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Originally Published 29 April 2020
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Effects of Angiotensin II Receptor Blockers and ACE (Angiotensin-Converting Enzyme) Inhibitors on Virus Infection, Inflammatory Status, and Clinical Outcomes in Patients With COVID-19 and Hypertension: A Single-Center Retrospective Study

Guang Yang, Zihu Tan, Ling Zhou, Min Yang, Lang Peng, Jinjin Liu, Jingling Cai, Ru Yang, Junyan Han, Yafei Huang [email protected], and Shaobin He https://orcid.org/0000-0002-5269-3000 [email protected]Author Info & Affiliations
Hypertension
Volume 76, Number 1
https://doi.org/10.1161/HYPERTENSIONAHA.120.15143
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VIEW EDITORIAL:Evidence That Renin-Angiotensin System Inhibitors Should Not Be Discontinued Due to the COVID-19 Pandemic

Graphical Abstract

Abstract

With the capability of inducing elevated expression of ACE2 (angiotensin-converting enzyme 2), the cellular receptor for severe acute respiratory syndrome coronavirus 2, angiotensin II receptor blockers (ARBs) or ACE inhibitors treatment may have a controversial role in both facilitating virus infection and reducing pathogenic inflammation. We aimed to evaluate the effects of ARBs/ACE inhibitors on coronavirus disease 2019 (COVID-19) in a retrospective, single-center study. One hundred twenty-six patients with COVID-19 and preexisting hypertension at Hubei Provincial Hospital of Traditional Chinese Medicine in Wuhan from January 5 to February 22, 2020, were retrospectively allocated to ARBs/ACE inhibitors group (n=43) and non-ARBs/ACE inhibitors group (n=83) according to their antihypertensive medication. One hundred twenty-five age- and sex-matched patients with COVID-19 without hypertension were randomly selected as nonhypertension controls. In addition, the medication history of 1942 patients with hypertension that were admitted to Hubei Provincial Hospital of Traditional Chinese Medicine from November 1 to December 31, 2019, before the COVID-19 outbreak were also reviewed for external comparison. Epidemiological, demographic, clinical, and laboratory data were collected, analyzed, and compared between these groups. The frequency of ARBs/ACE inhibitors usage in patients with hypertension with or without COVID-19 were comparable. Among patients with COVID-19 and hypertension, those received either ARBs/ACE inhibitors or non-ARBs/ACE inhibitors had comparable blood pressure. However, ARBs/ACE inhibitors group had significantly lower concentrations of hs-CRP (high-sensitivity C-reactive protein; P=0.049) and PCT (procalcitonin, P=0.008). Furthermore, a lower proportion of critical patients (9.3% versus 22.9%; P=0.061) and a lower death rate (4.7% versus 13.3%; P=0.216) were observed in ARBs/ACE inhibitors group than non-ARBs/ACE inhibitors group, although these differences failed to reach statistical significance. Our findings thus support the use of ARBs/ACE inhibitors in patients with COVID-19 and preexisting hypertension.

Introduction

See Editorial, pp 42–43
In December 2019, a novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, Hubei province of China. The disease has rapidly spread from Wuhan to other areas. As of March 25, 2020, 414 179 cases have been reported in 180 countries and areas from 6 continents, with the current crude case fatality rate of 4.5%.1 Thus, with accumulating cases and high case fatality rate, COVID-19 has posed a great challenge to public health.
According to a recent report, 91.1% of patients infected with SARS-CoV-2 were diagnosed with pneumonia during hospitalization, including 15.7% of them with severe disease.2 However, the underlying pathophysiological mechanisms by which this virus causes disease remain unclear. SARS-CoV-2 and SARS-CoV are both coronaviruses, and the 2 viruses share 79% identity in nucleotide sequence.3 Early studies have established that SARS-CoV uses ACE2 (angiotensin-converting enzyme 2) as a cellular receptor to facilitate its infection.4,5 In light of this, a recent investigation predicted that the RBD (receptor binding domain) of the spike glycoprotein from SARS-CoV-2 and SARS-CoV share almost identical conformation, and the binding affinity between RBD and ACE2 was estimated to be much stronger for SARS-CoV-2, as assessed by computer modeling.6 This notion was later confirmed by biophysical analysis.7 Indeed, SARS-CoV-2 can use ACE2 but not other tested proteins as a cellular entry receptor in virus infectivity studies using HeLa cell expressing human ACE2.8 ACE2 is widely expressed in many human tissues such as lung, intestine, heart, kidney, and endothelium, suggesting that these tissues may serve as entry sites for infection and replication for both SARS-CoV and SARS-CoV-2.9 Upon binding to ACE2, SARS-CoV subsequently induced the downregulation of ACE2 in host cells, resulting in increased concentration of Ang II which in turn caused severe acute lung injury.10,11 Taken together, early investigations in SARS-CoV suggest that ACE2 may have both a pathogenic role in facilitating virus infection and a protective effect in limiting lung injury during SARS-CoV-2 infection.12 Despite its implication in virus infection, ACE2 is initially recognized as a critical enzyme in the renin-angiotensin system that regulates blood pressure, fluid and electrolyte balance, and vascular resistance.13 In fact, drugs that can upregulate the expression of ACE2, such as ARBs and ACE inhibitors, have been extensively used in patients with hypertension and other cardiovascular diseases to maintain the stability of blood pressure and reduce the risk of adverse events in cardiocerebrovascular system and kidney.14–16
Hypertension represented a major comorbidity in patients infected with SARS-CoV-2. According to recent reports in China and Singapore, 12.8% to 31.2% of patients with COVID-19 had preexisting hypertension.2,17–22 These patients appeared to develop severe disease more frequently and were more susceptible to death.2,19 Because many of these patients used ARBs/ACE inhibitors as antihypertensive drugs, which can increase the expression of ACE2, and because of the seemly paradoxical role of ACE2 during SARS-CoV-2 infection, we designed this retrospective study to assess the effects of ARBs/ACE inhibitors on SARS-CoV-2 infection, inflammatory status, and clinical outcomes in patients with COVID-19 and preexisting hypertension.

Methods

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

Study Design and Participants

This retrospective study complied with the Declaration of Helsinki and was approved by the Hubei Provincial Hospital of Traditional Chinese Medicine’s (HPHTCM) ethical review board (Clinical Ethical Approval No. HBZY2020-C15-01). HPHTCM is responsible for the treatment of COVID-19 assigned by the Wuhan government. Patients with confirmed COVID-19, according to the guideline of SARS-CoV-2 (The Fifth Trial Version of the Chinese National Health Commission) admitted into HPHTCM from January 5 to February 22, 2020, were included for initial screen.23 Patients received a diagnosis of hypertension before admission to our hospital as SARS-CoV-2 infection was defined as patients with COVID-19 and preexisting hypertension, which were then retrospectively allocated into 2 subgroups, ARBs/ACE inhibitors and non-ARBs/ACE inhibitors group, according to their usage of antihypertensive drugs. Age- and sex-matched cases were randomly selected from the remaining patients with COVID-19 without preexisting hypertension as nonhypertension controls. The clinical outcomes (ie, discharges, mortality, length of stay) were monitored up to March 3, 2020, the final date of follow-up. In addition, the medication history of 1942 patients with hypertension who were admitted to HPHTCM from November 1 to December 31, 2019, before the COVID-19 outbreak were also reviewed for external comparison. Written informed consent was waived by the Ethics Commission of the hospital for emerging infectious diseases.

Data Collection

The medical records of patients were analyzed by the research team of HPHTCM. Disease onset was defined as the date when the symptom was reported. Data on the use of ACE inhibitors and ARBs before admission and during hospital stay were collected. Other information including demographic data, medical history, exposure history, comorbidities, symptoms, signs, laboratory findings, and treatment measures (ie, antiviral therapy, corticosteroid therapy) were extracted from electronic medical records and were recorded with standardized data collection forms. The data were reviewed by a trained team of physicians.
Assessment of disease status followed the guideline of SARS-CoV-2 (The Fifth Trial Version of the Chinese National Health Commission): mild type, with slight clinical symptoms but no imaging presentation of pneumonia; common type, with fever, respiratory tract and other symptoms, imaging findings of pneumonia; severe type, with any of the following conditions: respiratory distress, respiratory frequency ≥30 times/min, finger oxygen saturation at rest ≤93%, or oxygenation index (PaO2/FiO2)≤300 mm Hg (1 mm Hg=0.133 kPa); critical type, with any of the following conditions: respiratory failure requires mechanical ventilation, shock, combined with other organ failures that require intensive care unit care and treatment.21
Laboratory parameters, including complete blood count, hs-CRP (high-sensitivity C-reactive protein), arterial blood gas analysis, myocardial injury markers, coagulation profile, serum biochemical tests (including renal and liver function, lactate dehydrogenase), PCT (procalcitonin), BNP (b-type natriuretic peptide), were measured according to the manufacturer’s instructions.

Statistical Analysis

Data analysis was performed using SPSS (Statistical Package for the Social Sciences, version 23). Categorical variables were reported as absolute (relative frequencies) and compared by χ2 tests or Fisher exact tests. Continuous variables were expressed as mean (SD) if they are normally distributed or median (interquartile range, IQR) if they are not and compared by independent group t tests or Mann-Whitney U tests, respectively. In online supplementary tables, multivariable regression models were used for calculating the adjusted P value between the hypertension group and nonhypertension group to remove the interference of mismatches in the baseline data. Variables with non-normal distributions were transformed to logarithmic values for regression analysis. P<0.05 was considered statistically significant.

Results

Patient Grouping

After the initial screen, 462 patients with COVID-19 were allocated to 2 groups, the hypertension group that includes 126 patients with preexisting hypertension, and the nonhypertension group comprising 125 age- and sex-matched patients that were randomly selected from the remaining patients without hypertension (Figure). Patients with COVID-19 and hypertension were further allocated into 2 subgroups based on the usage of ARBs/ACE inhibitors as antihypertensive drugs: 43 in the ARBs/ACE inhibitors subgroup and 83 in the non-ARBs/ACE inhibitors subgroup. Alternatively, data for all patients with COVID-19 without preexisting hypertension (n=336) were collected to avoid selection bias. Tables S1, S2, and S3 in the Data Supplement summarize the comparisons between this unselected nonhypertension group, and other groups analyzed using multivariable regression.
Figure. Flowchart of the selection for study subjects. ACE indicates angiotensin-converting enzyme; ARB, angiotensin II receptor blockers; COVID-19, coronavirus disease 2019; and SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Presenting Characteristics

Baseline characteristics are shown in Table 1. The median age of the hypertension group was 66 (IQR, 61–73) years, and 62 (49.2%) were men, which is similar compared with 66 (IQR, 60–75) years and 61 (48.8%) in the nonhypertension group (Table 1 and Figure S1). Compared with nonhypertension controls, patients with preexisting hypertension had higher levels of systolic blood pressure (125 [IQR, 120–140] versus 120 [IQR, 120–134]; P=0.031) and diastolic blood pressure (75 [IQR, 70–85] versus 70 [IQR, 70–80]; P=0.004), as well as higher proportion of diabetes mellitus (30.2% [38 of 126] versus 13.6% [17 of 125]; P=0.002) and cardiopathy (18.3% [23 of 126] versus 9.6% [12 of 125]; P=0.048).
Table 1. Demographics, Baseline Characteristics, and Complications of 126 Patients With Hypertension and 125 Patients Without Hypertension With COVID-19 at Hubei Provincial Hospital of Traditional Chinese Medicine (January 5 to February 22, 2020)
CharacteristicsNonhypertensionHypertensionP ValueP Value
Total (n=125)Total (n=126)Non-ARBs/ACE Inhibitors (n=83)ARBs/ACE Inhibitors (n=43)Nonhypertension vs HypertensionNon-ARBs/ACE Inhibitors vs ARBs/ACE Inhibitors
Age, median (IQR)66 (60–72)66 (61–73)67 (62–75)65 (57–72)0.4600.122
Sex, N (%)    0.9490.952
 Female64 (51.2)64 (50.8)42 (50.6)22 (51.2)  
 Male61 (48.8)62 (49.2)41 (49.4)21 (48.8)  
Anthropometrics, median (IQR)
 Weight, kg60.0 (56.5–65.0)60.0 (57.5–70.0)60.0 (55.0–65.0)60.0 (60.0–70.0)0.5160.179
 Height, cm165.0 (160.0–170.0)165.0 (160.0–171.0)162.0 (159.0–170.0)166.0 (160.0–173.0)0.7350.345
 BMI, kg/m223.25 (20.28–24.20)22.86 (20.83–24.77)22.77 (20.81–24.61)23.42 (21.09–25.39)0.5250.305
Blood pressure, mm Hg, median (IQR)
 Systolic blood pressure120 (120–134)125 (120–140)124 (120–143)129 (120–140)0.031*0.966
 Diastolic blood pressure70 (70–80)75 (70–85)75 (70–85)77 (70–85)0.004*0.688
Symptom, N (%)
 Fever84 (67.2)90 (71.4)60 (72.3)30 (69.8)0.4680.766
 Cough84 (67.2)87 (69.0)57 (68.7)30 (69.8)0.7530.900
 Headache15 (12.1)20 (15.9)12 (14.5)8 (18.6)0.3760.546
 Diarrhea13 (10.5)19 (15.1)13 (15.7)6 (14.0)0.2660.779
Complications, N (%)
 Diabetes mellitus17 (13.6)38 (30.2)25 (30.1)13 (30.2)0.002*0.990
 Respiratory disease6 (4.4)6 (4.7)3 (3.6)3 (7.0)0.9030.690
 Kidney disease1 (0.8)3 (2.4)3 (3.6)0 (0.0)0.3170.207
 Hepatic disease5 (4.1)8 (6.3)5 (6.1)3 (7.0)0.4010.849
 Cardiopathy12 (9.6)23 (18.3)16 (19.3)7 (16.3)0.048*0.680
 Neurological disease5 (4.0)10 (7.9)6 (7.2)4 (9.3)0.1880.683
 Immune diseases0 (0.0)0 (0.0)0 (0.0)0 (0.0)……
Treatments, N (%)
 Glucocorticoid35 (28.0)39 (31.0)23 (27.7)16 (37.2)0.6080.274
 Antiviral100 (80.0)96 (76.2)66 (79.5)30 (69.8)0.4660.223
 Antibiotic74 (59.2)98 (77.8)69 (83.1)29 (67.4)0.002*0.045*
 Immunoglobulin28 (24.1)40 (31.7)25 (30.1)15 (34.9)0.1510.586
Data are median (IQR) or n (%). P values were obtained from χ2 test, Fisher exact tests, T tests, or Mann-Whitney U tests when appropriate. ACE indicates angiotensin-converting enzyme; ARB, angiotensin II receptor blockers; BMI, body mass index; COVID-19, coronavirus disease 2019; and IQR, interquartile range.
*
P <0.05 was considered statistically significant.
Among the hypertension group, the median ages of patients with and without ARBs/ACE inhibitors usage and were 67 (IQR, 62–75) and 65 (IQR, 57–72) years, respectively. There were no major differences in characteristics between the 2 subgroups except for the higher usage of antibiotics in the non-ARBs/ACE inhibitors subgroup.
Of note, the frequency of ARBs/ACE inhibitors usage in patients with COVID-19 and hypertension was 34.1% (43 of 126), which is not statistically different from that observed in patients with hypertension admitted to HPHTCM before COVID-19 emerged (35.4% [688 of 1952]; P=0.767), and the age/sex distributions are comparable between these 2 groups (Table 2).
Table 2. Usage of Antihypertensive Drugs, Sex Ratio, and Age Distribution In Patients With Hypertension With or Without COVID-19
ParametersHypertension Without COVID-19Hypertension With COVID-19P Value
Antihypertensive drugs, N (%)0.767
 Non-ARBs/ACE inhibitors1254 (64.6)83 (65.9) 
 ARBs/ACE inhibitors688 (35.4)43 (34.1) 
Sex, N (%)0.872
 Female973 (50.1)64 (50.8) 
 Male969 (49.9)62 (49.2) 
Age, median (IQR)66 (57-76)66 (61-73)0.685
Data are median (IQR) or n (%). P values were obtained from χ2 tests or Mann-Whitney U test, when appropriate. Hypertension without COVID-19: patients admitted to HPHTCM before COVID-19 outbreak (from November 1 to December 31, 2019). ACE indicates angiotensin-converting enzyme; ARB, angiotensin II receptor blockers; COVID-19, coronavirus disease 2019; HPHTCM, Hubei Provincial Hospital of Traditional Chinese Medicine; and IQR, interquartile range.

Disease Status, Course, and Outcome

Among the 126 patients with hypertension, 23 (18.3%) were critical type, 27 (21.4%) were severe, and 76 (60.3%) were mild and common. During the observation period, 13 (10.3%) patients in the hypertension group died, 71 (56.3%) discharged, and 42 (33.3%) remained in hospital (Table 3). Compared with the hypertension group, the nonhypertension group seemingly had fewer cases of critical illness (14 [11.2%]) and fewer deaths (8 [6.4%]), but this difference is not statistically significant.
Table 3. Classification of Severity, Outcome, and Disease Course of Patients With COVID-19 With or Without Hypertension
ParametersNonhypertensionHypertensionP ValueP Value
Total(n=125)Total (n=126)Non-ARBs/ACE Inhibitors (n=83)ARBs/ACE Inhibitors (n=43)Nonhypertension vs HypertensionNon-ARBs/ACE Inhibitors vs ARBs/ACE Inhibitors
Classification of severity N (%)    0.1560.162
 Mild/common89 (71.2)76 (60.3)48 (57.8)28 (65.1)  
 Severe22 (17.6)27 (21.4)16 (19.3)11 (25.6)  
 Critical14 (11.2)23 (18.3)19 (22.9)4 (9.3)0.1150.061
Outcome N (%)    0.5230.283
 Discharged72 (57.6)71 (56.3)44 (53.0)27 (62.8)  
 Remained in hospital45 (36.0)42 (33.3)28 (33.7)14 (32.6)  
 Died8 (6.4)13 (10.3)11 (13.3)2 (4.7)0.3830.216
Disease course, d, mean, SD    0.5010.880
 Discharged28.6±8.027.4±9.828.4±10.025.6±9.50.8110.227
 Remained in hospital31.6±7.736.7±12.437.5±12.335.2±12.80.024*0.597
 Died20.3±5.715.4±9.914.7±10.719.0±1.40.2230.598
Data are n (%) or mean ± SDs. P values were obtained from χ2 tests, Fisher exact tests, or Mann-Whitney U tests, when appropriate. ACE indicates angiotensin-converting enzyme; ARB, angiotensin II receptor blockers; COVID-19, coronavirus disease 2019.
*
P<0.05 was considered statistically significant.
Furthermore, within the hypertension group, patients on ARBs/ACE inhibitors had a marginally lower proportion of critical patients (9.3% [4 of 43] versus 22.9% [19 of 83]; P=0.061) and a lower death rate (4.7% [2 of 43] versus 13.3% [11 of 83]; P=0.283) than those on non-ARBs/ACE inhibitors medications, although these differences failed to reach statistical significance (Table 3).

Laboratory Testing

Compared with nonhypertensive controls, patients with COVID-19 and preexisting hypertension had lower arterial partial pressure of oxygen (10.1 [7.6–11.3] versus 11.3 [8.9–13.8]; P=0.001), oxygen index (95 [90–97] versus 97 [94–98]; P<0.001), higher blood urea (5.0 [3.8–8.5] versus 4.5 [3.5–5.5], P=0.020), ALT (alanine transaminase; 28 [17–55] versus 22 [14–43]; P=0.022) and cardiac troponin (0.006 [0–0.031] versus 0 [0–0.014]; P=0.015), and higher concentrations of high-sensitivity C-reactive protein (25.4 [4.6–100.8] versus 12.6 [2.6–53.3]; P=0.024), procalcitonin (0.092 [0.049–0.223] versus 0.062 [0.035–0.134]; P=0.017), and IL (interleukin)-6 (13.8 [4.8–51.3] versus 8.2 [1.8–22.8]; P=0.017). In patients with COVID-19 and preexisting hypertension, ARBs/ACE inhibitors treatment significantly reduced the concentrations of high-sensitivity C-reactive protein (11.5 [4.0–58.2] versus 33.9 [5.1–119.2]; P=0.049) and procalcitonin (0.061 [0.044–0.131] versus 0.121 [0.052–0.295]; P=0.008), when compared with non-ARBs/ACE inhibitors treatment (Table 4).
Table 4. Laboratory Findings of Patients Infected With SARS-CoV-2 at Admission to HPHTCM
Laboratory ParametersNormal RangeNonhypertensionHypertensionP ValueP Value
Total(n=125)Total (n=126)Non-ARBs/ACE Inhibitors (n=83)ARBs/ACE Inhibitors (n=43)Nonhypertension vs HypertensionNon-ARBs/ACE Inhibitors vs ARBs/ACE Inhibitors
Blood routine, median (IQR)
 Neutrophil count1.8–6.3 ×109/L3.2 (2.4–5.2)4.1 (2.9–6.7)4.2 (3.0–7.0)4.0 (2.9–6.3)0.001*0.934
 Lymphocyte count1.1–3.2 ×109/L1.13 (0.76–1.46)0.99 (0.63–1.47)1.03 (0.74–1.47)0.84 (0.51–1.39)0.2040.296
Blood oxygen index, median (IQR)
 Arterial partial pressure of oxygen10.6–13.3 KPa11.3 (8.9–13.8)10.1 (7.6–11.3)10.2 (7.2–11.1)10.1 (8.2–12.2)0.001*0.248
 Oxygen saturation95%–98%97 (94–98)95 (90–97)95 (89–97)95 (91–97)0.000*0.812
Coagulation marker, median (IQR)
 D-dimer, mg/L0–0.50 mg/L0.41 (0.28–0.94)0.42 (0.29–1.34)0.47 (0.29–1.82)0.40 (0.30–0.61)0.8950.284
 Prothrombin time10–14 s12.2 (11.5–12.7)12.2 (11.6–13.0)12.3 (11.6–13.1)12.1 (11.4–12.9)0.4760.257
Blood biochemistry, median(IQR)
 Urea3.6–9.5 μmol/L4.5 (3.5–5.5)5.0 (3.8–8.5)5.1 (3.6–6.4)4.8 (3.9–6.0)0.020*0.751
 Creatinine57–110 μmol/L65 (55–79)69 (58–88)69 (59–87)69 (58–90)0.0800.987
 Glomerular filtration rate>90 mL/(min·1.73m2)105.6 (88.2–128.4)101.8 (79.2–120.3)102.1 (78.2–119.2)101.4 (80.0–121.0)0.0960.927
 Direct bilirubin0–4 μmol/L3.0 (2.2–4.2)3.2 (2.3–4.6)3.1 (2.4–4.6)3.2 (2.1–5.0)0.2260.821
 Indirect bilirubin0–19 μmol/L5.6 (4.0–8.3)5.8 (4.4–8.5)5.6 (4.4–8.2)6.1 (4.8–9.1)0.4430.454
 ALT9–50 U/L22 (14–43)28 (17–55)26 (17–53)34 (18–58)0.022*0.620
 AST15–40 U/L21 (17–35)24 (17–38)24 (18–39)23 (17–31)0.3440.551
 Cardiac troponin0–0.06 ng/mL0 (0–0.014)0.006 (0–0.031)0.0075 (0–0.0493)0 (0–0.014)0.015*0.074
 Pro-BNP0–125.2 pg/mL174.7 (75.3–597.4)219.1 (92.0–1151.3)236.9 (72.0–3256.0)195.1 (106.2–651.4)0.1530.354
 Creatine kinase MB0–5 ng/mL0.88 (0.56–1.63)0.94 (0.65–1.73)0.93 (0.65–1.62)1.09 (0.60–2.35)0.3690.571
 Lactate dehydrogenase0–25 U/L200 (152–251)222 (182–302)228 (188–323)202 (179–258)0.0180.125
 Glucose3.9–6.1 mmol/L5.80 (5.20–8.00)7.00 (5.70–9.40)7.40 (5.85–10.40)6.95 (5.20–8.85)0.005*0.199
Infection-related biomarkers, median (IQR)
 high-sensitivity C-reactive protein0–3 mg/L12.6 (2.6–53.3)25.4 (4.6–100.8)33.9 (5.1–119.2)11.5 (4.0–58.2)0.024*0.049*
 Procalcitonin0–0.052 ng/mL0.062 (0.035–0.134)0.092 (0.049–0.223)0.121 (0.052–0.295)0.061 (0.044–0.131)0.017*0.008*
 Interleukin-6<7 pg/mL8.2 (1.8–22.8)13.8 (4.8–51.3)14.3 (3.7–121.1)10.1 (5.0–50.4)0.017*0.520
Data are median (IQR). P values were from T tests or Mann-Whitney U tests. ACE indicates angiotensin-converting enzyme; ALT, alanine transaminase; ARB, angiotensin II receptor blockers; AST, aspartate transferase; IQR, interquartile range; Pro-BNP, pro–brain natriuretic peptide; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; and HPHTCM, Hubei Provincial Hospital of Traditional Chinese Medicine.
*
P <0.05 was considered statistically significant.

Discussion

This retrospective investigation, to our knowledge, is the first case-control study aimed to examine the overall effect of ARBs/ACE inhibitors on SARS-CoV-2 infection, inflammatory status, and clinical outcome in patients with COVID-19 and preexisting hypertension. The major finding of this report is that without adding risk for SARS-CoV-2 infection, ARBs/ACE inhibitors treatment was superior to other antihypertensive treatments in reducing high-sensitivity C-reactive protein and procalcitonin levels in patients with COVID-19 and preexisting hypertension.
Hypertension is the leading cause of mortality globally. Approximately one-third of adults were estimated to have hypertension worldwide in 2010.24 Since the emerge of SARS-CoV-2 infection, hypertension has been frequently observed as a major comorbidity in patients with COVID-19.2,17,20–22 We reported here that 27.2% (126 of 462) of the patients with COVID-19 admitted to HPHTCM have preexisting hypertension. This incidence is similar to those reported by Young et al (28%), Zhang et al (30%), and Wang et al (31.2%)20–22 but higher than that reported in 2 large epidemiological studies (15% by Guan et al2 and 12.8% by Chinese CDC).17 This discordance could be explained by the age difference; the latter 2 studies had a median age of 47 and 48 years, respectively, compared with 67 years from our report. Patients with COVID-19 and hypertension appeared to have a higher death rate and were more frequently seen in severe cases.17 We also examined the death rate and the incidence of critical cases in our cohort. Compared with nonhypertension controls, patients with COVID-19 and hypertension had a higher death rate (10.3% [13 of 126] versus 6.4 [8 of 125]) and incidence of critical cases (18.3% [23 of 126] versus 11.2 [14 of 125]), but these differences failed to reach statistical significance. Therefore, our results, together with those from other groups, provided ample evidence that hypertension is a critical risk factor for the poor clinical outcome of patients with COVID-19. Indeed, this notion was further supported by laboratory testing results. Patients with COVID-19 with hypertension had much lower blood oxygen index (P<0.001), as well as higher blood urea (P=0.020) and ALT (P=0.022) than those without hypertension.
The mechanisms by which hypertension results in the poor clinical outcome of COVID-19 remain obscure. We found that compared with nonhypertension controls, patients with COVID-19 and hypertension have markedly increased levels of inflammatory high-sensitivity C-reactive protein (P=0.024), procalcitonin (P=0.017), and IL-6 (P=0.017), suggesting that dysregulated inflammatory response might contribute. In fact, hypertension has been well-known for its capacity to stimulate adaptive response and induce the elevated production of inflammation cytokines.25,26 Ang II, an effector peptide of the renin-angiotensin system, which is one of the systems that are responsible for pathophysiology of hypertension,27 has also been demonstrated to be capable of inducing the production of IL-6, IL-1β, TNF (tumor necrosis factor) α, IFN (interleukin) γ, IL-17, and IL-23 in multiple animal models.28 Not surprisingly, treatment of patients with hypertension with ACE inhibitors and ARBs, which can result in reduced production of Ang II and increased expression of ACE2, effectively downregulated the production of inflammatory cytokines.29
Increased levels of inflammatory cytokines have also been observed in patients with COVID-19 with or without hypertension as a coexisting illness. Huang et al19 reported that the plasma concentrations of IL-1β, IL-1RA, (Interleukin-1 receptor antagonist) IFNγ, TNFα, and other cytokines were significantly higher in both Intensive Care Unit patients and non–Intensive Care Unit patients with SARS-CoV-2 infection than in healthy adults. Further comparison found that IL-2, IL-7, IL-10, IP-10 (Interferon-induced protein 10), MCP1 (Monocyte chemoattractant protein 1), MIP1A (Macrophage inflammatory protein 1 alpha), and TNFα were higher in Intensive Care Unit patients than non–Intensive Care Unit patients. Elevated concentration of IL-6 was also demonstrated in patients with COVID-19 with severe and critical disease compared with those with mild and common illness.30,31 Based on these findings, a multicenter, randomized controlled trial was recently registered on Chinese Clinical Trial Registry (Unique identifier: ChiCTR2000029765) to evaluate the efficacy and safety of IL-6R (Interleukin-6 receptor) blockade with tocilizumab in the treatment of COVID-19.
As mentioned above, inhibiting dysregulated inflammatory response represents a promising therapeutic strategy for both patients with COVID-19 and patients with hypertension. Therefore, ACE inhibitors and ARBs that are capable of reducing the production of inflammatory cytokines are potential candidate drugs for treatment of patients with COVID-19 and preexisting hypertension, as suggested by several groups.12,32 However, the clinical evidence is still missing. In this report, we found that in the 43 patients with COVID-19 and hypertension treated with ARBs/ACE inhibitors before and after diagnosed with SARS-CoV-2 infection, the concentrations of inflammatory high-sensitivity C-reactive protein and procalcitonin were significantly lower compared with those treated with non-ARBs/ACE inhibitors. ARBs/ACE inhibitors treatment also resulted in a marginally lower death rate and less critical cases in these patients. We did not find the concentrations of IL-6 in the ARBs/ACE inhibitors group to be significantly different from that in the non-ARBs/ACE inhibitors controls, which suggests that ARBs/ACE inhibitors treatment alone might not be efficient in modulating the production of this cytokine. However, combining of ARBs/ACE inhibitors and IL-6R blockade could presumably have a synergic effect in regulating the elevated inflammatory response in patients with COVID-19 and preexisting hypertension, which could be tested in future clinical trials.
ARBs/ACE inhibitors treatment has been reported to increase the expression of ACE2,33,34 which is also the cellular receptor for SARS-CoV-2 infection.8 Although the downregulation of ACE2 following SARS-CoV infection has been reported to result in acute lung injury, suggesting a protective role of ACE2 upregulation and ARBs/ACE inhibitors treatment in COVID-19, it still raised concerns that ARBs/ACE inhibitors treatment could facilitate SARS-CoV-2 infection by increasing the expression of ACE2.12,35,36 Indeed, a recent report demonstrated the capacity of SARS-CoV-2 to infect human blood vessels and kidney that express high levels of ACE2 using an organoid system.37 Therefore, we compared the frequency of ARBs/ACE inhibitors usage in COVID-2019 patients and hypertension with those in patients with hypertension admitted to HPHTCM before COVID-19 emerged and found that they were not statistically different (34% [43 of 126] versus 35.4% [688 of 1942]; P=0.797). Our result thus indicated that ARBs/ACE inhibitors treatment did not pose an added risk for SARS-CoV-2 infection in our study cohort. ACE2 was reported to bind to SARS-CoV-2 with ≈10- to 20-fold higher affinity than that bind to SARS-CoV. This finding, together with the fact that people from different races, with different ages and sexes, were all susceptible to SARS-CoV-2 infection, suggest that physiological expression of ACE2 may be already sufficient for SARS-CoV-2 infection, and further upregulation might not increase the risk.
ARBs and ACE inhibitors are both antihypertensive drugs discovered to block the renin-angiotensin system and lower blood pressure. Thus, ARBs/ACE inhibitors treatment could result in hypotension in healthy subjects, which may prevent their application in patients with COVID-19 without hypertension. Alternatively, novel therapeutic options using ACE2 as target will be promising in treating SARS-CoV-2 infection without affecting blood pressure.
Our study has several limitations. First, due to the retrospective nature of this study and the fact that it was conducted in a single hospital, interpretation of our findings might be limited by the sample size and selection bias. We also realize that there are additional risk factors that may not be well-controlled, although as many confounders as possible were corrected for. Nevertheless, as far as we know, this is the largest retrospective cohort study designed to examine the usage of ARBs/ACE inhibitors and its effect on patients with COVID-19 and preexisting hypertension. Second, the severity and disease course were not identical among these patients, which resulted in the difficulty in collecting laboratory indicators at the same time point, we, therefore, selected the most extreme values beyond the normal range of laboratory indicators that could reflect the severity of condition for comparison. However, this strategy might still cause biases in presenting laboratory indicators. Third, the expression of ACE2 and other inflammatory factors were not determined in this study due to the sample availability and limited technical resources in our hospital; this limitation prevented us from further exploring the mechanisms by which ARBs/ACE inhibitors regulate the inflammatory status of patients with COVID-19 and hypertension.

Perspectives

The evidence presented in this study supports the use of ARBs/ACE inhibitors over other antihypertensive drugs in treating patients with COVID-19 and preexisting hypertension. Large prospective studies are required to confirm this finding and to explore the mechanisms by which ARBs/ACE inhibitors regulate the inflammatory response. These efforts might eventually lead to the development of novel therapeutic agents targeting ACE2 to treat patients with COVID-19 but no preexisting hypertension without affecting blood pressure.

Novelty and Significance

VIEW EDITORIAL:Evidence That Renin-Angiotensin System Inhibitors Should Not Be Discontinued Due to the COVID-19 Pandemic

What Is New?

•
Hypertension has been reported to be the leading coexisting illness of patients with coronavirus disease 2019 (COVID-19), and these patients were frequently treated with ARBs/ACE inhibitors to control their blood pressure.
•
The effects of ARBs/ACE inhibitors on COVID-19 has yet to be defined.

What Is Relevant?

•
We conducted the first and the largest case series to evaluate the effects of ARBs/ACE inhibitors on severe acute respiratory syndrome coronavirus 2 infection, inflammatory status, and clinical outcomes in patients with COVID-19 with preexisting hypertension.
•
We found that without increasing the risk for severe acute respiratory syndrome coronavirus 2 infection, ARBs/ACE inhibitors outcompeted other antihypertensive drugs in reducing high-sensitivity C-reactive protein and procalcitonin levels in patients with COVID-19 with preexisting hypertension.

Summary

Our results support the use of ARBs/ACE inhibitors over other antihypertensive drugs in treating patients with COVID-19 with preexisting hypertension. Large prospective studies are required to confirm this finding and to explore the mechanisms by which ARBs/ACE inhibitors regulate the inflammatory response.

Supplemental Material

File (hyp_hype202015143_supp2.pdf)

Acknowledgment

We thank all patients and their families involved in the study and all the healthcare professionals from Hubei Provincial Hospital of Traditional Chinese Medicine who helped and took care of the patients with coronavirus disease 2019 (COVID-19) for their great effort and selfless dedication in the medical relief operation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

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Jun. 12, 2020

Musadique Hussain

Inhibitors of the renin–angiotensin–aldosterone system and COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), main cause of COVID-19, uses the aminopeptidase angiotensin-converting enzyme 2 (ACE2) for entry into the host cell. ACE2, part of the renin–angiotensin–aldosterone system (RAAS), is abundantly expressed in heart, lungs, and other tissues, while ACE inhibitors (ACEI) and angiotensin-receptor blockers (ARBs) are considered drugs of first-choice in hypertension, post–myocardial infarction states, heart failure and chronic kidney disease. Multicenter study has revealed that hypertension, coronary artery disease and diabetes are most frequent comorbidities in severe COVID-19 patients than nonsevere illness.

Various preclinical and clinical studies have speculated that ACEI and/or ARBs could theoretically worsen outcomes via increasing the ACE2 expression for SARS-CoV-2 entry into the host cell. These speculated discoveries have stimulated discussions about whether ACEI and ARBs may potentially treat COVID-19 or, conversely, worsen disease (1) while arguments need aroused potential concerns.

This hypothesis gained traction via social media and medical press. For instance, COVID-19 patients with hypertension and diabetes could be at increased risk of severe coronavirus symptoms and are four times as likely to die if they are taking one of these drugs, prior to coronavirus exposure. Anxiety among physicians and patients has been profound because ACEI and/or ARBs are most widely prescribed drugs globally for treatment of hypertension, heart disease, and chronic kidney disease. In this regard, physicians are weighing the dangers of continuing these drugs for which ACEI and/or ARBs known benefit against the harm to their cardiovascular and kidney health associated with discontinuing them. Accordingly, many observational studies are ongoing to access whether ACEI and/or ARBs are indeed harmful, fuelled by speculation, in the context of the COVID-19 epidemic.

In this rapidly evolving setting, observational studies (2, 3, 4, 5, 6, 7), with the looming possibility of confounding, were conducted between December 20, 2019, and April 15, 2020 in different populations with different designs, but their message was consistent because none of these provide evidence to support the hypothesis that neither ACEI nor ARBs were associated with the increased risk for SARS-CoV-2 infection, severe illness, or death. Additionally, secondary analysis involving hypertension patients also did not show harm between these drugs and severe COVID-19. However, several other smaller studies conducted in United Kingdom and China also revealed same conclusion (8-11).

Unexpectedly, Francisco et al. [2] and Mehra et al. [3] revealed that use of either ACEI and/or ARBs or statins may be associated with a lower risk of in-hospital death than non-use, but neither of the other studies revealed such effect. Other studies have also suggested that use of RAAS inhibitors might confer protective effects against complications and death in patients with COVID-19 versus other antihypertensive drugs, although these studies were not restricted to patients with diabetes [9, 11]. The unexpected result may be due to absence of a randomized trial and unmeasured confounding, and should not be regarded as evidence to prescribe these drugs in COVID-19 patients.

Taken together, several professional societies and experts have put forward their guidance with one voice that COVID-19 patients should not discontinue ACEI or ARB therapy during the Covid-19 pandemic because no appropriate evidence exist in this regard (12-15). Ultimately, one or more randomized trials will be needed to answer definitively the question of whether ACEI and/or ARB pose harm to COVID-19 patients.

References:

1. Sunden-Cullberg, J., 2020. Chronic Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers Is High Among Intensive Care Unit Patients With Non–COVID-19 Sepsis but Carries a Moderately Increased Risk of Death. Hypertension (Dallas, Tex.: 1979). (DOI: 10.1161/HYPERTENSIONAHA.120.15178).

2. Francisco, J., et al., Use of renin–angiotensin–aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. The Lancet, 2020. (DOI:https://doi.org/10.1016/S0140-6736(20)31030-8)

3. Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. New England Journal of Medicine. 2020. (DOI: 10.1056/NEJMoa2007621)

4. Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19. New England Journal of Medicine. 2020. (DOI: 10.1056/NEJMoa2006923)

5. Reynolds HR, Adhikari S, Pulgarin C, et al. Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19. New England Journal of Medicine. 2020. (DOI: 10.1056/NEJMoa2008975)

6. Yang, G., Tan, Z., Zhou, L., Yang, M., Peng, L., Liu, J., Cai, J., Yang, R., Han, J., Huang, Y. and He, S., 2020. Effects Of ARBs And ACEIs On Virus Infection, Inflammatory Status And Clinical Outcomes In COVID-19 Patients With Hypertension: A Single Center Retrospective Study. Hypertension.

7. Conversano, A., Melillo, F., Napolano, A., Fominskiy, E., Spessot, M., Ciceri, F. and Agricola, E., 2020. RAAs inhibitors and outcome in patients with SARS-CoV-2 pneumonia. A case series study. Hypertension.

8. Meng J, Xiao G, Zhang J, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerging Microbes & Infections. 2020;9(1):757-760.

9. Zhang P, Zhu L, Cai J, et al. Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circulation Research. 2020.

10. Li J, Wang X, Chen J, Zhang H, Deng A. Association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease 2019 (COVID-19) infection in Wuhan, China. JAMA cardiology. 2020.

11. Bean D, Kraljevic Z, Searle T, et al. Treatment with ACE-inhibitors is associated with less severe disease with SARS-Covid-19 infection in a multi-site UK acute Hospital Trust. medRxiv. 2020.

12. Vaduganathan M, Vardeny O, Michel T, McMurray JJ, Pfeffer MA, Solomon SD. Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19. New England Journal of Medicine. 2020;382(17):1653-1659.

13. Jarcho JA, Ingelfinger JR, Hamel MB, D’Agostino Sr RB, Harrington DP. Inhibitors of the Renin–Angiotensin–Aldosterone System and Covid-19. Mass Medical Soc; 2020.

14. American College of Cardiology. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. March 17, 2020 (https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19)

15. European Society of Cardiology. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. March 13, 2020 (https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang).

Competing Interests
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Hypertension
Volume 76 • Number 1 • July 2020
Pages: 51 - 58
PubMed: 32348166

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History

Received: 26 March 2020
Revision received: 3 April 2020
Accepted: 20 April 2020
Published online: 29 April 2020
Published in print: July 2020

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Keywords

  1. angiotensin-converting enzyme inhibitors
  2. angiotensin receptor blocker
  3. coronavirus
  4. COVID-19
  5. hypertension
  6. inflammation

Subjects

  1. ACE/Angiotensin Receptors/Renin Angiotensin System
  2. Hypertension
  3. Inflammation
  4. Risk Factors

Authors

Affiliations

Guang Yang*
From the Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China (G.Y., Z.T., L.P., J.L., J.C., S.H.)
Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, China (G.Y., Z.T., L.P., J.L., J.C., S.H.)
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Zihu Tan*
From the Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China (G.Y., Z.T., L.P., J.L., J.C., S.H.)
Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, China (G.Y., Z.T., L.P., J.L., J.C., S.H.)
View all articles by this author
Ling Zhou*
Zhongnan Hospital of Wuhan University, China (L.Z.)
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Min Yang*
Department of Preventive Medicine, School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, China (M.Y.)
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Lang Peng*
From the Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China (G.Y., Z.T., L.P., J.L., J.C., S.H.)
Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, China (G.Y., Z.T., L.P., J.L., J.C., S.H.)
View all articles by this author
Jinjin Liu
From the Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China (G.Y., Z.T., L.P., J.L., J.C., S.H.)
Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, China (G.Y., Z.T., L.P., J.L., J.C., S.H.)
View all articles by this author
Jingling Cai
From the Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China (G.Y., Z.T., L.P., J.L., J.C., S.H.)
Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, China (G.Y., Z.T., L.P., J.L., J.C., S.H.)
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Ru Yang
Wuhan Blood Center, China (R.Y.).
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Junyan Han
Department of Immunology (J.H.), School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Yafei Huang [email protected]
Department of Pathogen Biology (Y.H.), School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Shaobin He https://orcid.org/0000-0002-5269-3000 [email protected]
From the Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China (G.Y., Z.T., L.P., J.L., J.C., S.H.)
Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, China (G.Y., Z.T., L.P., J.L., J.C., S.H.)
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Notes

*
These authors contributed equally to this work.
The Data Supplement is available with this article at Supplemental Material.
Correspondence to Shaobin He, Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430070, China, Email [email protected]
Yafei Huang, Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China. Email [email protected]

Disclosures

None.

Sources of Funding

This work was supported by research grants from the National Natural Science Foundation of China (2017NSFC81670825 and 2020NSFC31970865). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.

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