Modulation of the Renin-Angiotensin System against COVID-19: A path forward?

Soon after the pandemic outbreak in 2020, it was proposed that binding of SARS-CoV-2 to the angiotensin converting enzyme-2 may explain most of COVID-19's manifestations. Therefore, manipulation of the renin-angiotensin system (RAS) by using well known and commercialized blockers of its classical arm or by repurposing new stimulators of the alternative RAS pathway in clinical development was seen as a potentially effective strategy for the treatment of COVID-19. Moreover, this therapeutic approach had previously shown significant promise in the treatment of other respiratory viral respiratory infections and forms of acute respiratory distress syndrome. Consequently, several randomized clinical trials (RCTs) were launched to test the efficacy of rebalancing the RAS to reduce the severity of COVID-19. While most of these trials produced neutral results, certain studies reached their primary endpoints. In the present collaborative review, sponsors and main investigators of some of these trials attempt to reach a consensus regarding their clinical significance and which factors influenced their differing outcomes. The knowledge gained through the careful analysis of these RCTs of RAS modulators in patients with severe COVID-19 may prove useful for other forms of acute lung injury.