Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people

Hippisley‐Cox, Julia; Young, Duncan; Coupland, Carol; Channon, Keith M.; Tan, Pui San; Harrison, David A; Rowan, Kathy; Aveyard, Paul; Pavord, Ian; Watkinson, Peter

doi:10.1136/heartjnl-2020-317393

Cited by 325 publications

(299 citation statements)

References 27 publications

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“…Another study in France by Liabeuf [21]. Interestingly, in another large cohort study from the UK, Black Africans on ACEI/ARB were found to have higher risk of COVID-19 disease [50]. Our population may be considered similar to a study conducted in Turkey [51].…”

Section: Discussionsupporting

confidence: 65%

Severity of COVID-19 Infection in ACEI/ARB Users in Two Saudi Public Specialty Hospitals; Retrospective Cohort Study

Alrashed

Khan

Alhusseini

et al. 2020

Preprint

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The uncertainty about COVID-19 outcomes in angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) users continues with contradictory findings. The aim of this study was to determine the effect of ACEI/ARB use in patients with severe COVID-19. This retrospective cohort study done in two Saudi public specialty hospitals designated as COVID-19 referral facilities. We included 354 patients with confirmed diagnosis of COVID-19 between April and June 2020, of which 146 were ACEI/ARB users and 208 were non-ACEI/ARB users. Controlling for confounders, we conducted a multivariate logistic regression and a sensitivity analysis using propensity score matched (PSM) patients. Compared to non-ACEI/ARB users, ACEI/ARB users had an eight-fold higher risk of developing critical or severe COVID-19 (OR=8.25, 95%CI=3.32-20.53); a nearly 7-fold higher risk of intensive care unit (ICU) admission (OR=6.76, 95%CI=2.88-15.89) and a nearly 5-fold higher risk of requiring noninvasive ventilation (OR=4.77,95%CI=2.15-10.55). Patients with diabetes, hypertension, and/or renal disease had a five-fold higher risk of severe COVID-19 disease (OR=5.40,95%CI=2.0-14.54]. These results were confirmed in the PSM analysis. In general, but especially among patients with hypertension, diabetes, and/or renal disease, ACEI/ARB use is associated with a significantly higher risk of severe or critical COVID-19 disease, and ICU care.

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Section: Discussionsupporting

confidence: 65%

Severity of COVID-19 Infection in ACEI/ARB Users in Two Saudi Public Specialty Hospitals; Retrospective Cohort Study

Alrashed

Khan

Alhusseini

et al. 2020

Preprint

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“…(19) Most recently, a prospective cohort study using data from general practices in England found that use of ACE inhibitors or ARBs was associated with a significantly reduced risk of COVID-19 but not associated ICU admission. (33) This study also found that ethnicity modified the association between use of RAS inhibitors and COVID-19, with those from Black ethnic groups being at increased risk, a trend we were not able to explore in our study.…”

Section: Ace2 Expression(22)(10)contrasting

confidence: 54%

Renin-angiotensin system inhibitors and susceptibility to COVID-19 in patients with hypertension: a propensity score-matched cohort study in primary care

Haroon

Subramanian

Cooper

et al. 2020

Preprint

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Introduction A significant proportion of patients with Coronavirus Disease-19 (COVID-19) have hypertension and are treated with renin-angiotensin system (RAS) inhibitors, namely angiotensin-converting enzyme I inhibitors (ACE inhibitors) or angiotensin II type-1 receptor blockers (ARBs). These medications have been postulated to influence susceptibility to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The objective of this study was to assess a possible association between prescription of RAS inhibitors and the incidence of COVID-19 and all-cause mortality. Methods We conducted a propensity-score matched cohort study to assess the incidence of COVID-19 among patients with hypertension who were prescribed ACE inhibitors or ARBs compared to patients treated with calcium channel blockers (CCBs) in a large UK-based primary care database (The Health Improvement Network). We estimated crude incidence rates for confirmed/suspected COVID-19 among those prescribed ACE inhibitors, ARBs and CCBs. We used a Cox proportional hazards model to produce adjusted hazard ratios for COVID-19 comparing patients prescribed ACE inhibitors or ARBs to those prescribed CCBs. We further assessed all-cause mortality as a secondary outcome and a composite of accidents, trauma or fractures as a negative control outcome to assess for residual confounding. Results In the propensity score matched analysis, 83 of 18,895 users (0.44%) of ACE inhibitors developed COVID-19 over 8,923 person-years, an incidence rate of 9.3 per 1000 person-years. 85 of 18,895 (0.45%) users of CCBs developed COVID-19 over 8,932 person-years, an incidence rate of 9.5 per 1000 person-years. The adjusted hazard ratio for suspected/confirmed COVID-19 for users of ACE inhibitors compared to CCBs was 0.92 (95% CI 0.68 to 1.26). 79 out of 10,623 users (0.74%) of ARBs developed COVID-19 over 5010 person-years, an incidence rate of 15.8 per 1000 person-years, compared to 11.6 per 1000 person-years among users of CCBs. The adjusted hazard ratio for suspected/confirmed COVID-19 for users of ARBs compared to CCBs was 1.38 (95% CI 0.98 to 1.95). There were no significant associations between use of ACE inhibitors or ARBs and all-cause mortality, compared to use of CCBs. We found no evidence of significant residual confounding with the negative control analysis. Conclusion Current use of ACE inhibitors was not associated with the risk of suspected or confirmed COVID-19 whereas use of ARBs was associated with a statistically non-significant 38% relative increase in risk compared to use of CCBs. However, no significant associations were observed between prescription of either ACE inhibitors or ARBs and all-cause mortality during the peak of the pandemic.

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“…The country-cluster analysis is not well-suited to answer this question, and more studies among different ethnic groups are needed. For example, in a large cohort in the UK, it was found that Blacks being treated with ACEI/ARB were more susceptible to COVID-19 compared to Whites [21].…”

Section: Discussionmentioning

confidence: 99%

Mortality, Severity, and Hospital Admission Among COVID-19 Patients with ACEI/ARB Use: A Meta-analysis Stratifying Countries Based on Response to the First Wave of the Pandemic

Alamer

Almulhim

Alrashed

et al. 2020

Preprint

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BackgroundThe use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) is controversial for treating COVID-19 patients. We aimed to estimate pooled risks of mortality, disease severity, and hospitalization associated with ACEI/ARB use and stratify them by country and country clusters. MethodsWe conducted a search in various databases through 7/4/2020 and then applied random-effects models to estimate pooled risks (ORp) across stratifications by country cluster. Clusters were chosen to reflect outbreak times (China followed by Korea/Italy, others subsequently) and mobility restrictions (China and Denmark/France/Spain with stricter lockdowns than the UK/US). ResultsOverall analysis showed no increase in mortality; however, a statistical increase in mortality was seen in the US/UK cluster with ORp=1.28[95%CI=1.04; 1.56] and a decrease in China with ORp=0.65[95%CI=0.43; 0.96] and France with OR=0.31[95%CI=0.14; 0.69]. Severity and hospitalization were not statistically significant in the analysis; however, several associations were seen in specific countries but not in country clusters. ConclusionThe country-cluster meta-analysis provided a reasonable explanation for COVID-19 mortality among ACEI/ARB users. The analysis did not explain differences in severity and suggested the involvement of other factors. Hospitalization findings may be considered informative as they may have been subjected to clinical decisions and hospital-bed availability.

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Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people

Cited by 325 publications

References 27 publications

Severity of COVID-19 Infection in ACEI/ARB Users in Two Saudi Public Specialty Hospitals; Retrospective Cohort Study

Severity of COVID-19 Infection in ACEI/ARB Users in Two Saudi Public Specialty Hospitals; Retrospective Cohort Study

Renin-angiotensin system inhibitors and susceptibility to COVID-19 in patients with hypertension: a propensity score-matched cohort study in primary care

Mortality, Severity, and Hospital Admission Among COVID-19 Patients with ACEI/ARB Use: A Meta-analysis Stratifying Countries Based on Response to the First Wave of the Pandemic

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