A recent trial by Dr. Jordana B Cohen, published in The LANCET, indicated that consistent with international society recommendations, patients admitted to the hospital with COVID-19 can safely continue treatment with renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB)) unless there is a distinct medical contraindication to ongoing therapy.
Starting in December 2019, the COVID-19 pandemic has caused high morbidity and mortality worldwide. Patients with cardiovascular disease, diabetes, and hypertension have been recognized as those at the highest risk of hospital admission and mortality due to this infection. Renin-angiotensin system inhibitors are among the most commonly used medications by these patients. Given that COVID-19 uses Angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells, there is concern among clinicians regarding the impact of renin-angiotensin system inhibitors and COVID-19 infection. The REPLACE COVID trial evaluated whether continuation or cessation of these medications in patients who are admitted to hospital with COVID-19 affects acute hospitalization outcomes.
The REPLACE COVID, a prospective, multicenter, open-label trial, recruited participants who were admitted to the hospital with COVID-19 and were taking a renin-angiotensin system inhibitor before admission. The study excluded patients with a negative test result of COVID-19 and contraindications to continuation or cessation of renin-angiotensin system inhibitors. A permuted block randomization, with allocation using a secure web-based system, was used for the randomization process. The primary endpoint of the study was a global rank score in which participants were ranked across four hierarchical tiers including time to death, duration of invasive mechanical ventilation or extracorporeal membrane oxygenation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalization.
A total of 152 patients hospitalized with COVID-19 were randomized in a 1:1 ratio to discontinue angiotensin-converting enzyme inhibitors or angiotensin receptor blockers therapy or continue their treatment at the previously recommended dose over the course of hospitalization (continuation group n=75; discontinuation group n=77). In the primary intention-to-treat analyses no significant differences were observed in the global rank score of the two groups (median rank: 73 [IQR: 40–110] for continuation vs. median rank: 81 [IQR: 38–117] for discontinuation; β-coefficient: 8 [95% CI: 13-29]). A total of 16 out of 75 participants in the continuation arm and 14 out of 77 in the discontinuation arm required intensive care unit admission or invasive mechanical ventilation. No difference was observed in blood pressure, serum potassium, or creatinine during follow-up across the two groups.
The study demonstrated that ACEI or ARB continuation therapy in patients admitted with COVID-19 did not affect the COVID-19 severity during the hospitalization. The results of this trial were in line with previously published observational studies, which have generally shown no difference in the risk of SARS-CoV-2 infection and COVID-19 severity among patients who are treated with renin-angiotensin system inhibitors compared with those who are not.
There are several caveats that should be taken into account while interpreting the results of this trial. First, the sample size was small, which decreases the power of the study. Second, although the two arms of the study were balanced in terms of baseline covariates, the use of ACEI therapy was significantly different between the two groups. Finally, the trial was open-label, and providers were aware of the patient’s medication use or discontinuation.
In conclusion, the REPLACE COVID trial demonstrated that ACEI and ARBS can be safely continued among patients hospitalized with COVID-19.