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.

COVID-19 and metabolic syndrome

“…Benefits and risks of common medications used in metabolic syndrome management in the setting of COVID-19 are an area of intense research and discussion and have been reviewed in detail elsewhere [68] , [69] , [70] , [71*] , [72] , [73] . Data from meta-analyses [74] , [75] , [76] , [77] , [78] , [79] , [80] , [81] , [82] , [83] , observational studies [25] and randomized controlled trials [84] , [85*] , [86] , [87] , [88*] , [89] have emerged while several studies are on-going. These are summarized in Table 2 .…”

“… Enhancing ACE2 expression – increases risk of viral entry, but decreases in inflammatory response [68] ↓mortality (MOB) b [76] - semaglutide [NCT04615871] DPP4 inhibitors Possible benefit through favourable immunomodulatory and anti-fibrotic effects [68] ↓ or ↔ mortality (MOB) b [78] ↓ mortality (MOB) b [78] linagliptin [NCT04542213], sitagliptin [NCT04365517] Insulin Possible harm through proinflammatory response and formation of reactive oxygen species [69] ↑mortality (MOB) b [77] - NCT04542213 (insulin vs linagliptin) Despite theoretical risks and observational data of harm, insulin remains the best option for glucose control in critically ill Statins Possible benefit through anti-inflammatory effects and limiting viral entry in to cells [70] ↓mortality (MOB) b [79] ↓mortality (MOB) b [82] [NCT04486508, NCT04631536., NCT04472611, NCT04904536] Continue during pandemic / acute infection – guided by standard cautions / contraindications Consider interactions with remdesivir / other antivirals [90] Omega-3 fatty acids Possible benefit through favourable immunomodulation [70] - ↓ symptoms and mortality (RCT) d [86] NCT04647604 Continue during pandemic / acute infection – guided by standard cautions / contraindications: Consider risks of: AKI with ACEI Major bleeding with aspirin ACEI/ARB Possible benefit through suppression of RAS activation. Increases ACE2 – benefit of anti-inflammatory effects of Ang-II likely to override the risk of facilitation of viral entry in to cells [71] ↓mortality (MOB) b [80] ↔ mortality & ↑ AKI (MCT) [83] , ...…”

Hypertension management before and under the COVID-19 pandemic: lessons and future directions

“…And there are also no clinical reports showing that oral RAS inhibitors make COVID-19 more likely or more severe. In this meaning, there is no clear rationale for changing or discontinuing RAS inhibitors [ 9 – 12 ]. It is now recommended by the various relevant societies that hypertension treatment with anti-hypertensive medication including RAS inhibitors should be continued in accordance with current guidelines [ 13 – 15 ].…”

A Review of Heart Failure in Patients with COVID-19

“…However, multiple subsequent studies found no relationship between the use of ACEIs or ARBs and the severity of COVID-19 infection, and a meta-analysis of 11 randomized controlled trials suggested no difference in the risk of all-cause mortality. 16 Overall, despite longer length of stay and higher short-term mortality in patients with HF and concomitant COVID-19 infection, adherence to heart failure quality measures such as sustained to minimally increased prescription of guideline-directed medical therapies was largely maintained during the pandemic. 17 In terms of withdrawing from guideline-directed medical therapy (GDMT) and mortality rates, discontinuing the GDMT medications prescribed during hospitalization was significantly associated with an increased risk of in-hospital mortality.…”