COVID-19 Evidence Alerts
from McMaster PLUSTM

Current best evidence for clinical care (more info)

Treatment Bauer A, Schreinlechner M, Sappler N, et al. Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial. Lancet Respir Med. 2021 Aug;9(8):863-872. doi: 10.1016/S2213-2600(21)00214-9. Epub 2021 Jun 11.
Abstract

BACKGROUND: SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin-angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19.

METHODS: ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUCSOFA), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596.

FINDINGS: Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00-2·00) vs 1·00 (0·00-3·00); p=0·12). Discontinuation was associated with a significantly lower AUCSOFA (0·00 [0·00-9·25] vs 3·50 [0·00-23·50]; p=0·040), mean SOFA score (0·00 [0·00-0·31] vs 0·12 [0·00-0·78]; p=0·040), and 30-day SOFA score (0·00 [10-90th percentile, 0·00-1·20] vs 0·00 [0·00-24·00]; p=0·023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score =1) or were dead (p=0·017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group.

INTERPRETATION: Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options.

FUNDING: Austrian Science Fund and German Center for Cardiovascular Research.

Ratings
Discipline / Specialty Area Score
Cardiology
Endocrine
Hospital Doctor/Hospitalists
Internal Medicine
Infectious Disease
Emergency Medicine
Comments from MORE raters

Emergency Medicine rater

This is an interesting question that clearly remains unanswered. The relative risk for death was 150% in the continuation group, with an absolute increase of 4%, representing a number needed to treat (for death) of 25. It would certainly be worth doing something as simple as stopping a medication; however, with only 200 enrolled patients (across 35 centers), this difference was not statistically significant. These trends also go against the bulk of the observational data, including some very large datasets that have not found an association between these drugs and COVID mortality or severity.

Endocrine rater

This is a relatively small study adding to our previous knowledge of the subject and confirming the relative safety of continuing ACE-I therapy in patients with COVID-19.

Infectious Disease rater

Although a lot of information is available in this domain, this open label randomized study certainly adds credence to the ACEi inhibitors’ role in Covid-19 infection. Treatment teams should be wary of discontinuing ACEi.

Infectious Disease rater

This fairly small randomized trial found no benefit to discontinuing ACEI/ARB treatment in patients with COVID-19, reinforcing previous data from nonrandomized studies.

Internal Medicine rater

Important study that adds to the growing literature about not discontining RAS inhibitors in COVID-19. We wrote about this at the start of the pandemic, and I am glad we now have numerous trials providing iron-clad data.