Renin-Angiotensin System Inhibitors in Patients With COVID-19: A Meta-Analysis of Randomized Controlled Trials Led by the International Society of Hypertension

Abstract

Background Published randomized controlled trials are underpowered for binary clinical end points to assess the safety and efficacy of renin-angiotensin system inhibitors (RASi) in adults with COVID-19. We therefore performed a meta-analysis to assess the safety and efficacy of RASi in adults with COVID-19. Methods and Results MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane Controlled Trial Register were searched for randomized controlled trials that randomly assigned patients with COVID-19 to RASi continuation/commencement versus no RASi therapy. The primary outcome was all-cause mortality at ≤30 days. A total of 14 randomized controlled trials met the inclusion criteria and enrolled 1838 participants (aged 59 years, 58% men, mean follow-up 26 days). Of the trials, 11 contributed data. We found no effect of RASi versus control on all-cause mortality (7.2% versus 7.5%; relative risk [RR], 0.95; [95% CI, 0.69-1.30]) either overall or in subgroups defined by COVID-19 severity or trial type. Network meta-analysis identified no difference between angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers. RASi users had a nonsignificant reduction in acute myocardial infarction (2.1% versus 3.6%; RR, 0.59; [95% CI, 0.33-1.06]), but increased risk of acute kidney injury (7.0% versus 3.6%; RR, 1.82; [95% CI, 1.05-3.16]), in trials that initiated and continued RASi. There was no increase in need for dialysis or differences in congestive cardiac failure, cerebrovascular events, venous thromboembolism, hospitalization, intensive care admission, inotropes, or mechanical ventilation. Conclusions This meta-analysis of randomized controlled trials evaluating angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers versus control in patients with COVID-19 found no difference in all-cause mortality, a borderline decrease in myocardial infarction, and an increased risk of acute kidney injury with RASi. Our findings provide strong evidence that RASi can be used safely in patients with COVID-19.

Keywords: COVID‐19; acute kidney injury; angiotensin II receptor blockers; angiotensin‐converting enzyme inhibitors; hypertension; renin‐angiotensin system inhibitors.

Figure 1. Flowchart of study selection methodology.

Figure 2. Outcomes at short‐term follow‐up (≤30 days)., , , , , , , ,

ACEI‐COVID, the stopping ace‐inhibitors in COVID‐19 trial; ALPS‐COVID IP, angiotensin receptor blocker based lung protective strategy for COVID‐19 inpatient trial; ALPS‐COVID OP, angiotensin receptor blocker based lung protective strategy for COVID‐19 outpatient trial; BRACE CORONA, blockers of angiotensin receptor and angiotensin‐converting enzyme inhibitors suspension in hospitalized patients with coronavirus infection; COVERAGE‐France, randomized trial to evaluate the safety and efficacy of outpatient treatments to reduce the risk of worsening in individuals with COVID‐19 with risk factors; COVID MED, comparison of therapeutics for hospitalized patients infected with SARS‐CoV‐2; M‐H indicates Mantel–Haenszel; PRAETORIAN‐COVID, randomised clinical trial with valsartan for prevention of acute respiratory distress syndrome in hospitalised patients with SARS‐COV‐2 infection disease; RAAS‐COVID, renin‐angiotensin aldosterone system inhibitors in COVID‐19 trial; RASi, renin‐angiotensin system inhibitors; REPLACE COVID, the randomized elimination or prolongation of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in coronavirus disease 2019; STAR‐COVID, telmisartan in respiratory failure due to COVID‐19; and SWITCH‐COVID, switch of renin‐angiotensin system inhibitors in patients with COVID‐19.

Figure 3. Adverse outcomes at short‐term follow‐up (≤30 days)., , , , , , , ,

ACEI‐COVID, the stopping ace‐inhibitors in COVID‐19 trial; ALPS‐COVID IP, angiotensin receptor blocker based lung protective strategy for COVID‐19 inpatient trial; ALPS‐COVID OP, angiotensin receptor blocker based lung protective strategy for COVID‐19 outpatient trial; BRACE CORONA, blockers of angiotensin receptor and angiotensin‐converting enzyme inhibitors suspension in hospitalized patients with coronavirus infection; COVERAGE‐France, randomized trial to evaluate the safety and efficacy of outpatient treatments to reduce the risk of worsening in individuals with COVID‐19 with risk factors; COVID MED, comparison of therapeutics for hospitalized patients infected with SARS‐CoV‐2; M‐H indicates Mantel–Haenszel; PRAETORIAN‐COVID, randomised clinical trial with valsartan for prevention of acute respiratory distress syndrome in hospitalised patients with SARS‐COV‐2 infection disease; RAAS‐COVID, renin‐angiotensin aldosterone system inhibitors in COVID‐19 trial; RASi, renin‐angiotensin system inhibitors; REPLACE COVID, the randomized elimination or prolongation of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in coronavirus disease 2019; STAR‐COVID, telmisartan in respiratory failure due to COVID‐19; and SWITCH‐COVID, switch of renin‐angiotensin system inhibitors in patients with COVID‐19.