REPLACE COVID: No Reason to Discontinue ACEs/ARBs in Hospitalized COVID-19 Patients

Patrick Campbell

Results of the REPLACE COVID trial offer clinicians an opportunity to better understand the impact of discontinuing therapy with ACEs or ARBs.

New data from a clinical trial conducted by the Perelman School of Medicine at the University of Pennsylvania found there was no additional risk incurred by patients taking ACE inhibitors or ARBs when hospitalized with coronavirus disease 2019 (COVID-19).

After some initial data suggested use of these agents could upregulate cellular receptors for the SARS-CoV-2 virus, the trial, which was named REPLACE COVID, results of the study indicate patients can continue taking either hypertension medication safely if hospitalized with COVID-19.

"Observational studies were rapidly done, but randomized trials are important to establish a definitive answer regarding the potential impact of these commonly used blood pressure medications in the setting of COVID-19," said senior investigator Julio A. Chirinos, MD, PhD, an associate professor of Cardiovascular Medicine in the Perelman School of Medicine, in a statement. "Our trial results importantly show that these medications can be safely continued for patients hospitalized with COVID-19."

Early in the COVID-19 pandemic, cardiologists became inundated with concerns and worry over the impact of the novel disease on their patients. Chief among these concerns were early reports detailing increased risk of blood clotting and observational studies suggesting uses of ACEs and ARBs could increase risk of viral replication or disease severity.

While major organizations released statements advocating for these therapies to be continued, investigators from Penn Medicine sought to determine the effect of ACEs/ARBs in a randomized clinical trial. The REPLACE COVID trial was designed as a prospective, randomized, open-label trial conducted across 20 hospitals in 7 countries.

Beginning on March 31, 2020 and ending on August 20, 2020, investigators enrolled 152 participants and randomly assigned them to continue or discontinue use of the aforementioned therapies. In total, 75 patients were randomized to continuation and 77 were randomized to discontinuation. The mean age of participants included in the study was 62 (SD, 12) years, 45% were female, the mean BMI was 33 (SD, 8) kg/m2, and 52% had diabetes.

All patients included in the study were randomized in a 1:1 ratio using permuted block randomization. All patients included in the study were aged 18 years or older, were receiving ACEs or ARBs prior to hospital admission, and must have been hospitalized with COVID-19. The primary outcome of the study was a global rank score where participants were ranked across 4 tiers—this score incorporated data related to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalization.

When comparing to discontinuation, results indicated continuation had no effect one global rank score (Continuation: median rank 73 [IQR, 40-110] vs Discontinuation: 81 [IQR, 38-117]; β-coefficient 8 [95% CI, −13 to 29]). Further analysis indicated 21% of the continuation arm and 18% of the discontinuation arm required intensive care unit admission or invasive mechanical ventilation. Additionally, results indicated 15% of the continuation group and 13% of the discontinuation group died during the study.

Investigators also pointed out 39% of the continuation group and 36% of the discontinuation group experienced at least one adverse events during the study (χ2 test of adverse events between treatment groups P=.77). Further analysis indicated there was no differences in blood pressure, serum potassium, or creatinine during the follow-up in both groups.

"At the start of the pandemic, patients were worried about perceived harm based on limited and incomplete information, and unfortunately, some insisted on stopping their medications. However, stopping these medications unnecessarily can increase the risk for severe complications, including heart attack and stroke," said study investigator Jordana Cohen, MD, MSCE, an assistant professor in the division of Renal-Electrolyte and Hypertension, and a co-principal investigator with Chirinos, in the aforementioned statement. "Now we have high quality evidence to support our recommendation that patients continue to take these medications as prescribed."

This study, “Continuation versus discontinuation of renin–angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial,” was published in The Lancet Respiratory Medicine.