key: cord-0997213-5dk197bt
authors: Zhou, J.; Tse, G.; Lee, S.; Wong, W. T.; Wang, X.; Wu, W. K.; Liu, T.; cao, z.; Zeng, D. D.; Wong, I. C.; Cheung, B. M.; Zhang, Q.
title: Renin-angiotensin system blockers and mortality in COVID-19: a territory-wide study from Hong Kong
date: 2020-12-23
journal: nan
DOI: 10.1101/2020.12.21.20248645
sha: 6015567bd9412a987b1dffebcb614114147cb026
doc_id: 997213
cord_uid: 5dk197bt

Aims: Renin-angiotensin system blockers such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may increase the risk of adverse outcomes in COVID-19. In this study, the relationships between ACEI/ARB use and COVID-19 related mortality were examined. Methods: Consecutive patients diagnosed with COVID-19 by RT-PCR at the Hong Kong Hospital Authority between 1st January and 28th July 2020 were included. Results: This study included 2774 patients. The mortality rate of the COVID-19 positive group was 1.5% (n=42). Those who died had a higher median age (82.3[76.5-89.5] vs. 42.9[28.2-59.5] years old; P<0.0001), more likely to have baseline comorbidities of cardiovascular disease, diabetes mellitus, hypertension, and chronic kidney disease (P<0.0001). They were more frequently prescribed ACEI/ARBs at baseline, and steroids, lopinavir/ritonavir, ribavirin and hydroxychloroquine during admission (P<0.0001). They also had a higher white cell count, higher neutrophil count, lower platelet count, prolonged prothrombin time and activated partial thromboplastin time, higher D-dimer, troponin, lactate dehydrogenase, creatinine, alanine transaminase, aspartate transaminase and alkaline phosphatase (P<0.0001). Multivariate Cox regression showed that age, cardiovascular disease, renal disease, diabetes mellitus, the use of ACEIs/ARBs and diuretics, and various laboratory tests remained significant predictors of mortality. Conclusions: We report that an association between ACEIs/ARBs with COVID-19 related mortality even after adjusting for cardiovascular and other comorbidities, as well as medication use. Patients with greater comorbidity burden and laboratory markers reflecting deranged clotting, renal and liver function, and increased tissue inflammation, and ACEI/ARB use have a higher mortality risk.

with greater comorbidity burden and laboratory markers reflecting deranged clotting, renal and liver function, and increased tissue inflammation, and ACEI/ARB use have a higher mortality risk.

The use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has been associated with poor disease outcomes in coronavirus disease 2019 .

For example, a population-based cohort study from Korea found that ACE-I or ARB therapy in patients with severe COVID-19 was associated with the occurrence of severe complications and increased in-hospital mortality [1] . By contrast, other studies did not identify an increased risk of severe 3] or mortality [4] among patients taking ACEIs or ARBs. A systematic review and meta-analysis of 33 studies found that ACE inhibitor use was marker of increased mortality risk in some, but not all, COVID-19 disease settings [5] , whilst another found that The risk of mortality and severe outcomes are also unchanged among COVID-19 patients taking ACEI/ARB [6] . Nevertheless, prior use of RAAS inhibitors was associated with lower risk mortality from COVID-19 specifically in patients with hypertension [7] . Given these conflicting findings, we examined whether the use of ACEIs/ARBs is related to COVID-19 mortality using territory-wide data from Hong Kong.

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A total of 2774 patients with confirmed COVID-19 were included. Their baseline characteristics are shown in Table 1 . A total of 42 deaths occurred (1.5%) in the 2774 patients who were diagnosed with COVID-19. Those who died had a higher median age (82.3[76.5-89.5] vs. 42.9[28.2-59 .5] years old), more likely to have baseline comorbidities of cardiovascular disease, diabetes mellitus, hypertension, and chronic kidney disease. Moreover, they were more frequently prescribed ACEI/ARBs at baseline, and steroids, lopinavir/ritonavir, ribavirin and hydroxychloroquine during admission. Finally, patients who died had a higher white cell count, higher neutrophil count, lower platelet count, prolonged PT and activated partial thromboplastin time, higher D-dimer, troponin and lactate dehydrogenase. Moreover, creatinine, alanine transaminase, aspartate transaminase and alkaline phosphatase were significantly higher for the mortality group.

Univariate Cox regression was used to identify predictors of mortality in patients who were positive for COVID-19 (Table 2) . This identified age, baseline cardiovascular and renal diseases, diabetes, hypertension, the use of ACEIs/ARBs, other anti-hypertensive agents, and anti-viral drugs in COVID-19, as well as various haematology and biochemical tests. On multivariate analysis, age, cardiovascular disease, renal disease, diabetes mellitus, the use of ACEIs/ARBs and diuretics, and various laboratory tests remained significant predictors of mortality (Table 3) .

The main findings of this territory-wide cohort study are that 1) a higher proportion of ACEI/ARB prescription was observed for the COVID-19 positive compared to COVID-19 negative . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 23, 2020. ; group and 2) those who died had a higher median age and more likely to have baseline comorbidities of cardiovascular disease, diabetes mellitus, hypertension, and chronic kidney disease and 3) ACEI/ARB use was significantly associated with mortality even after adjusting for cardiovascular comorbidities and the use of other anti-hypertensive agents. Moreover, they were more frequently prescribed ACEI/ARBs at baseline, and steroids, lopinavir/ritonavir, ribavirin and hydroxychloroquine during admission.

The relationship between ACEI/ARB use and disease outcomes in COVID-19 has been investigated. Many of the previous studies have included hospitalized patients only. For example, in a multi-centre study from China, it was found that in hospitalized patients with COVID-19 and existing hypertension, ACEI/ARB inpatient users had a lower risk of all-cause mortality compared with nonusers [12] . In our study, we found that in those who died, there was a higher frequency of patients with ACE inhibitor/ARB use compared to those who remained alive. However, on multivariate Cox regression, ACEI/ARB use retained its significance for mortality prediction even after multivariate adjustment for cardiovascular comorbidities and the use of other anti-hypertensive agents. Nevertheless, the frequency of hypertension, diabetes mellitus and cardiovascular disease were also higher in the mortality group. This is in keeping with previous demonstrations that patients with pre-existing cardio-metabolic comorbidities are at higher risk of severe disease or mortality [13] .

In terms of laboratory findings, prior studies have demonstrated the presence of organ damage in COVID-19. Indeed, there have been reported associations between elevations in myocardial biomarkers and mortality [14] [15] [16] . Alterations in other laboratory markers that have been associated . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 23, 2020. ;  with adverse outcomes in COVID-19 include increases in D-dimer levels [17] , liver enzymes [18], neutrophil count [19] , activated partial thromboplastin time and prothrombin time [20] . In our study, we also found that patients who died had a higher white cell count, higher neutrophil count, lower platelet count, prolonged prothrombin time and activated partial thromboplastin time, D-dimer, troponin, lactate dehydrogenase, creatinine, alanine transaminase, aspartate transaminase and alkaline phosphatase.

Taken together, we report that an association between ACEIs or ARBs with COVID-19 related mortality even after adjusting for cardiovascular and other comorbidities, as well as medication use.

Our findings suggest that patients with greater comorbidity burden and laboratory markers reflecting deranged clotting, renal and liver function, and increased tissue inflammation, as well as ACEI/ARB use have a higher mortality risk.

None.

None.

. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 23, 2020. ;

GT: study conception, study design, data acquisition, statistical analysis, data interpretation, manuscript drafting, critical revision of manuscript JZ: statistical analysis, data interpretation, manuscript drafting, critical revision of manuscript SL, WTW, XW, WKKW, TL, ZC, DZ, KCKW: data interpretation, critical revision of manuscript BMYC, QZ: project administration and supervision, statistical analysis, data interpretation, critical revision of manuscript Guarantor of overall content: GT . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 23, 2020. ; . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 23, 2020. ; . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 23, 2020. ; . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 23, 2020. ; Table 1 . Demographic, epidemiological, clinical characteristics and laboratory details of patients who were tested positive for COVID-19 in Hong Kong up to and including 28 th July 2020. Patients were stratified by mortality status with latest available death information on 5 th August 2020. COVID-19 = coronavirus disease 2019; APTT = Activated partial thromboplastin time; IQR = Interquartile range; * for p≤ 0.05, ** for p ≤ 0.01, *** for p ≤ 0.001

Age 

Alkaline Phosphatase, U/L 64.4(54.0-80.0)

); 5.8-12.0); n=2587 10.1(6.65-29.65)

APTT, sec 30.55(27.4-34.45); n=518 31.9(30.2-33.6)

Diabetes mellitus tests HbA1c, g/dL