E. Vidal-Petiot, N. Gault
BMC Medicine, 2021
Background Early in the coronavirus 2019 (COVID-19) pandemic, angiotensin-converting enzyme 2 (ACE2)—the main counter-regulatory enzyme of the classical reninangiotensin system (RAS)—was identified as the receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two contradictory hypotheses emerged in the scientific literature. Some authors warned against the potential deleterious effect of RAS blockers, which had been shown to increase ACE2 expression in some animal models [1], and advocated for the preventive discontinuation of these drugs [2]. In contrast, others argued that RAS blockers may be beneficial against SARS-CoV-2-induced acute lung injury and should even be introduced in patients with COVID-19 [1, 3]. The latter hypothesis relied on experimental murine models of acute lung injury demonstrating the protective role of ACE2, via the anti-inflammatory and anti-fibrotic actions of angiotensin (1–7) after binding to its Mas receptor, and the deleterious role of ACE, via the actions of angiotensin II after binging to its type 1 receptor (AT1R) [1]. SARS-CoV-2 allegedly downregulates ACE2 and thereby amplifies angiotensin II-mediated injury: RAS blockers, and in particular AT1-R blockers (ARBs), may thus help restore the disrupted ACE2-angiotensin (1–7)/ ACE-angiotensin II homeostasis [3]. Main text Multiple observational studies were conducted to clarify this controversial issue and showed no significant association between the chronic use of RAS blockers and either the risk to contract an infection or the risk the develop a severe or lethal form of the disease in infected patients, [4] confirming the statements of scientific societies which all took position against the preventive discontinuation of these drugs. In contrast, most observational studies which analyzed in-hospital exposure to RAS-blockers concluded in favor of a strong protective effect associated with treatment continuation [1, 5]. However, among the myriad of observational studies published on RAS blockers and COVID-19 since the SARS-CoV-2 outbreak, many have suffered from important methodological limitations [6]. In particular, studies based on in-hospital treatment exposure were criticized for being majorly biased [5]. Exposure assignment in these studies generated immortal-time bias (patients have to survive, or be clinically stable, long enough to achieve the exposure) and a strong indication bias. After hospital admission, RAS blockers tend to be continued in healthier patients and discontinued in patients with hypotension, acute kidney injury, or admitted in intensive care unit, hence with severe forms of the disease, the so-called healthy user-sick stopper bias [5]. Authors often disregarded this typical case of reverse causality and concluded that treatment discontinuation caused disease severity, when the causal relationship was the other way around (disease severity caused treatment discontinuation, and benign disease allowed treatment continuation).
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Field of study: Medicine