Current best evidence for clinical care (more info)
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; ß-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 (?2 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.
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Small study but important conclusion.
This randomized trial adds to the evidence that ACE-inhibitor treatment can be safely continued in patients with COVID-19 infection.
As many patients I treat for COVID are on ACE/ARB, this study with good design and outcome points gives me confidence in continuing their medications.
The study addresses an important unresolved issue about the use of ACEI/ARBs in COVID. It is clearly demonstrated that renin–angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19; however, the study had a small-sized population with its consequent limitations.
As a US hospitalist, COVID is pretty much all we are seeing. We have been continuing ACE inhibition if there is no AKI, or restarting it when AKI clears, but this is based on retrospective data. This study uses a nice design that accounts for death, ventilator use, and renal replacement and found no difference in patients randomized to stopping ACE-inhibition versus continuing. At this point, I will continue to follow the guidelines that recommend continuing if possible. Whether it is useful to start someone on de novo was not answered by this trial.
Well done study to document that ACE-inhibitors do not effect the outcome of COVID-19 (that enters cells via the ACE-associate spike protein).