Hospitalized COVID-19 patients may safely continue taking their angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), according to the small REPLACE COVID trial.
The study’s primary hierarchical endpoint — a global rank score in which patients were ranked by the severity of their COVID disease course according to various biomarkers and clinical events, with a lower rank score meaning more severe COVID-19 hospitalization — was about the same whether people were randomized to continue or discontinue these common blood pressure medications (median rank 73 vs 81, β-coefficient 8, 95% CI –13 to 29).
Continuation and discontinuation groups also showed no differences in the secondary endpoints of:
- All-cause death: 15% vs 13% (P=0.99)
- At least one adverse event: 39% vs 36% (P=0.77)
- Length of hospitalization: 6 vs 5 days (P=0.56)
The REPLACE COVID results were reported by Julio Chirinos, MD, PhD, of the University of Pennsylvania in Philadelphia, and colleagues, and published online in The Lancet Respiratory Medicine.
“Consistent with current international society recommendations, providers should continue to prescribe these medications in patients admitted to hospital with COVID-19 unless there is a distinct medical contraindication to ongoing therapy,” the trialists concluded.
Their results are consistent with observational studies as well as the larger BRACE CORONA trial, which found COVID-19 patients in Brazil to have similar outcomes whether they stayed on or stopped taking their ACE inhibitors or ARBs in the hospital.
“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 co-author Jordana Cohen, MD, MSCE, also of the the University of Pennsylvania, in a Penn Medicine press release.
It had been theorized that renin-angiotensin system (RAS) inhibitor use might lead to increased cellular expression of ACE2, a receptor for SARS-CoV-2, thereby facilitating coronavirus entry into host cells.
A counter hypothesis suggested that ACE2 upregulation could be protective as it results in anti-inflammatory effects in the lung.
Yet both points may be moot, according to recent evidence cited by Bryan Williams, MD, of University College London.
“The irony is, that alongside these RCTs [randomized controlled trials], we have also discovered that the COVID-19 RAS-inhibition controversy was most likely ill-founded in the first place, as recent data suggest that these drugs do not seem to increase ACE2 expression, especially in the lung, after all,” Williams wrote in an accompanying editorial.
REPLACE COVID was conducted as an open-label trial at 20 large hospitals in the U.S., Canada, Mexico, Sweden, Peru, Bolivia, and Argentina.
From March 31 to August 20, people were recruited upon admission to the hospital for COVID-19. Eligible patients were 152 adults on ACE inhibitors or ARBs before hospitalization who tested positive for SARS-CoV-2 infection by polymerase chain reaction testing (except one person who had a clinical presentation consistent with COVID-19 and died before testing was possible).
Mean age was 62 years, and 45% were women. Body mass index (BMI) averaged 33, and the prevalence of diabetes was 52%.
Participants were randomized to continuation of the RAS inhibitor dose previously prescribed during routine care (75 patients) vs discontinuation of RAS inhibitors and temporary use of other antihypertensive classes instead (77 patients).
Chirinos’ group noted that there was no effect modification by age, sex, race, baseline ACE inhibitor versus ARB therapy, chronic kidney disease, diabetes, or BMI for the primary endpoint of the global rank score.
There was also no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups.
Intensive care unit admission or invasive mechanical ventilation, an exploratory endpoint, occurred at similar rates between groups (21% vs 18%, P=0.61).
The study authors noted that treating clinicians were allowed to change a patient’s RAS inhibitor strategy in response to an adverse event (e.g., hypotension, severe uncontrolled hypertension, acute kidney injury, hyperkalemia, new-onset heart failure with reduced ejection fraction).
As a result, there were substantial crossovers: the continuation group had 17 people discontinue ACE inhibitors and ARBs, and the discontinuation group had seven re-initiate their use of these medications.
Sensitivity analyses censoring patients at the time of crossover were consistent with the primary intention-to-treat analysis.
Major limitations of REPLACE COVID include its small sample and lack of blinding of bedside clinicians, the researchers noted.
“Alone, a small study like this one would not provide sufficient reassurance regarding the impact of RAS inhibition on the outcomes of patients hospitalized with COVID-19,” Williams said. “Nor does it address the question about whether chronic treatment with RAS inhibition affects the risk of becoming infected in the first place.”
Moreover, he cautioned that REPLACE COVID and BRACE CORONA both included participants who were younger than those typically hospitalized with COVID-19, and that people taking RAS inhibitors for heart failure were excluded.
REPLACE COVID was supported by participating investigators and centers.
Chirinos reported consulting relationships with Sanifit, Bristol Myers Squibb, Edwards Lifesciences, Bayer, and Johnson & Johnson; research grants from the National Institutes of Health, Microsoft, Fukuda-Denshi, and Bristol Myers Squibb; compensation from the American Heart Association and the American College of Cardiology for editorial roles; and visiting speaker honoraria from Washington University and University of Utah.
Williams reported receiving honoraria from Pfizer, Daiichi Sankyo, Boehringer Ingelheim, Menarini, and Servier.