Very early into the coronavirus disease 2019 (COVID-19) pandemic, several authors hypothesized that angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) may increase the risk for SARS-CoV-2 infection, raising the question of temporary treatment cessation during the pandemic or in patients with confirmed infection. The issue is highly controversial as others conversely argued that blockers of the renin-angiotensin system (RAS) might actually be beneficial in COVID-19 patients. Many observational studies have attempted to establish whether ACEI/ARBs increased the risk to get infected with COVID-19 and/or modified the prognosis of the disease in infected patients. While an increased risk to get infected seems to have been ruled out, studies regarding the association between exposure and outcome in patients with established infection yielded discrepant results. We analysed RAS blocker prescription before and during hospital stay in 347 patients hospitalized with COVID-19 in Bichat Hospital (Paris, France), and the corresponding outcomes, in order to explain these discrepant results. We found no significant association between chronic exposure to ACEI/ARBs and mortality, while in-hospital exposure was associated with a seemingly protective effect of these drugs. We demonstrated that the latter was biased, resulting from treatment cessation in patients with severe disease (a typical case of the so-called reverse causality), and from treatment continuation in stable patients (immortal-time bias). In conclusion, there are no data supporting discontinuation of RAS blockers during the pandemic. Observational studies are unsuited to guide management of these drugs after hospital admission: only randomized controlled trials will provide answers to this issue. In light of our results, conclusions of previous observational studies showing a protective effect of in-hospital exposure to RAS blockers need to be reconsidered.

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