• Gianluca Trifirò, Marco Massari, Roberto Da Cas, Menniti Ippolito Francesca F Pharmacoepidemiology Unit, National Centre for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rom, Janet Sultana, Salvatore Crisafulli, Paolo Giorgi Rossi, Massimiliano Marino, Manuel Zorzi, Emanuela Bovo, Olivia Leoni, Monica Ludergnani, Stefania Spila Alegiani, and ITA-COVID-19: RAAS inhibitor group.
• Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy.
• Drug Saf. 2020 Dec 1; 43 (12): 1297-1308.

IntroductionThe epidemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been spreading globally, raising increasing concerns. There are several controversial hypotheses on the potentially harmful or beneficial effects of antihypertensive drugs acting on the renin-angiotensin-aldosterone system (RAAS) in coronavirus disease 2019 (COVID-19). Furthermore, there is accumulating evidence, based on several observational studies, that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) do not increase the risk of contracting SARS-CoV-2 infection. On the other hand, conflicting findings regarding the role of ACEIs/ARBs as prognosis modifiers in COVID-19 hospitalised patients have been reported.ObjectiveThe aim of this large-scale, retrospective cohort study was to investigate whether prior exposure to ACEIs and/or ARBs was associated with all-cause mortality among over 40,000 hospitalised COVID-19 patients compared with calcium channel blockers (CCBs), a potential therapeutic alternative.MethodsThis study was conducted using COVID-19 registries linked to claims databases from Lombardy, Veneto and Reggio Emilia (overall, 25% of Italian population). Overall, 42,926 patients hospitalised between 21 February and 21 April 2020 with a diagnosis of COVID-19 confirmed by real-time polymerase chain reaction tests were included in this study. All-cause mortality occurring in or out of hospital, as reported in the COVID-19 registry, was estimated. Using Cox models, adjusted hazard ratios (HRs) of all-cause mortality (along with 95% confidence intervals [CIs]) were estimated separately for ACEIs/ARBs and other antihypertensives versus CCBs and non-use.ResultsOverall, 11,205 in- and out-of-hospital deaths occurred over a median of 24 days of follow-up after hospital admission due to COVID-19. Compared with CCBs, adjusted analyses showed no difference in the risk of death among ACEI (HR 0.97, 95% CI 0.89-1.06) or ARB (HR 0.98, 95% CI 0.89-1.06) users. When non-use of antihypertensives was considered as a comparator, a modest statistically significant increase in mortality risk was observed for any antihypertensive use. However, when restricting to drugs with antihypertensive indications only, these marginal increases disappeared. Sensitivity and subgroup analyses confirmed our main findings.ConclusionsACEI/ARB use is not associated with either an increased or decreased risk of all-cause mortality, compared with CCB use, in the largest cohort of hospitalised COVID-19 patients exposed to these drugs studied to date. The use of these drugs therefore does not affect the prognosis of COVID-19. This finding strengthens recommendations of international regulatory agencies about not withdrawing/switching ACEI/ARB treatments to modify COVID-19 prognosis.

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