Lack of Benefit of Renin-Angiotensin System Inhibitors in COVID-19

Abstract

There has been considerable interest in the potential role of renin-angiotensin system (RAS) inhibitors in patients with COVID-19 given that angiotensin-converting enzyme 2 (ACE2) is the functional receptor for SARS-CoV-2. 1 Because ACE inhibitors and angiotensin receptor blockers (ARBs) may upregulate ACE2, there is a theoretical concern that these agents might increase susceptibility to, or the severity of, SARS-CoV-2 infection. Conversely, ACE2 is the primary enzyme breaking down angiotensin II and, in the process, produces angiotensin 1-7, a physiological antagonist of angiotensin II. SARS-CoV-2 downregulates ACE2, potentially leading to an increase in angiotensin II and reduced levels of angiotensin 1-7. Excess and unopposed angiotensin II may be harmful, and in experimental models of lung injury, administration of RAS inhibitors, ACE2, and angiotensin 1-7 reduced pulmonary damage and mortality. Consequently, there has been uncertainty about the place of RAS inhibitors in patients with COVID-19. 1 In this issue of JAMA, 3 randomized trials are reported 2,3 that extend the evidence base regarding the use of these agents in patients with COVID-19. 4 The Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) trial assessed the efficacy of initiating either an ACE inhibitor or ARB, compared with usual care, in 779 adult patients (721 critically ill and 58 non-critically ill) hospitalized for COVID-19 at 69 centers in 7 countries. Critical illness was defined as the need for at least 1 of the following organ supports in an intensive care unit: high-flow nasal cannula oxygenation, invasive or noninvasive mechanical ventilation, vasopressor, or inotropic infusion. Treatment was given for up to 10 days or until discharge, whichever came first. Neither ACE inhibitor nor ARB therapy were blinded, and doses were titrated according to the treating clinician's judgement. The primary outcome, evaluated over 21 days, was organ support-free days, a composite of hospital survival and duration of intensive care respiratory or cardiovascular support.REMAP-CAP was terminated prematurely, on advice from the data and safety monitoring board, due to safety concerns. Among critically ill patients, median (IQR) organ supportfree days was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231), corresponding to median adjusted odds ratios of 0.77 (95% credible interval, 0.58-1.06) for the ACE inhibitor group and 0.76 (95% credible interval, 0.56-1.05) for the ARB group compared with usual care (with odds ratios <1 representing worse outcomes compared with control). Among Opinion EDITORIAL

Role of the Renin-Angiotensin System in Long COVID’s Cardiovascular Injuries

“…Based on an assumption that overactivation of the RAS pathway would result in worse COVID-19 results, the REMAP-CAP investigators have studied the use of an ACE inhibitor or an ARB against no RAS inhibition [31]. In two trials, TXA-127 and TRV-027, respectively, which have both been evaluated versus placebo, researchers from the ACTIV-4 Host Tissue platform got a novel approach to correct imbalances in Ang (1-7) and Ang II caused by RAS dysregulation [32,33]. However, it should be noted that the US and European heart associations have recommended changing RAS-inhibitor administrations.…”