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. 2020 May 30;395(10238):1705-1714.
doi: 10.1016/S0140-6736(20)31030-8. Epub 2020 May 14.

Use of Renin-Angiotensin-Aldosterone System Inhibitors and Risk of COVID-19 Requiring Admission to Hospital: A Case-Population Study

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Use of Renin-Angiotensin-Aldosterone System Inhibitors and Risk of COVID-19 Requiring Admission to Hospital: A Case-Population Study

Francisco J de Abajo et al. Lancet. .
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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 PCR-confirmed 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.


Figure 1
Figure 1
Case-population study design COVID-19 cases requiring admission to hospital were selected consecutively from seven hospitals in Madrid, Spain. Data were collected for ten individuals per case who were matched for age, sex, and index date (day and month) of hospital admission of cases (matched controls) from the 2018 Madrid region database of BIFAP, a national primary health-care database. Drug exposure and comorbidities before the index date (2020 for cases and 2018 for controls) were collected from primary health-care records of the NHS in Madrid: for cases through HORUS (an online platform to access primary-care clinical records from any health-care centre of the NHS in Madrid) and for controls through BIFAP. BIFAP=Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria. NHS=National Health System.
Figure 2
Figure 2
Association between current use of RAAS inhibitors and risk of COVID-19 requiring admission to hospital compared with current use of other antihypertensive drugs, stratified by different variables Number (%) of cases and controls given is the number exposed to RAAS inhibitors in each stratum and the resulting odds ratio, adjusted for the matching variables and other comorbidities different from the one examined. RAAS=renin–angiotensin–aldosterone system.

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