Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Death in Patients Hospitalised with COVID-19: A Retrospective Italian Cohort Study of 43,000 Patients

Gianluca Trifirò, Marco Massari, Roberto Da Cas, Francesca Menniti Ippolito, Janet Sultana, Salvatore Crisafulli, Paolo Giorgi Rossi, Massimiliano Marino, Manuel Zorzi, Emanuela Bovo, Olivia Leoni, Monica Ludergnani and Stefania Spila Alegiani ()
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Gianluca Trifirò: University of Messina
Marco Massari: National Centre for Drug Research and Evaluation, Istituto Superiore di Sanità
Roberto Da Cas: National Centre for Drug Research and Evaluation, Istituto Superiore di Sanità
Francesca Menniti Ippolito: National Centre for Drug Research and Evaluation, Istituto Superiore di Sanità
Janet Sultana: University of Messina
Salvatore Crisafulli: University of Messina
Paolo Giorgi Rossi: Azienda Unità Sanitaria Locale-IRCCS
Massimiliano Marino: Azienda Unità Sanitaria Locale-IRCCS
Manuel Zorzi: Azienda Zero - Department of Health of Veneto Region
Emanuela Bovo: Azienda Zero - Department of Health of Veneto Region
Olivia Leoni: Epidemiology Observatory - Department of Health of Lombardy Region
Monica Ludergnani: Epidemiology Observatory - Department of Health of Lombardy Region
Stefania Spila Alegiani: National Centre for Drug Research and Evaluation, Istituto Superiore di Sanità

Drug Safety, 2020, vol. 43, issue 12, No 11, 1297-1308

Abstract: Abstract Introduction The 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. Objective The 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. Methods This 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. Results Overall, 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. Conclusions ACEI/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.

Date: 2020
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DOI: 10.1007/s40264-020-00994-5

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