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 | Cardiology | JAMA Cardiology | JAMA Network
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Table 1.  Characteristics of the ACEI/ARB Group Compared With the Non–ACEI/ARB Group in Patients With Hypertension
Characteristics of the ACEI/ARB Group Compared With the Non–ACEI/ARB Group in Patients With Hypertension
Table 2.  Characteristics and Clinical Outcomes of Patients With Hypertension and COVID-19
Characteristics and Clinical Outcomes of Patients With Hypertension and COVID-19
Table 3.  ACEI/ARB and Non–ACEI/ARB Therapy and Comorbid Conditions in Patients With Hypertension
ACEI/ARB and Non–ACEI/ARB Therapy and Comorbid Conditions in Patients With Hypertension
1.
Wu  Z, McGoogan  JM.  Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.   JAMA. Published online February 24, 2020. doi:10.1001/jama.2020.2648PubMedGoogle Scholar
2.
Guan  WJ, Ni  ZY, Hu  Y,  et al; China Medical Treatment Expert Group for COVID-19.  Clinical characteristics of coronavirus disease 2019 in China.   N Engl J Med. Published online February 28, 2020. doi:10.1056/NEJMoa2002032PubMedGoogle Scholar
3.
Huang  C, Wang  Y, Li  X,  et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.   Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5PubMedGoogle ScholarCrossref
4.
Zhang  H, Penninger  JM, Li  Y, Zhong  N, Slutsky  AS.  Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target.   Intensive Care Med. 2020;46(4):586-590. doi:10.1007/s00134-020-05985-9PubMedGoogle ScholarCrossref
5.
Zou  X, Chen  K, Zou  J, Han  P, Hao  J, Han  Z.  Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection.   Front Med. Published online March 12, 2020. doi:10.1007/s11684-020-0754-0PubMedGoogle Scholar
6.
Ferrario  CM, Jessup  J, Chappell  MC,  et al.  Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.   Circulation. 2005;111(20):2605-2610. doi:10.1161/CIRCULATIONAHA.104.510461PubMedGoogle ScholarCrossref
7.
Klimas  J, Olvedy  M, Ochodnicka-Mackovicova  K,  et al.  Perinatally administered losartan augments renal ACE2 expression but not cardiac or renal Mas receptor in spontaneously hypertensive rats.   J Cell Mol Med. 2015;19(8):1965-1974. doi:10.1111/jcmm.12573PubMedGoogle ScholarCrossref
8.
Lu  J, Lu  Y, Wang  X,  et al.  Prevalence, awareness, treatment, and control of hypertension in China: data from 1·7 million adults in a population-based screening study (China PEACE Million Persons Project).   Lancet. 2017;390(10112):2549-2558. doi:10.1016/S0140-6736(17)32478-9PubMedGoogle ScholarCrossref
9.
Zhou  F, Yu  T, Du  R,  et al.  Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.   Lancet. 2020;395(10229):1054-1062. doi:10.1016/S0140-6736(20)30566-3PubMedGoogle ScholarCrossref
10.
Wang  D, Hu  B, Hu  C,  et al.  Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.   JAMA. Published online February 7, 2020. doi:10.1001/jama.2020.1585PubMedGoogle Scholar
11.
Zhang  JJ, Dong  X, Cao  YY,  et al.  Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.   Allergy. 2020;(Feb):19. doi:10.1111/all.14238PubMedGoogle Scholar
12.
Fang  L, Karakiulakis  G, Roth  M.  Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?   Lancet Respir Med. 2020;8(4):e21. doi:10.1016/S2213-2600(20)30116-8PubMedGoogle Scholar
13.
Imai  Y, Kuba  K, Rao  S,  et al.  Angiotensin-converting enzyme 2 protects from severe acute lung failure.   Nature. 2005;436(7047):112-116. doi:10.1038/nature03712PubMedGoogle ScholarCrossref
14.
Kuba  K, Imai  Y, Rao  S,  et al.  A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.   Nat Med. 2005;11(8):875-879. doi:10.1038/nm1267PubMedGoogle ScholarCrossref
15.
American Heart Association. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. Accessed April 6, 2020. https://professional.heart.org/professional/ScienceNews/UCM_505836_HFSAACCAHA-statement-addresses-concerns-re-using-RAAS-antagonists-in-COVID-19.jsp
Brief Report
April 23, 2020

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

Author Affiliations
  • 1Department of Pharmacy, Key Laboratory for Molecular Diagnosis of Hubei Province, Tongji Medical College, The Central Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, Hubei, China
  • 2Department of Pain, Tongji Medical College, The Central Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, Hubei, China
  • 3Department of Information, Tongji Medical College, The Central Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, Hubei, China
  • 4Department of Endocrinology, Tongji Medical College, The Central Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, Hubei, China
JAMA Cardiol. 2020;5(7):825-830. doi:10.1001/jamacardio.2020.1624
Key Points

Question  Among patients with hypertension, do those taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have greater illness severity or increased risk of mortality during hospitalization for coronavirus disease 2019 (COVID-19) infection?

Findings  In this single-center case series involving 362 patients with hypertension hospitalized with COVID-19 infection, there was no difference in severity of the disease, complications, and risk of death in those who were taking ACEIs/ARBs compared with those not treated with these medications.

Meaning  In this single-center study, ACEI/ARB was not associated with severity and outcomes of COVID-19 infection in hospitalized patients with hypertension. These results support current guidelines and societal recommendations for treating hypertension.

Abstract

Importance  Data are lacking whether patients with hypertension who are taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have increased severity or risk of mortality during hospitalization for coronavirus disease 2019 (COVID-19).

Objective  To investigate the association between ACEIs/ARBs and severity of illness and mortality in patients with hypertension hospitalized for COVID-19 infection.

Design, Setting, and Participants  Retrospective, single-center case series of the 1178 hospitalized patients with COVID-19 infections at the Central Hospital of Wuhan, China, from January 15 to March 15, 2020.

Main Outcomes and Measures  COVID-19 was confirmed by real-time reverse transcription–polymerase chain reaction and epidemiologic, clinical, radiologic, laboratory, and drug therapy data were analyzed in all patients. The percentage of patients with hypertension taking ACEIs/ARBs was compared between those with severe vs nonsevere illness and between survivors vs nonsurvivors.

Results  Of the 1178 patients with COVID-19, the median age was 55.5 years (interquartile range, 38-67 years) and 545 (46.3%) were men. The overall in-hospital mortality was 11.0%. There were 362 patients with hypertension (30.7% of the total group; median age, 66.0 years [interquartile range, 59-73 years]; 189 [52.2%] were men), of whom 115 (31.8%) were taking ACEI/ARBs. The in-hospital mortality in the patients with hypertension was 21.3%. The percentage of patients with hypertension taking ACEIs/ARBs did not differ between those with severe and nonsevere infections (32.9% vs 30.7%; P = .65) nor did it differ between nonsurvivors and survivors (27.3% vs 33.0%; P = .34). Similar findings were observed when data were analyzed for patients taking ACEIs and those taking ARBs.

Conclusions and Relevance  This study provides clinical data on the association between ACEIs/ARBs and outcomes in patients with hypertension hospitalized with COVID-19 infections, suggesting that ACEIs/ARBs are not associated with the severity or mortality of COVID-19 in such patients. These data support current guidelines and societal recommendations for treating hypertension during the COVID-19 pandemic.

Introduction

The epidemiology and clinical characterization of patients with coronavirus disease 2019 (COVID-19) has been reported.1-3 As angiotensin-converting enzyme (ACE) 2 serves as the receptor for severe acute respiratory syndrome coronavirus 2 to gain entry into cells,4 ACE2-expressing cells are susceptible to COVID-19 infection.5 The use of ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) is common treatment in cardiovascular disorders, including hypertension, and data regarding the association of these drugs with ACE2 levels are conflicting.6,7 However, to our knowledge, there are no clinical data indicating whether patients with hypertension who are taking ACEIs/ARBs have increased severity of illness or risk of mortality during COVID-19 infection and whether these patients should continue to use ACEIs/ARBs or switch to other antihypertensive drugs.

Methods

Patients with COVID-19 admitted to the Central Hospital of Wuhan (Hubei Province, China) from January 15, 2020, to March 15, 2020, were included in this retrospective analysis. The study was approved by the institutional ethics board of the Central Hospital of Wuhan and the requirement for informed consent was waived because of the retrospective nature of the study. Epidemiologic, clinical characterization, radiologic, laboratory, treatment, and clinical outcomes data were collected and analyzed.

Definitions

The severity of COVID-19 pneumonia was classified according to the diagnosis and treatment scheme for COVID-19 of Chinese (5th edition).1 Severe illness was defined as blood oxygen saturation levels of 93% or less, respiratory frequency of 30/min or greater, a partial pressure of arterial oxygen to fraction of inspired oxygen ratio of less than 300, lung infiltrates more than 50% within 24 to 48 hours, septic shock, respiratory failure, and/or multiple organ dysfunction or failure. Nonsevere illness was defined as the absence of the previously described characteristics. Hypertension was defined as a history of diastolic blood pressure of 90 mm Hg or greater or a systolic blood pressure of 140 mm Hg or greater or history of antihypertensive medication use.8 A patient’s ACEI/ARB use was defined as use of these drugs at the time of admission that continued through hospitalization.

Statistical Analysis

Continuous and categorical variables were represented as median (interquartile range [IQR]) and numbers (%), respectively, with comparisons using the Mann-Whitney U test, t test, χ2 test, or Fisher exact test. A 2-sided α of less than .05 was considered statistically significant. All the analyses were done using SPSS, version 20 (IBM).

Results

As of March 15, 2020, there were 1178 patients hospitalized with COVID-19. The median age was 55.5 years and 545 (46.3%) were men. There were 130 in-hospital deaths (mortality rate, 11.0%), of whom 84 (64.6%) were men. Among the 1178 patients, there were 362 patients with hypertension (30.7%). The characteristics and clinical outcomes of the patients with hypertension compared with those without hypertension are summarized in the eTable in the Supplement. Patients with hypertension were older and had greater prevalence of chronic diseases; they also had more severe manifestations of COVID-19, including higher rates of acute respiratory distress syndrome and greater in-hospital mortality (21.3% vs 6.5%; P < .001).

The 362 patients with hypertension were further analyzed and form the basis of this article. There were 189 men (52.2%), 259 (71.5%) were older than 60 years, and 115 (31.8%) were taking ACEIs/ARBs. In-hospital mortality was 21.3% (n = 77). The characteristics and clinical outcomes of these patients are summarized in Table 1 with respect to treatment with ACEIs/ARBs. Aside from a greater prevalence of coronary artery disease in those taking ACEIs/ARBs, patients with and without ACEI/ARB treatment had similar comorbidities and, with the exception of higher alkaline phosphatase in those not taking ACEIs/ARBs, had similar laboratory profile results, including blood cell counts, inflammatory markers, renal and liver function tests, and cardiac biomarkers. The frequency of severity of illness, acute respiratory distress syndrome, and mortality did not differ with respect to ACEI/ARB therapy.

The characteristics of patients with severe vs nonsevere infections and survivors vs nonsurvivors are presented in Table 2 along with antihypertensive treatments. The most commonly used antihypertensive drugs were calcium-channel blockers. The percentage of patients with hypertension taking any drug or drug combination did not differ between those with severe and nonsevere infections and nonsurvivors and survivors.

With respect to ACEI/ARB use, there was no difference between those with severe vs nonsevere illness in use of ACEIs (9.2% vs 10.1%; P = .80), ARBs (24.9% vs 21.2%; P = .40), or the composite of ACEIs/ARBs (32.9% vs 30.7%; P = .65). Similarly, there were no differences between nonsurvivors and survivors in use of ACEIs (9.1% vs 9.8%; P = .85), ARBs (19.5% vs 23.9%; P = .42), or the composite of ACEIs/ARBs (27.3% vs 33.0%; P = .34).

Because comorbidities may affect treatment options for hypertension, we analyzed the use of ACEIs/ARBs among patients with hypertension and various comorbid conditions, including coronary heart disease, cerebrovascular disease, diabetes, neurological disease, and chronic renal disease, with respect to disease progression and mortality (Table 3). In patients with each of these chronic conditions, the frequency of severe illness and death did not differ between those treated with and without ACEIs/ARBs.

Discussion

In this study, we report data demonstrating that there was no difference in the disease progression and risk of death during hospitalization for COVID-19 with respect to various antihypertensive drugs and in the use of ACEIs/ARBs between those with severe vs nonsevere illness and between nonsurvivors and survivors. Further, there was no difference in comorbidities associated with hypertension and the length of hospital stay in patients who were taking ACEIs/ARBs or non–ACEIs/ARBs.

The prevalence of hypertension in our patient cohort (30.7%) is similar to that reported in previous studies in which 15.0% to 31.2% of patients with COVID-19 infection had hypertension.2,9-11 Our findings also confirm data in these prior reports that patients with hypertension have more severe illness and higher mortality rates than those without hypertension. However, these previous reports did not indicate how many patients were taking ACEIs or ARBs.2,9-11 Based on previously reported data, it was legitimate to assume that an association may exist between ACEI or ARB therapy and disease severity or risk of death in patients with hypertension infected with COVID-19. Our data provide some reassurance that ACEIs/ARBs are not associated with the progression or outcome of COVID-19 hospitalizations in patients with hypertension.

Levels of ACE2 are a double-edged sword. On one hand, the increased expression of ACE2 may facilitate infection with COVID-19 and increase the risk of developing severe and fatal COVID-19.12 On the other hand, decreased expression of ACE2 can induce pulmonary edema and reduce lung function, which can be reversed by recombinant ACE213 or losartan14; therefore, increased expression of ACE2 appears to be protective against acute lung injury. Currently, almost all major societies recommend that patients with hypertension do not discontinue using ACEIs, ARBs, or other renin-angiotensin-aldosterone antagonists in this setting15 except for clinical reasons rather than COVID-19. The clinical data in the current report support these societal recommendations.

In this study, we found that patients with hypertension had more than 3 times the mortality rate of all other patients hospitalized with COVID-19. Hypertension combined with cardiovascular and cerebrovascular diseases, diabetes, and chronic kidney disease would predispose patients to an increased risk of severity and mortality of COVID-19. Therefore, patients with these underlying conditions who develop COVID-19 require particularly intensive surveillance and care.

Limitations

This study was limited by a small number of patients with hypertension taking ACEIs/ARBs who were hospitalized with COVID-19. The current findings may not be generalizable to all patients with hypertension, and it is possible that ACEIs/ARBs could affect the chance of hospitalization. This could not be evaluated in the current data set and warrants further research. In this cohort, a nonsevere disease course of COVID-19 was still severe enough to require hospitalization. In addition, it is not certain whether the ACEI/ARB treatment at baseline was maintained throughout the hospitalization for all patients. Finally, this is an observational treatment comparison and may be biased by differences in patients taking vs not taking ACEIs/ARBs at the time of hospitalization. However, the measured baseline characteristics were similar in both groups (Table 1), suggesting that these groups are reasonably comparable.

Conclusions

The current findings did not identify an association between treatment with ACEIs/ARBs and either severity or clinical outcomes of COVID-19 hospitalizations in patients with hypertension. These data support current guidelines and societal recommendations for treating hypertension during the COVID-19 pandemic.

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Article Information

Accepted for Publication: April 7, 2020.

Corresponding Author: Aiping Deng, BS (dapyxb@163.com), and Hongmei Zhang, MD (zhm7001@163.com), The Central Hospital of Wuhan, No. 21 Shengli Rd, Wuhan 430021, China.

Author Contributions: Prof Deng and Dr Li had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Li, Deng.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Li, Wang, Chen, Deng.

Critical revision of the manuscript for important intellectual content: Li, Wang, Zhang, Deng.

Statistical analysis: Li, Wang, Chen, Deng.

Obtained funding: Zhang.

Administrative, technical, or material support: Li, Wang, Zhang, Deng.

Supervision: Deng.

Conflict of Interest Disclosures: None reported.

Published Online: April 23, 2020. doi:10.1001/jamacardio.2020.1624

Correction: This article was corrected on June 17, 2020, to fix errors in the Author Contributions.

Funding/Support: This study was supported by the Health and Family Planning Commission of Wuhan City, China (grants WX18M02 and WX18C25).

Role of the Funder/Sponsor: The Health and Family Planning Commission of Wuhan City, China, had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Wu  Z, McGoogan  JM.  Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.   JAMA. Published online February 24, 2020. doi:10.1001/jama.2020.2648PubMedGoogle Scholar
2.
Guan  WJ, Ni  ZY, Hu  Y,  et al; China Medical Treatment Expert Group for COVID-19.  Clinical characteristics of coronavirus disease 2019 in China.   N Engl J Med. Published online February 28, 2020. doi:10.1056/NEJMoa2002032PubMedGoogle Scholar
3.
Huang  C, Wang  Y, Li  X,  et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.   Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5PubMedGoogle ScholarCrossref
4.
Zhang  H, Penninger  JM, Li  Y, Zhong  N, Slutsky  AS.  Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target.   Intensive Care Med. 2020;46(4):586-590. doi:10.1007/s00134-020-05985-9PubMedGoogle ScholarCrossref
5.
Zou  X, Chen  K, Zou  J, Han  P, Hao  J, Han  Z.  Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection.   Front Med. Published online March 12, 2020. doi:10.1007/s11684-020-0754-0PubMedGoogle Scholar
6.
Ferrario  CM, Jessup  J, Chappell  MC,  et al.  Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.   Circulation. 2005;111(20):2605-2610. doi:10.1161/CIRCULATIONAHA.104.510461PubMedGoogle ScholarCrossref
7.
Klimas  J, Olvedy  M, Ochodnicka-Mackovicova  K,  et al.  Perinatally administered losartan augments renal ACE2 expression but not cardiac or renal Mas receptor in spontaneously hypertensive rats.   J Cell Mol Med. 2015;19(8):1965-1974. doi:10.1111/jcmm.12573PubMedGoogle ScholarCrossref
8.
Lu  J, Lu  Y, Wang  X,  et al.  Prevalence, awareness, treatment, and control of hypertension in China: data from 1·7 million adults in a population-based screening study (China PEACE Million Persons Project).   Lancet. 2017;390(10112):2549-2558. doi:10.1016/S0140-6736(17)32478-9PubMedGoogle ScholarCrossref
9.
Zhou  F, Yu  T, Du  R,  et al.  Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.   Lancet. 2020;395(10229):1054-1062. doi:10.1016/S0140-6736(20)30566-3PubMedGoogle ScholarCrossref
10.
Wang  D, Hu  B, Hu  C,  et al.  Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.   JAMA. Published online February 7, 2020. doi:10.1001/jama.2020.1585PubMedGoogle Scholar
11.
Zhang  JJ, Dong  X, Cao  YY,  et al.  Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.   Allergy. 2020;(Feb):19. doi:10.1111/all.14238PubMedGoogle Scholar
12.
Fang  L, Karakiulakis  G, Roth  M.  Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?   Lancet Respir Med. 2020;8(4):e21. doi:10.1016/S2213-2600(20)30116-8PubMedGoogle Scholar
13.
Imai  Y, Kuba  K, Rao  S,  et al.  Angiotensin-converting enzyme 2 protects from severe acute lung failure.   Nature. 2005;436(7047):112-116. doi:10.1038/nature03712PubMedGoogle ScholarCrossref
14.
Kuba  K, Imai  Y, Rao  S,  et al.  A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.   Nat Med. 2005;11(8):875-879. doi:10.1038/nm1267PubMedGoogle ScholarCrossref
15.
American Heart Association. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. Accessed April 6, 2020. https://professional.heart.org/professional/ScienceNews/UCM_505836_HFSAACCAHA-statement-addresses-concerns-re-using-RAAS-antagonists-in-COVID-19.jsp
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