To determine whether discontinuation compared with continuation of ACEIs or ARBs changed the number of days alive and out of the hospital through 30 days.

Design, setting, and participants: A randomized clinical trial of 659 patients hospitalized in Brazil with mild to moderate COVID-19 who were taking ACEIs or ARBs prior to hospitalization (enrolled: April 9-June 26, 2020; final follow-up: July 26, 2020).

Interventions: Discontinuation (n = 334) or continuation (n = 325) of ACEIs or ARBs.

Main outcomes and measures: The primary outcome was the number of days alive and out of the hospital through 30 days. Secondary outcomes included death, cardiovascular death, and COVID-19 progression.

Results: Among 659 patients, the median age was 55.1 years (interquartile range [IQR], 46.1-65.0 years), 14.7% were aged 70 years or older, 40.4% were women, and 100% completed the trial. The median time from symptom onset to hospital admission was 6 days (IQR, 4-9 days) and 27.2% of patients had an oxygen saturation of less than 94% of room air at baseline. In terms of clinical severity, 57.1% of patients were considered mild at hospital admission and 42.9% were considered moderate. There was no significant difference in the number of days alive and out of the hospital in patients in the discontinuation group (mean, 21.9 days [SD, 8 days]) vs patients in the continuation group (mean, 22.9 days [SD, 7.1 days]) and the mean ratio was 0.95 (95% CI, 0.90-1.01). There also was no statistically significant difference in death (2.7% for the discontinuation group vs 2.8% for the continuation group; odds ratio [OR], 0.97 [95% CI, 0.38-2.52]), cardiovascular death (0.6% vs 0.3%, respectively; OR, 1.95 [95% CI, 0.19-42.12]), or COVID-19 progression (38.3% vs 32.3%; OR, 1.30 [95% CI, 0.95-1.80]). 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%, respectively), 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%).

Conclusions and relevance: Among patients hospitalized with mild to moderate COVID-19 and who were taking ACEIs or ARBs before hospital admission, there was no significant difference in the mean number of days alive and out of the hospital for those assigned to discontinue vs continue these medications. 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.

Trial registration: ClinicalTrials.gov Identifier: NCT04364893.

Figure 1.. Study Enrollment and Analysis in the BRACE CORONA Trial on the Use of Angiotensin-Converting Enzyme Inhibitors (ACEIs) or Angiotensin II Receptor Blockers (ARBs) Among Patients Hospitalized With Coronavirus Disease 2019 (COVID-19)

^aMay have met more than 1 exclusion criterion.

Figure 2.. Primary Outcome and Clinical Status at 30 Days

For the primary outcome, the mean number of days alive and out of the hospital was 21.9 days (SD, 8.0 days) in the discontinue use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) group vs 22.9 days (SD, 7.1 days) in the continue use of ACEI or ARB group (median, 25.0 days [interquartile range, 20.0-27.0 days] vs 25.0 days [interquartile range, 21.0-27.0 days], respectively) and the between-group mean ratio was 0.95 (95% CI, 0.90-1.01; P = .09).

Figure 3.. Subgroup Analysis for the Primary Outcome

ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; CT, computed tomographic; RAAS, renin-angiotensin-aldosterone system. ^aThe subgroup analyses were performed using the same generalized additive model of location, scale, and shape with beta binomial distribution inflated at zero that was used for the primary outcome, including interaction terms between each subgroup and study treatments. ^bCalculated as weight in kilograms divided by height in meters squared. ^cEstimated by visual assessment performed by a radiologist. ^dDefined as change in clinical severity status during hospitalization. Mild defined as blood oxygen saturation of 94% or greater and lung infiltrates less than or equal to 50%; moderate, blood oxygen saturation less than 94%, or lung infiltrates greater than 50%, or ratio of partial pressure of arterial oxygen to fraction of inspired oxygen less than 300; and severe, invasive mechanical ventilation or hemodynamic instability or multiple organ dysfunction or failure.