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Frontiers of Medicine

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Front. Med.    2022, Vol. 16 Issue (1) : 102-110    https://doi.org/10.1007/s11684-021-0850-9
RESEARCH ARTICLE
Renin--angiotensin system inhibitor is associated with the reduced risk of all-cause mortality in COVID-19 among patients with/without hypertension
Huai-yu Wang1, Suyuan Peng1, Zhanghui Ye2, Pengfei Li2, Qing Li2, Xuanyu Shi1, Rui Zeng3, Ying Yao4, Fan He3, Junhua Li3, Liu Liu3, Shuwang Ge3, Xianjun Ke5, Zhibin Zhou5, Gang Xu3, Ming-hui Zhao7,8, Haibo Wang6, Luxia Zhang1,2,7(), Erdan Dong9
1. National Institute of Health Data Science at Peking University, Beijing 100191, China
2. Peking University Advanced Institute of Information Technology, Hangzhou 311215, China
3. Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
4. Department of Clinical Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
5. Taikang Tongji (Wuhan) Hospital, Wuhan 430050, China
6. First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
7. Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Beijing 100034, China
8. Peking-Tsinghua Center for Life Sciences, Beijing 100871, China
9. Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China
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Abstract

Consecutively hospitalized patients with confirmed coronavirus disease 2019 (COVID-19) in Wuhan, China were retrospectively enrolled from January 2020 to March 2020 to investigate the association between the use of renin–angiotensin system inhibitor (RAS-I) and the outcome of this disease. Associations between the use of RAS-I (angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)), ACEI, and ARB and in-hospital mortality were analyzed using multivariate Cox proportional hazards regression models in overall and subgroup of hypertension status. A total of 2771 patients with COVID-19 were included, with moderate and severe cases accounting for 45.0% and 36.5%, respectively. A total of 195 (7.0%) patients died. RAS-I (hazard ratio (HR)=0.499, 95% confidence interval (CI) 0.325–0.767) and ARB (HR=0.410, 95% CI 0.240–0.700) use was associated with a reduced risk of all-cause mortality among patients with COVID-19. For patients with hypertension, RAS-I and ARB applications were also associated with a reduced risk of mortality with HR of 0.352 (95% CI 0.162–0.764) and 0.279 (95% CI 0.115–0.677), respectively. RAS-I exhibited protective effects on the survival outcome of COVID-19. ARB use was associated with a reduced risk of all-cause mortality among patients with COVID-19.
Keywords COVID-19      RAS inhibitor      hypertension      all-cause mortality     
Corresponding Author(s): Luxia Zhang   
About author:

Tongcan Cui and Yizhe Hou contributed equally to this work.
Just Accepted Date: 04 June 2021   Online First Date: 13 July 2021    Issue Date: 28 March 2022
 Cite this article:   
Huai-yu Wang,Suyuan Peng,Zhanghui Ye, et al. Renin--angiotensin system inhibitor is associated with the reduced risk of all-cause mortality in COVID-19 among patients with/without hypertension[J]. Front. Med., 2022, 16(1): 102-110.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0850-9
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I1/102
Fig.1  Flowchart of enrollment process.
Factors Overall
(n = 2771)		 RAS-I administration P value
Yes (n = 280) No (n = 2491)
Age, n (%) <0.001
<18 years 16 (0.6%) 0 (0.0%) 16 (0.6%)
18–44 years 477 (17.2%) 12 (4.3%) 465 (18.7%)
45–64 years 1262 (45.5%) 113 (40.4%) 1149 (46.1%)
≥65 years 1016 (36.7%) 155 (55.4%) 861 (34.6%)
Male, n (%) 1328 (47.9%) 147 (52.5%) 1181 (47.4%) 0.110
Comorbidity, n (%)
Hypertension 590 (21.5%) 141 (50.4%) 449 (18.2%) <0.001
Diabetes 299 (10.9%) 56 (20.0%) 243 (9.8%) <0.001
Cardiovascular disease 133 (4.8%) 31 (11.1%) 102 (4.1%) <0.001
Chronic kidney disease 26 (0.9%) 4 (1.4%) 22 (0.9%) 0.330
Chronic obstructive pulmonary disease 56 (2.0%) 5 (1.8%) 51 (2.1%) 0.750
Cancer 30 (1.1%) 6 (2.1%) 24 (1.0%) 0.120
None of above 1947 (70.3%) 128 (45.7%) 1819 (73.0%) <0.001
Laboratory test
WBC (× 109 cells/L) 6.8 (5.4, 8.9) 7.9 (5.6, 13.2) 6.8 (5.4, 8.8) 0.007
LYM (× 109 cells/L) 1.2 (0.7, 1.6) 0.9 (0.4, 1.3) 1.2 (0.7, 1.6) <0.001
hs-CRP (mg/L) 19.9 (2.4, 78.4) 65.7 (5.0, 161.6) 19.3 (2.3, 75.6) <0.001
PCT (ng/L) 0.07 (0.04, 0.21) 0.14 (0.05, 0.61) 0.07 (0.04, 0.21) 0.003
IL-6 (pg/mL) 6.3 (2.1, 14.4) 12.7 (4.0, 72.6) 6.3 (2.1, 14.2) <0.001
hs-cTn (ng/mL) 4.5 (1.9, 11.7) 11.5 (4.7, 29.6) 4.4 (1.9, 11.4) <0.001
SCr (µmol/L) 70.0 (58.0, 86.0) 88.4 (71.0, 133.0) 70.0 (58.0, 85.6) <0.001
SBP (mmHg) 124.4 (116.7, 132.5) 119.5 (71.9, 135.6) 124.4 (116.8, 132.5) 0.087
DBP (mmHg) 75.4 (71.1, 80.7) 86.2 (74.7, 117.3) 75.2 (71.0, 80.5) <0.001
Complication, n (%)
Acute respiratory distress syndrome 416 (15.0%) 68 (24.3%) 348 (14.0%) <0.001
Heart failure 296 (10.7%) 59 (21.1%) 237 (9.5%) <0.001
Acute myocardial infarction 250 (9.0%) 41 (14.6%) 209 (8.4%) <0.001
Acute kidney injury 107 (3.9%) 22 (7.9%) 85 (3.4%) <0.001
Multiple organ dysfunction syndrome 265 (9.6%) 52 (18.6%) 213 (8.6%) <0.001
Treatment, n (%)
Anti-virus drug 1861 (67.2%) 198 (70.7%) 1663 (66.8%) 0.180
Glucocorticoid 625 (22.6%) 73 (26.1%) 552 (22.2%) 0.140
Chloroquine/hydroxychloroquine 293 (10.6%) 37 (13.2%) 256 (10.3%) 0.130
Tocilizumab 41 (1.5%) 10 (3.6%) 31 (1.2%) 0.002
NPPV 316 (11.4%) 49 (17.5%) 267 (10.7%) <0.001
IPPV 129 (4.7%) 19 (6.8%) 110 (4.4%) 0.074
CRRT 51 (1.8%) 15 (5.4%) 36 (1.4%) <0.001
Severity, n (%) <0.001
Mild cases 109 (3.9%) 5 (1.8%) 104 (4.2%)
Moderate cases 1247 (45.0%) 96 (34.3%) 1151 (46.2%)
Severe cases 1012 (36.5%) 119 (42.5%) 893 (35.8%)
Critical 403 (14.5%) 60 (21.4%) 343 (13.8%)
Outcome, n (%) 0.072
Recovery 2576 (93.0%) 253 (90.4%) 2323 (93.3%)
Death 195 (7.0%) 27 (9.6%) 168 (6.7%)
Tab.1  Demographic characteristics
Variable Unadjusted model Model 1 Model 2 Model 3
Crude HR (95% CI) P value Adjusted HR (95% CI) P value Adjusted HR (95% CI) P value Adjusted HR (95% CI) P value
RAS-I administration
No Ref. Ref. Ref. Ref. Ref. Ref. Ref. Ref.
Yes 1.160 (0.771–1.743) 0.477 0.845 (0.561–1.272) 0.419 0.562 (0.371–0.852) 0.007 0.499 (0.325–0.767) 0.002
ACEI administration
No Ref. Ref. Ref. Ref. Ref. Ref. Ref. Ref.
Yes 2.767 (1.542–4.967) 0.001 1.962 (1.091–3.528) 0.024 0.885 (0.488–1.605) 0.688 0.892 (0.473–1.682) 0.724
ARB administration
No Ref. Ref. Ref. Ref. Ref. Ref. Ref. Ref.
Yes 0.775 (0.464–1.295) 0.331 0.579 (0.346–0.967) 0.037 0.457 (0.272–0.770) 0.003 0.410 (0.240–0.700) 0.001
Tab.2  Association between RAS-I administration and all-cause mortality
Factors Overall (n = 590) RAS-I administration P value
Yes (n = 141) No (n = 449)
Age, n (%) 0.540
<18 years 0 (0.0%) 0 (0.0%) 0 (0.0%)
18–44 years 21 (3.6%) 7 (5.0%) 14 (3.1%)
45–64 years 230 (39.0%) 55 (39.0%) 175 (39.0%)
≥65 years 339 (57.5%) 79 (56.0%) 260 (57.9%)
Male, n (%) 293 (49.7%) 68 (48.2%) 225 (50.1%) 0.700
Laboratory test
WBC (× 109 cells/L) 7.1 (5.6, 9.5) 6.4 (5.3, 9.0) 7.2 (5.6, 9.5) 0.260
LYM (× 109 cells/L) 1.1 (0.7, 1.6) 1.1 (0.6, 1.5) 1.1 (0.7, 1.6) 0.690
hs-CRP (mg/L) 38.0 (4.5, 102.1) 22.2 (4.6, 72.3) 42.8 (4.5, 111.3) 0.980
PCT (ng/L) 0.09 (0.05, 0.24) 0.08 (0.04, 0.23) 0.09 (0.05, 0.24) 0.340
IL-6 (pg/mL) 8.3 (3.2, 15.6) 9.7 (3.0, 15.5) 8.3 (3.3, 15.6) 0.790
hs-cTn (ng/mL) 7.9 (3.3, 20.6) 8.6 (4.1, 14.3) 7.8 (3.3, 20.6) 0.780
SCr (µmol/L) 73.4 (61.0, 92.0) 86.0 (69.0, 103.0) 73.0 (60.1, 92.0) 0.100
SBP (mmHg) 129.7 (122.3, 137.0) 135.6 (124.6, 141.9) 129.6 (122.3, 137.0) 0.220
DBP (mmHg) 76.6 (72.1, 82.3) 80.5 (74.1, 86.2) 76.5 (72.1, 82.3) 0.180
Complication, n (%)
Acute respiratory distress syndrome 84 (14.2%) 13 (9.2%) 71 (15.8%) 0.051
Heart failure 85 (14.4%) 18 (12.8%) 67 (14.9%) 0.520
Acute myocardial infarction 98 (16.6%) 19 (13.5%) 79 (17.6%) 0.250
Acute kidney injury 38 (6.4%) 8 (5.7%) 30 (6.7%) 0.840
Multiple organ dysfunction syndrome 76 (12.9%) 12 (8.5%) 64 (14.3%) 0.076
Severity, n (%) 0.730
Mild cases 10 (1.7%) 2 (1.4%) 8 (1.8%)
Moderate cases 209 (35.4%) 53 (37.6%) 156 (34.7%)
Severe cases 265 (44.9%) 65 (46.1%) 200 (44.5%)
Critical 106 (18.0%) 21 (14.9%) 85 (18.9%)
Outcome, n (%) 0.029
Recovery 526 (89.2%) 133 (94.3%) 393 (87.5%)
Death 64 (10.8%) 8 (5.7%) 56 (12.5%)
Tab.3  Demographic characteristics among patients with COVID-19 with hypertension
Variable Unadjusted model Model 1 Model 2
Crude HR (95% CI) P value Adjusted HR (95% CI) P value Adjusted HR (95% CI) P value
RAS-I administration
No Ref. Ref. Ref. Ref. Ref. Ref.
Yes 0.402 (0.192–0.845) 0.016 0.433 (0.206–0.909) 0.027 0.352 (0.162–0.764) 0.008
ACEI administration
No Ref. Ref. Ref. Ref. Ref. Ref.
Yes 0.691 (0.169–2.824) 0.606 0.663 (0.162–2.713) 0.567 1.008 (0.231–4.391) 0.992
ARB administration
No Ref. Ref. Ref. Ref. Ref. Ref.
Yes 0.353 (0.152–0.818) 0.015 0.381 (0.164–0.884) 0.025 0.279 (0.115–0.677) 0.005
Tab.4  Association between RAS-I administration and all-cause mortality among patients with hypertension
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