Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in context of COVID-19 outbreak: a retrospective analysis

doi:10.1007/s11684-020-0800-y

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 Fan^3,^4,⁵, Zhibo Liu^3,⁴, Lianhan Shang^3,^4,⁶, Fei Zhou^3,⁴, Yeming Wang^3,^4,⁷, Jiapei Yu¹, Luning Yang¹, Ke Xie^3,⁷, Zhisheng Huang^3,⁸, Lixue Huang^3,⁷, Xiaoying Gu^3,^4,⁵, Hui Li^3,⁴, Yi Zhang^3,⁴, Yimin Wang^3,⁴, Frederick G. Hayden⁹, Peter W. Horby¹⁰, Bin Cao^3,^4,^7,¹¹(

), Chen Wang^3,^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:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-020-0800-y
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I5/601

Fig.1 Physiology of ACE/AngII/AT1 and ACE2/Ang_1–7/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) (Ang_1–7), 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

Tab.2 Anti-hypertensive treatment therapies

Tab.3 Anti-hypertensive treatment therapies by combination

Tab.4 Treatments and clinical outcomes

Tab.5 Risk of ACEI/ARB administration on severe COVID-19 outcome

Tab.6 Risk factors associated with in-hospital death in hypertensive patients on medication

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