key: cord-0956109-6um6wkaj authors: Chen, Renzheng; Yang, Jie; Gao, Xubin; Ding, Xiaohan; Yang, Yuanqi; Shen, Yang; He, Chunyan; Xiang, Hedong; Ke, Jingbin; Yuan, Fangzhengyuan; Cheng, Ran; Lv, Hailin; Li, Ping; Zhang, Limin; Liu, Chuan; Tan, Hu; Huang, Lan title: Influence of blood pressure control and application of renin‐angiotensin‐aldosterone system inhibitors on the outcomes in COVID‐19 patients with hypertension date: 2020-10-02 journal: J Clin Hypertens (Greenwich) DOI: 10.1111/jch.14038 sha: 475e2b3d560e85c6c05a81cb745bacbe8b297926 doc_id: 956109 cord_uid: 6um6wkaj Hypertension is proved to be associated with severity and mortality in coronavirus disease 2019 (COVID‐19). However, little is known about the effects of pre‐admission and/or in‐hospital antihypertension treatments on clinical outcomes. Thus, this study aimed to investigate the association between in‐hospital blood pressure (BP) control and COVID‐19–related outcomes and to compare the effects of different antihypertension treatments. This study included 2864 COVID‐19 patients and 1628 were hypertensive. Patients were grouped according to their BP during hospitalization and records of medication application. Patients with higher BP showed worse cardiac and renal functions and clinical outcomes. After adjustment, subjects with pre‐admission usage of renin‐angiotensin‐aldosterone system (RAAS) inhibitors (HR = 0.35, 95%CI 0.14‐0.86, P = .022) had a lower risk of adverse clinical outcomes, including death, acute respiratory distress syndrome, respiratory failure, septic shock, mechanical ventilation, and intensive care unit admission. Particularly, hypertension patients receiving RAAS inhibitor treatment either before (HR = 0.35, 95%CI 0.13‐0.97, P = .043) or after (HR = 0.18, 95%CI 0.04‐0.86, P = .031) admission showed a significantly lower risk of adverse clinical outcomes than those receiving application of other antihypertensive medicines. Furthermore, consecutive application of RAAS inhibitors in COVID‐19 patients with hypertension showed better clinical outcomes (HR = 0.10, 95%CI 0.01‐0.83, P = .033) than non‐RAAS inhibitors users. We revealed that COVID‐19 patients with poor BP control during hospitalization had worse clinical outcomes. Compared with other antihypertension medicines, RAAS inhibitors were beneficial for improving clinical outcomes in COVID‐19 patients with hypertension. Our findings provide direct evidence to support the administration of RAAS inhibitors to COVID‐19 patients with hypertension before and after admission. Coronavirus disease 2019 (COVID-19) is a current pandemic infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has presented an unprecedented challenge for the healthcare community across the globe. Until now, over 13 million people are infected by SARS-CoV-2 with considerable mortality, and the number is continuously rising. This pandemic of SARS-CoV-2 is considered as a long-term public health events around the worldwide. The clinical and epidemiological characteristics of COVID-19 have been reported in previous studies. 1, 2 Hypertension has been verified to be associated with increased risk of infection and adverse clinical outcomes in patients with COVID-19. 3, 4 Previous studies have stressed the importance of blood pressure control, but little information showed an association between poorly controlled blood pressure during hospitalization and outcomes in COVID-19 patients. Furthermore, some patients with hypertension were treated with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs), which increase the expression of angiotensin-converting enzyme 2 (ACE2) receptor in cardiovascular and respiratory systems, 5 a known cellular receptor and a necessary binding site for SARS-CoV-2 infection. 6 Although recent studies pointed out that in-hospital application of RAAS inhibitors do not show significant difference in mortality and other adverse clinical outcomes, 7 very limited information presented that clinical outcomes are associated with pre-admission and/or in-hospital application of RAAS inhibitors compared with other antihypertensive medicines. Therefore, this study aimed to investigate the association between in-hospital blood pressure control and COVID-19-related outcomes and to compare the effects of different antihypertension treatments. We hypothesized that pre-admission, in-hospital and consecutive application of RAAS inhibitors treatment might influence the clinical outcomes of COVID-19 patients. This single-center retrospective cohort study was performed at Huo Shen Shan Hospital, which is dedicated solely to the treatment COVID-19 in Wuhan, China. It was urgently constructed for the diagnosis and management of COVID-19 patients. In total, 2864 adult patients (≥18 years old) were consecutively admitted from February 4, 2020, to April 11, 2020, All the data were collected from electronic and traditional clinical medical records, including demographic information, signs, comorbidities, nursing records, laboratory tests, chest computed tomography (CT) images, treatments, and outcomes. The time of illness onset was defined as the day when the symptom was initially reported. Diagnoses of septic shock, respiratory failure, acute respiratory distress syndrome (ARDS), intensive care unit (ICU) admission, mechanical ventilation, and death were recorded. Hospital length of stay, the time from the illness onset to normothermia, inflammatory resorption from CT images, viral shedding, and adverse clinical events occurred were calculated. All the data were carefully checked by two physicians and the third researcher, who adjudicated any differences in the interpretation between the two physicians. The clinical end points were death, ARDS, respiratory failure and septic shock during hospitalization, mechanical ventilation, ICU admission, as well as clinical cure and discharges. The discharge criteria included absence of fever for ≥ 3 days; obvious pulmonary inflammatory resorption in chest CT, clinical remission of respiratory symptoms, and two negative results for SARS-CoV-2 RNA at least 24 h apart. 13 The clinical outcomes were monitored for 75 days and 64 days after the initial symptom onset among different groups. In this retrospective study, we included 2828 COVID-19 con- Table 2, Supplement Table S1 ). In this study, 2745 (97.1%) patients were successfully recovered and discharged, 20 (0.71%) were still remain in the hospital. Moreover, 63 (2.2%) patients died during hospitalization, and the median time from illness onset to death was 26.5 days (IQR 16.8-40.0) ( Table 1 ). The patients were classified into four groups based on the blood pressure grade after admission. 1391 patients were hypertensive according to blood pressure control during hospitalization. Thus, 1628 patients with hypertension were involved, including 867 patients with history of hypertension and 761 patients diagnosed newly after admission. Older age patients had higher blood pressure grade. Furthermore, patients with higher blood pressure grade in line with higher rate of history of hypertension and had the tendency to suffer comorbidities of diabetes, coronary heart disease, and chronic kidney diseases (Table 1 ). In addition, patients with higher blood pressure grade exhibited higher leukocyte and neutrophil counts but lower lymphocyte count. Particularly, patients with increased blood pressure grade showed higher hs-CRP and procalcitonin levels, which suggested a higher inflammatory response. Levels of urea nitrogen, creatinine, and cystatin C increased with blood pressure grade elevated, indicating a worse kidney function in hypertension patients. Nearly all the biomarkers of cardiomyocyte damage were elevated in grades 2 and 3 groups, indicating that patients with higher blood pressure were more likely to suffer cardiac injury after SARS-CoV-2 infection. Patients in grade 3 group had the highest B-type natriuretic peptide and demonstrated a worse cardiac function. Besides, patients with higher blood pressure also had lower concentration of potassium (Table 2, Supplement Table S1 ). Moreover, we found a significant linear relationship between the blood pressure and the incidence of mortality (P for trend < .001), septic shock (P for trend < .001), respiratory failure (P for trend < .001), ARDS (P for trend < .001), mechanical ventilation (P for trend < .001), and ICU admission (P for trend < .001) ( Figure 1) . Interestingly, the proportion of patients who developed adverse clinical events was higher in grade 2 and grade 3 groups than in normotensive and grade 1 group. Furthermore, the length of time from symptoms onset to normothermia, inflammatory resorption, and viral shedding increased with blood pressure grade elevated (Table 1 ). In the multivariable regression analysis, age (OR 1.02, 95% con- Note: Data were expressed as n (%) and median (IQR). Abbreviations: ARDS, acute respiratory distress syndrome; ICU, intensive care unit; IQR, interquartile range; P value, Kruskal-Wallis H test; Time, time from illness onset to clinical outcomes. outcomes was significantly lower in patients with pre-admission application of RAAS inhibitors than those without (HR 0.35, 95% CI 0.14-0.86, P = .022) (Supplement Table S3 ). Besides, the results demonstrated that patients with persistent users of RAAS inhibitors had a lower incidence of progressing to adverse clinical outcomes than non-users (HR 0.11, 95% CI 0.02-0.88, P = .037) ( Figure 3C , Supplement Table S3 ). To compare the outcomes between RAAS inhibitors and other antihypertensive medications, including beta blockers, calcium antagonists, and diuretics (Supplement Table S7 Table S4 ). In addition, we found hypertension patients with persistent RAAS inhibitors treatment showed better clinical outcomes (HR 0.10, 95% CI 0.01-0.83, P = .033) ( Figure 3F , Supplement Table S4 ). In this retrospective study, we analyzed the medical records of 2828 Note: Data were expressed as n (%) and median (IQR). Abbreviations: ALT, alanine aminotransferase; APTT, Activated partial thromboplastin time; BNP, brain natriuretic peptide; Hs-CRP, high-sensitivity C-reactive protein; Hs-cTnI, high-sensitivity assay for troponin I; IQR, interquartile range; P value, Kruskal-Wallis H test; PT, prothrombin time. higher blood pressure grade showed worse cardiac, renal function, Hypertension has been confirmed as a major comorbidity, which increased the risks of adverse outcomes in COVID-19 patients in recent clinical studies. 14 In line with these findings, we demonstrated that blood pressure up to grade 2 was an independent risk factor of adverse clinical outcomes after adjustment for confounders. Besides, we further revealed that COVID-19 patients with the higher blood pressure grade showed worse clinical outcomes ( Figure 2 ). We considered that hypertension patients commonly co-existed with organ damage or dysfunction, such as the kidney and heart. COVID-19 infection further aggravated the primary disease and these comorbidities. In addition, patients with hypertension due to older age were more likely to be infected and progressed to severe and critical cases. 15 However, the underlying pathogenic mechanism linking hypertension and severity and prognosis of COVID-19 infection remains to be elucidated. Until now, SARS-CoV-2 was known to invade host cells by binding to ACE2 localized on the membrane surface through spike protein of the virus. 16 application of RAAS inhibitors, we evaluated the blood pressure among groups with different antihypertensive medication therapies. No significantly statistical difference was found in the four groups. The potential protective effect for improving clinical outcome might be more attributed to organ protection than blood pressure control (Supplement Tables S5 and S6 ). However, our speculation needed to be clarified in further studies. There are some limitations in this study. Firstly, the multivariable-adjusted Cox proportional hazard models were performed to estimate the true treatment effects of RAAS inhibitors. However, observational studies usually exist the deficiency of the inability to include all relevant confounders, including the classes of RAAS inhibitors and other antihypertensive drugs, and the application of traditional Chinese medicines as well as some other unmeasured parameters, such as body mass index, might causing bias that cannot be adjusted. Secondly, this is a single-center study; thus, larger prospective studies from multiple centers are needed to confirm our findings. Thirdly, considering short period of inclusion, long-term prospective studies are also needed to assess the effects of these treatments. We appreciated all the patients who enrolled and all the staffs involved in this study. None. Prof. Lan Huang had full access to all of the data in this study and take responsibility for the integrity and accuracy of the data analysis. Drs F I G U R E 3 Event-free survival of COVID 19 patients using RAAS inhibitors. A, Pre-admission use of RAAS inhibitors improve clinical outcomes in COVID-19 patients versus without pre-admission application (HR 0.35, 95% CI 0.14-0.86, P = .022). B, In-hospital use of RAAS inhibitors improve clinical outcomes in COVID-19 patient versus without application of RAAS inhibitors after admission (HR 0.40, 95% CI 0.15-1.03, P = .058). C, Persistent use of RAAS inhibitors improve clinical outcomes in COVID-19 patients versus without RAAS application (HR 0.11, 95% CI 0.02-0.88, P = .037). D, Pre-admission use of RAAS inhibitors improve clinical outcomes in COVID-19 patients versus preadmission use of other antihypertensive medications (HR 0.35, 95% CI 0.13-0.97, P = .043). E, In-hospital use of RAAS inhibitors improve clinical outcomes in COVID-19 patients versus in-hospital use of other antihypertensive medications (HR 0.18, 95% CI 0.04-0.86, P = .031). F, Persistent use of RAAS inhibitors improve clinical outcomes in COVID-19 patients versus persistent use of other antihypertensive medicines medications (HR 0.10, 95% CI 0.01-0.83, P = .033). 95% CI, 95% confidence interval; HR, hazard ratio; RAAS, renin-angiotensinaldosterone system Hu Tan and Chuan Liu. Acquisition, analysis, or interpretation of data Drafting of the manuscript: Renzheng Chen and Jie Yang. Critical revision of the manuscript for important intellectual content Obtained funding: Hu Tan. Administrative, technical, or material support Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan Clinical Characteristics of Coronavirus Disease 2019 in China Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2 ACE2: from vasopeptidase to SARS virus receptor 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 Clinical management of severe acute respiratory infection when Novel coronavirus (nCoV) infection is suspected: interim guidance Chinese Guidelines for Prevention and Treatment of Hypertension-A report of the Revision Committee of Chinese Guidelines for Prevention and Treatment of Hypertension ESC/ESH Guidelines for the management of arterial hypertension Acute respiratory distress syndrome: the Berlin Definition KDIGO clinical practice guidelines for acute kidney injury Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease Epidemiology Working Group for NCIP Epidemic Response A pneumonia outbreak associated with a new coronavirus of probable bat origin Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence? Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19 Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives Clinical Features of COVID-19 in Patients With Essential Hypertension and the Impacts of Renin-angiotensin-aldosterone System Inhibitors on the Prognosis of COVID-19 Patients Joint HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19 Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg(9) bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration Angiotensin-converting enzyme 2 in lung diseases Angiotensin-converting enzyme 2 protects from severe acute lung failure Transplantation of ACE2(-) Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2 Additional supporting information may be found online in the Supporting Information section.