Use of renin–angiotensin–aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study

Abstract

Background Concerns have been raised about the possibility that inhibitors of the renin-angiotensin-aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19.Methods In this case-population study, we consecutively selected patients aged 18 years or older with a PCRconfirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437.Findings We collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39•0%) were female and the mean age was 69•1 years (SD 15•4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1•98, 95% CI 1•62-2•41) and risk factors (1•46, 1•23-1•73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0•94 (95% CI 0•77-1•15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0•80, 0•64-1•00) or angiotensin-receptor blockers (1•10, 0•88-1•37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0•53, 95% CI 0•34-0•80). The adjusted ORs were similar across severity degrees of COVID-19.Interpretation RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19.Funding Instituto de Salud Carlos III.

Use of distinct anti‐hypertensive drugs and risk for COVID‐19 among hypertensive people: A population‐based cohort study in Southern Catalonia, Spain

“…Our results are in accordance with data reported in two recent large population‐based case‐control studies conducted in Lombardy (Italy) and Madrid (Spain), where neither ACEIs nor ARBs were associated with the likelihood of SARS‐CoV‐2 infection in hospitalized patients 8,9 …”

“…Concerns have been raised about the possible association between the use of RAAS inhibitors (mainly ACEIs and/or ARBs) with the risk of SARS‐CoV‐2 infection, the risk of severe COVID‐19 among those infected, or the risk of in‐hospital death among those with a positive test 4,5,6 . Several studies have concluded that there is no evidence of poor outcomes (increased severity or in‐hospital death) in patients infected with SARS‐CoV‐2 taking RAAS inhibitors 8,9,10 . A recent review even concluded that ACEIs and ARBs may be associated with lower incidence and/or improved outcome in patients with lower respiratory tract infection, 20 But there are not data assessing specifically whether the previous use of RAAS inhibitors affects the likelihood of COVID‐19 infection in ambulatory patients.…”

“…Since ACE2 was identified as functional receptors to SARS‐CoV‐2, 7 it has been speculated that renin‐angiotensin‐aldosterone system (RAAS) inhibition could increase ACE2 expression and, thus, ACEIs/ARBs might be harmful in patients with COVID‐19 4,5,6 . However, most recent publications have not found evidence of harm with the continued use of RAAS inhibitors 8,9,10 . Of note, while some studies have examined the relationship between the ambulatory use of RAAS inhibitors and severe outcomes (hospital or ICU admission or death), 8,9,10 there is less evidence about the association with mild outcomes (such as COVID‐19 cases not requiring hospital admission).…”

“…However, most recent publications have not found evidence of harm with the continued use of RAAS inhibitors 8,9,10 . Of note, while some studies have examined the relationship between the ambulatory use of RAAS inhibitors and severe outcomes (hospital or ICU admission or death), 8,9,10 there is less evidence about the association with mild outcomes (such as COVID‐19 cases not requiring hospital admission).…”

Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and The Risk of SARS-CoV-2 Infection: A Systematic Review and Meta-analysis 

“…Six case control studies [17][18][19][20][21][22][23] that enrolled a total of 5657 patients (2536 patients in ACEIs arm and 3121 patients in ARBs arm ) and 721,859 controls were included in our meta-analysis. Figure 1 shows the result of our search strategy.…”