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Frontiers of Medicine

Front. Med.    2020, Vol. 14 Issue (5) : 601-612     https://doi.org/10.1007/s11684-020-0800-y
RESEARCH ARTICLE
Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in context of COVID-19 outbreak: a retrospective analysis
Jiuyang Xu1, Chaolin Huang2, Guohui Fan3,4,5, Zhibo Liu3,4, Lianhan Shang3,4,6, Fei Zhou3,4, Yeming Wang3,4,7, Jiapei Yu1, Luning Yang1, Ke Xie3,7, Zhisheng Huang3,8, Lixue Huang3,7, Xiaoying Gu3,4,5, Hui Li3,4, Yi Zhang3,4, Yimin Wang3,4, Frederick G. Hayden9, Peter W. Horby10, Bin Cao3,4,7,11(), Chen Wang3,4,11,12()
1. Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing 100084, China
2. Department of Infectious Diseases, Jinyintan Hospital, Wuhan 430030, China
3. Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing 100029, China
4. Institute of Respiratory Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
5. Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
6. Beijing University of Chinese Medicine, Beijing 100029, China
7. Department of Respiratory Medicine, Capital Medical University, Beijing 100029, China
8. Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
9. Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22904, USA
10. Centre for Tropical Medicine and Global Health, University of Oxford, Oxford OX1 2JD, UK
11. Tsinghua University–Peking University Joint Center for Life Sciences, Beijing 100084, China
12. Chinese Academy of Engineering, Beijing 100088, China
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Abstract

The possible effects of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on COVID-19 disease severity have generated considerable debate. We performed a single-center, retrospective analysis of hospitalized adult COVID-19 patients in Wuhan, China, who had definite clinical outcome (dead or discharged) by February 15, 2020. Patients on anti-hypertensive treatment with or without ACEI/ARB were compared on their clinical characteristics and outcomes. The medical records from 702 patients were screened. Among the 101 patients with a history of hypertension and taking at least one anti-hypertensive medication, 40 patients were receiving ACEI/ARB as part of their regimen, and 61 patients were on anti-hypertensive medication other than ACEI/ARB. We observed no statistically significant differences in percentages of in-hospital mortality (28% vs. 34%, P=0.46), ICU admission (20% vs. 28%, P=0.37) or invasive mechanical ventilation (18% vs. 26%, P=0.31) between patients with or without ACEI/ARB treatment. Further multivariable adjustment of age and gender did not provide evidence for a significant association between ACEI/ARB treatment and severe COVID-19 outcomes. Our findings confirm the lack of an association between chronic receipt of renin-angiotensin system antagonists and severe outcomes of COVID-19. Patients should continue previous anti-hypertensive therapy until further evidence is available.

Keywords COVID-19      SARS-CoV-2      hypertension      angiotensin-converting enzyme inhibitor      angiotensin II receptor blocker     
Corresponding Author(s): Bin Cao,Chen Wang   
Just Accepted Date: 04 June 2020   Online First Date: 06 July 2020    Issue Date: 12 October 2020
 Cite this article:   
Jiuyang Xu,Chaolin Huang,Guohui Fan, et al. Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in context of COVID-19 outbreak: a retrospective analysis[J]. Front. Med., 2020, 14(5): 601-612.
 URL:  
http://journal.hep.com.cn/fmd/EN/10.1007/s11684-020-0800-y
http://journal.hep.com.cn/fmd/EN/Y2020/V14/I5/601
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Jiuyang Xu
Chaolin Huang
Guohui Fan
Zhibo Liu
Lianhan Shang
Fei Zhou
Yeming Wang
Jiapei Yu
Luning Yang
Ke Xie
Zhisheng Huang
Lixue Huang
Xiaoying Gu
Hui Li
Yi Zhang
Yimin Wang
Frederick G. Hayden
Peter W. Horby
Bin Cao
Chen Wang
Fig.1  Physiology of ACE/AngII/AT1 and ACE2/Ang1–7/Mas axes. (A) Schematic structures of angiotensin and its derivatives. The three-letter codes were used to represent amino acid residues. (B) Physiology of angiotensin processing and blood regulation. In hypovolemic conditions, renin, secreted by cells in macula densa in the kidney, cleaves angiotensinogen into a decapeptide angiotensin I (Ang I). The angiotensin-converting enzyme (ACE) further cleaves the peptide into an octapeptide angiotensin II (Ang II), which acts on the cellular receptor angiotensin II receptor I (AT1) to constrict the blood vessels and increases blood pressure (“yang”). ACE2 is a mono-carboxypeptidase transforming the Ang II into angiotensin-(1–7) (Ang1–7), which binds to the G protein-coupled receptor Mas to dilate the blood vessels and counter-balance ACE/Ang II in blood pressure regulation (“yin”). Figure was generated with BioRender.
Fig.2  Schematic for patient selection in this study.
Characteristics Total
n = 101
ACEI/ARB
n = 40
Non-ACEI/ARB
n = 61
P value
Age (year) 65.0 (58.0, 73.0) 66.5 (58.0, 72.0) 65.0 (58.0, 74.0) 0.8024
Gender, male, n (%) 53 (52) 19 (48) 34 (56) 0.4175
Smoking, n (%) 4 (4) 3 (8) 1 (2) 0.3394
Time from illness onset to admission (day) 13.0 (8.5, 16.0) 12.5 (8.5, 16.0) 13.0 (8.5, 15.5) 0.7805
Comorbidity
Hypertension, n (%) 101 (100) 40 (100) 61 (100) NA
Diabetes, n (%) 19 (19) 8 (20) 11 (18) 0.8046
Heart failure, n (%) 1 (1) 0 (0) 1 (2) 1.0000
Coronary heart disease, n (%) 12 (12) 5 (13) 7 (11) 1.0000
COPD, n (%) 2 (2) 1 (3) 1 (2) 1.0000
Carcinoma, n (%) 5 (5) 2 (5) 3 (5) 1.0000
Chronic kidney disease, n (%) 2 (2) 0 (0) 2 (3) 0.5168
Vital signs
Respiratory rate>24 /min, n (%) 19 (19) 6 (15) 13 (21) 0.4273
Systolic BP (mmHg) 135 (122, 152) 138 (131, 152) 134 (123, 147) 0.6617
≥140, n (%) 39 (39) 17 (43) 22 (36) 0.5160
Diastolic BP (mmHg) 81 (75, 88) 79 (74, 90) 82 (76, 87) 0.4222
≥90 mmHg, n (%) 22 (22) 11 (28) 11 (18) 0.2596
Symptoms
Fever, n (%) 88 (87) 31 (78) 57 (93) 0.0193
Cough, n (%) 80 (79) 30 (75) 50 (82) 0.3988
Sputum, n (%) 30 (30) 11 (28) 19 (31) 0.6948
Myalgia, n (%) 9 (9) 2 (5) 7 (11) 0.4472
Headache, n (%) 9 (9) 5 (13) 4 (7) 0.5040
Fatigue, n (%) 39 (39) 15 (38) 24 (39) 0.8523
Diarrhea, n (%) 8 (8) 3 (8) 5 (8) 1.0000
Dyspnea, n (%) 64 (63) 23 (58) 41 (67) 0.3217
Laboratory findings
Na (mmol/L) 140.0 (139.0, 142.0) 141.0 (139.0, 143.0) 140.0 (139.0, 142.0) 0.1949
<135 2 (2) 0 (0) 2 (3) 0.7669
135–145 97 (96) 39 (98) 58 (95)
>145 2 (2) 1 (3) 1 (2)
K (mmol/L) 4.1 (3.7, 4.5) 4.1 (3.6, 4.6) 4.1 (3.7, 4.4) 0.5923
<3.5 15 (15) 4 (10) 11 (18) 0.5247
3.5–5.5 81 (80) 34 (85) 47 (77)
>5.5 5 (5) 2 (5) 3 (5)
White blood cell count (×109/L) 6.0 (4.5, 8.7) 6.1 (5.0, 9.7) 5.8 (4.4, 8.2) 0.5289
4–10, n (%) 66/100 (66) 26 (65) 40/60 (67) 0.9049
<4, n (%) 16/100 (16) 6 (15) 10/60 (17)
>10, n (%) 18/100 (18) 8 (20) 10/60 (17)
Lymphocyte count (×109/L) 0.8 (0.6, 1.3) 0.8 (0.6, 1.3) 0.8 (0.6, 1.2) 0.8301
<0.8, n (%) 51/100 (51) 22 (55) 29/60 (48) 0.5135
Hemoglobin (g/L) 121.0 (110.0, 135.5) 117.5 (108.5, 134.0) 123.0 (113.0, 136.5) 0.2601
Platelet count (×109/L) 202.5 (150.0, 261.5) 189.0 (145.5, 251.5) 206.0 (162.0, 269.5) 0.5129
<100, n (%) 3/100 (3) 1 (3) 2/60 (3) 1.0000
Alanine transaminase (U/L) 32.0 (21.0, 54.0) 32.0 (23.0, 54.0) 34.0 (20.0, 53.0) 0.6342
≤40, n (%) 62 (61) 25 (63) 37 (61) 0.8523
>40, n (%) 39 (39) 15 (38) 24 (39)
Creatinine>133 (mmol/L), n (%) 6 (6) 2 (5) 4 (7) 1.0000
Lactate dehydrogenase (U/L) 336.0 (238.0, 455.0) 307.0 (230.0, 403.0) 357.0 (248.0, 481.5) 0.0828
≤245, n (%) 28/100 (28) 13 (33) 15/60 (25) 0.4132
>245, n (%) 72/100 (72) 27 (68) 45/60 (75)
Creatine kinase (U/L) 15.0 (12.0, 36.0) 15.0 (11.0, 23.5) 17.0 (13.0, 43.0) 0.2639
≤185, n (%) 95/99 (96) 38 (95) 57/59 (97) 1.0000
>185, n (%) 4/99 (4) 2 (5) 2/59 (3)
Brain natriuretic peptide (pg/mL) 58.6 (29.9, 110.6) 55.7 (28.9, 119.7) 61.2 (32.6, 108.6) 0.6878
≥100, n (%) 17/62 (27) 7/25 (28) 10/37 (27) 0.9329
Cardiac troponin I (pg/mL) 7.2 (3.1, 19.9) 5.7 (2.5, 20.8) 9.1 (4.1, 17.2) 0.2629
>28, n (%) 18/99 (18) 7 (18) 11/59 (19) 0.8848
Prothrombin time (s) 11.4 (10.4, 12.4) 11.5 (10.2, 12.6) 11.3 (10.5, 12.3) 0.9857
<16, n (%) 97/99 (98) 38/39 (97) 59/60 (98) 1.0000
≥16, n (%) 2/99 (2) 1/39 (3) 1/60 (2)
D-dimer (mg/mL) 1.3 (0.6, 4.5) 1.2 (0.5, 2.7) 1.4 (0.7, 5.5) 0.1759
≤1, n (%) 41/99 (41) 16/39 (41) 25/60 (42) 0.9496
>1, n (%) 58/99 (59) 23/39 (59) 35/60 (58)
Serum ferritin (mg/L) 576.9 (334.5, 980.4) 577.1 (334.5, 938.8) 548.8 (336.6, 1001.0) 0.9853
≤300, n (%) 17/83 (20) 8/35 (23) 9/48 (19) 0.6471
>300, n (%) 66/83 (80) 27/35 (77) 39/48 (81)
Procalcitonin (ng/mL) 0.1 (0.1, 0.2) 0.1 (0.1, 0.1) 0.1 (0.1, 0.2) 0.2729
<0.1, n (%) 36/65 (55) 16/24 (67) 20/41 (49) 0.4237
≥0.1 to <0.25, n (%) 21/65 (32) 5/24 (21) 16/41 (39)
≥0.25 to <0.5, n (%) 2/65 (3) 1/24 (4) 1/41 (2)
≥0.5, n (%) 6/65 (9) 2/24 (8) 4/41 (10)
Interleukin 6 (pg/mL) 7.5 (6.0, 10.9) 7.0 (5.7, 9.8) 8.0 (6.1, 11.4) 0.1429
Imaging features
Consolidation, n (%) 64 (63) 24 (60) 40 (66) 0.5696
Ground-glass opacity, n (%) 82 (81) 32 (80) 50 (82) 0.8046
Bilateral pulmonary infiltration, n (%) 82 (81) 33 (83) 49 (80) 0.7847
Disease severity scores
SOFA 3.5 (2.0, 4.0) 2.0 (1.0, 4.0) 4.0 (2.0, 4.5) 0.2917
CURB-65 1.0 (1.0, 2.0) 1.0 (1.0, 2.0) 1.0 (0.0, 2.0) 0.6631
0–1, n (%) 73 (72) 28 (70) 45 (74) 0.7230
2, n (%) 20 (20) 9 (23) 11 (18)
3–5, n (%) 8 (8) 3 (8) 5 (8)
Tab.1  Demographic, clinical, laboratory, and radiologic findings on admission
Treatment Total
n = 101
ACEI/ARB
n = 40
Non-ACEI/ARB
n = 61
P value
ACEI 8 (8) 8 (20) 0 0.0011
ARB 33 (33) 33 (83) 0 <0.0001
a-blocker 2 (20) 1 (3) 1 (2) 1.0000
b-blocker 15 (15) 5 (13) 10 (16) 0.5905
CCB 77 (77) 19 (48) 58 (95) <0.0001
Diuretics 9 (9) 6 (15) 3 (5) 0.1669
Tab.2  Anti-hypertensive treatment therapies
Treatment Number
Aa 14
B 3
C 48
A+ B 3
A+ C 17
A+ D 2
B+ C 7
C+ D 3
A+ C+ D 2
A+ B+ C+ D 2
Total 101
Tab.3  Anti-hypertensive treatment therapies by combination
Total
n = 101
ACEI/ARB
n = 40
Non-ACEI/ARB
n = 61
P value
Treatments
Antibiotic drugs, n (%) 95 (94) 36 (90) 59 (97) 0.3334
Antiviral drugsa, n (%) 44 (44) 17 (43) 27 (44) 0.8613
Lopinavir-ritonavir, n (%) 16 (16) 6 (15) 10 (16) 0.8512
Corticosteroids, n (%) 28 (28) 11 (28) 17 (28) 0.9677
Intravenous immunoglobin, n (%) 36 (36) 15 (38) 21 (34) 0.7524
Highest oxygenation support therapy
No oxygenation support, n (%) 6 (6) 5 (12) 1 (2) 0.1087
NC, n (%) 56 (55) 23 (58) 33 (54)
HFNC, n (%) 16 (16) 5 (12) 11 (18)
NIMV, n (%) 4 (4) 0 (0) 4 (6)
IMV, n (%) 19 (19) 7 (18) 12 (20)
Renal replacement therapy, n (%) 8 (8) 3 (8) 5 (8) 1.0000
Complications
Respiratory failure, n (%) 53 (52) 17 (43) 36 (59) 0.1040
Sepsis, n (%) 55 (54) 19 (48) 36 (59) 0.2557
Sepsis shock, n (%) 13 (13) 5 (13) 8 (13) 0.9281
ARDS, n (%) 33 (33) 11 (28) 22 (36) 0.3694
Acute kidney injury, n (%) 11 (11) 5 (13) 6 (10) 0.9253
Acute cardiac injury, n (%) 24 (24) 9 (23) 15 (25) 0.8093
Acidosis, n (%) 9 (9) 3 (8) 6 (10) 0.9633
Secondary infection, n (%) 9 (9) 4 (10) 5 (8) 1.0000
Hypoproteinemia, n (%) 21 (21) 10 (25) 11 (18) 0.3988
Coagulopathy, n (%) 15 (15) 7 (18) 8 (13) 0.5444
Outcomes
ICU admission, n (%) 25 (25) 8 (20) 17 (28) 0.3702
Death, n (%) 32 (32) 11 (28) 21 (34) 0.4643
Mechanical ventilationb, n (%) 23 (23) 7 (18) 16 (26) 0.3062
Hospital length of stayc (day) 12.0 (8.5, 15.0) 13.0 (9.0, 15.0) 12.0 (7.0, 14.5) 0.1955
Duration of viral shedding after illness onsetc (day) 18.0 (15.0, 23.0) 19.0 (15.0, 23.0) 18.0 (14.5, 23.0) 0.8123
Tab.4  Treatments and clinical outcomes
Death ICU admission IMV
OR (95% CI) P value OR (95% CI) P value OR (95% CI) P value
ACEI/ARB 0.73 (0.29–1.82) 0.4994 0.65 (0.25–1.70) 0.3798 0.87 (0.31–2.43) 0.7860
ACEI/ARB (adjusted)a 0.78 (0.32–1.93) 0.5894 0.68 (0.26–1.81) 0.4431 0.92 (0.32–2.63) 0.8796
Tab.5  Risk of ACEI/ARB administration on severe COVID-19 outcome
Univariable OR (95% CI) P value Multivariable OR (95% CI) P value
Age (year) 1.07 (1.03–1.12) 0.0025 1.04 (0.99–1.10) 0.1059
Diabetes 1.76 (0.63–4.91) 0.2820
qSOFA score 4.77 (2.07–10.96) 0.00024 5.41 (2.18–13.48) 0.00028
D-dimer >1 µg/mL 3.43 (1.30–9.02) 0.0125 3.64 (1.10–11.99) 0.0341
Tab.6  Risk factors associated with in-hospital death in hypertensive patients on medication
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