Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial

Abstract

Background: Biological considerations suggest that renin-angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19.

Methods: The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin-angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin-angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin-angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009.

Findings: Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin-angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m² (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin-angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40-110] for continuation vs 81 [38-117] for discontinuation; β-coefficient 8 [95% CI -13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ² test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups.

Interpretation: Consistent with international society recommendations, renin-angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19.

Funding: REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants.

Figure 1

Trial profile ACEI=angiotensin-converting enzyme inhibitor. ARB=angiotensin receptor blocker.

Figure 2

Outcomes for the primary endpoint, all-cause death, and intensive care unit admission or invasive mechanical ventilation (A) The distribution of the primary endpoint (hierarchical rank score) in the continuation and discontinuation groups. The x-axis (and shaded area) shows the frequency density of rank distributions in each treatment group, the white dots show the median global rank score, the solid boxes show the IQR, and the vertical lines show the upper-adjacent and lower-adjacent values. (B) The cumulative hazard for all-cause death. (C) The cumulative hazard for intensive care unit admission or invasive mechanical ventilation.

Figure 3

Forest plot of the differences in rank scores across subgroups Positive values indicate better outcomes in the discontinuation group. The p value for all likelihood ratio tests for effect modification were >0·05. The dots represent the differences in median rank scores between participants in the continuation group versus the discontinuation group in each subgroup. The bars show the 95% CIs. For the figure, continuous variables (age and body-mass index) were stratified at the median value for the study population. ACEI=angiotensin-converting enzyme inhibitor. ARB=angiotensin receptor blocker.

Figure 4

Blood pressure, serum potassium concentration, and serum creatinine concentration during follow-up (A) The distribution of systolic blood pressure values during follow-up. (B) The distribution of serum potassium concentrations during follow-up. (C) The distribution of serum creatinine concentrations during follow-up. For all three panels, the x-axis (and shaded area) represents the frequency density of the parameter in each treatment group, the white dot shows the median value of the parameter, the solid box shows the IQR, and the vertical lines show the upper-adjacent and lower-adjacent values.