Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19

Peng Zhang, Lihua Zhu, Jingjing Cai, Fang Lei, Juan-Juan Qin, Jing Xie, Ye-Mao Liu, Yan-Ci Zhao, Xuewei Huang, Lijin Lin, Meng Xia, Ming-Ming Chen, Xu Cheng, Xiao Zhang, Deliang Guo, Yuanyuan Peng, Yan-Xiao Ji, Jing Chen, Zhi-Gang She, Yibin Wang, Qingbo Xu, Renfu Tan, Haitao Wang, Jun Lin, Pengcheng Luo, Shouzhi Fu, Hongbin Cai, Ping Ye, Bing Xiao, Weiming Mao, Liming Liu, Youqin Yan, Mingyu Liu, Manhua Chen, Xiao-Jing Zhang, Xinghuan Wang, Rhian M Touyz, Jiahong Xia, Bing-Hong Zhang, Xiaodong Huang, Yufeng Yuan, Rohit Loomba, Peter P Liu, Hongliang Li, Peng Zhang, Lihua Zhu, Jingjing Cai, Fang Lei, Juan-Juan Qin, Jing Xie, Ye-Mao Liu, Yan-Ci Zhao, Xuewei Huang, Lijin Lin, Meng Xia, Ming-Ming Chen, Xu Cheng, Xiao Zhang, Deliang Guo, Yuanyuan Peng, Yan-Xiao Ji, Jing Chen, Zhi-Gang She, Yibin Wang, Qingbo Xu, Renfu Tan, Haitao Wang, Jun Lin, Pengcheng Luo, Shouzhi Fu, Hongbin Cai, Ping Ye, Bing Xiao, Weiming Mao, Liming Liu, Youqin Yan, Mingyu Liu, Manhua Chen, Xiao-Jing Zhang, Xinghuan Wang, Rhian M Touyz, Jiahong Xia, Bing-Hong Zhang, Xiaodong Huang, Yufeng Yuan, Rohit Loomba, Peter P Liu, Hongliang Li

Abstract

Rationale: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension.

Objective: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19.

Methods and results: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension.

Conclusions: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.

Keywords: COVID-19; angiotensin II receptor blocker; angiotensin-converting enzyme inhibitor; coronavirus; hypertension; inpatients.

Figures

Figure 1.
Figure 1.
The flowchart showing the strategy of participant enrollment. a, 1128 participants with a history of hypertension enrolled in the hypertension cohort. b, 2302 participants without a history of hypertension enrolled in the nonhypertension cohort. c, 188 patients with hypertension who taking ACEI (angiotensin-converting enzyme inhibitor) or ARB (angiotensin II receptor blocker) during hospitalization were enrolled in the ACEI/ARB cohort. Patients discontinued treatment of hypertension due to inability to take medications or hypotension were not excluded from the cohort. d, 940 patients with hypertension who never taking ACEI and ARB during hospitalization were enrolled in the non-ACEI/ARB cohort. e, Propensity score-matched age, gender, cough, dyspnea, comorbidities (diabetes mellitus, coronary heart disease, and chronic renal disease), chest computerized tomography (CT)-diagnosed lung lesions, and incidence of increased CRP (C-reactive protein) and creatine. Hospital site as a random effect in the mixed-effect Cox model. f, 557 patients with antihypertension drug who never taking ACEI and ARB during hospitalization were enrolled in the secondary non-ACEI/ARB cohort. SARS-COV-2 indicates severe acute respiratory syndrome coronavirus 2.
Figure 2.
Figure 2.
Kaplan-Meier curves for cumulative probability of Coronavirus disease 2019 (COVID-19) mortality during 28-day follow-up duration in ACEI (angiotensin-converting enzyme inhibitor)/ARB (angiotensin II receptor blocker) or non-ACEI/ARB cohort among 1128 patients with hypertension. The unmatched model and the median (interquartile range [IQR]) observation time was 28 (20–28) in ACEI/ARB cohort and 28 (19–28) in non-ACEI/ARB cohort (A). Propensity-score matched model and the median (IQR) observation time was 28 (20.5–28) in ACEI/ARB cohort and 28 (18–28) in non-ACEI/ARB cohort (B). The blips indicate censoring. HR indicates hazard ratio.

References

    1. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020;5:536–544. doi: 10.1038/s41564-020-0695-z.
    1. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708–1720. doi: 10.1056/NEJMoa2002032.
    1. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, China. JAMA. 2020;323:1061–1069. doi: 10.1001/jama.2020.1585.
    1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet (London, England) 2020;395:1054–1062. doi:10.1016/S0140-6736(20)30566-3.
    1. Flack JM, Adekola B. Blood pressure and the new ACC/AHA hypertension guidelines. Trends Cardiovasc Med. 2020;30:160–164. doi: 10.1016/j.tcm.2019.05.003.
    1. Kovell LC, Ahmed HM, Misra S, Whelton SP, Prokopowicz GP, Blumenthal RS, McEvoy JW. US hypertension management guidelines: a review of the recent past and recommendations for the future. J Am Heart Assoc. 2015;4:e002315. doi: 10.1161/JAHA.115.002315.
    1. Igase M, Kohara K, Nagai T, Miki T, Ferrario CM. Increased expression of angiotensin converting enzyme 2 in conjunction with reduction of neointima by angiotensin II type 1 receptor blockade. Hypertens Res. 2008;31:553–559. doi: 10.1291/hypres.31.553.
    1. Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, Diz DI, Gallagher PE. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111:2605–2610. doi: 10.1161/CIRCULATIONAHA.104.510461.
    1. Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, Hu Y, Tao ZW, Tian JH, Pei YY, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579:265–269. doi: 10.1038/s41586-020-2008-3.
    1. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11:875–879. doi: 10.1038/nm1267.
    1. National Health Commission of China. New Coronavirus Pneumonia Prevention and Control Program. 2020. : National Health Commission of China; 2020. Accessed February 8, 2020.
    1. World Health Organization. Laboratory testing for 2019 novel coronavirus (2019-nCoV) in suspected human cases Interim guidance. 2020. Available at: . Accessed March 19, 2020.
    1. World Health Organization. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected. 2020. Available at: . Accessed March 13, 2020.
    1. Kellum JA, Lameire N, Aspelin P, Barsoum RS, Burdmann EA, Goldstein SL, Herzog CA, Joannidis M, Kribben A, Levey AS, et al. Kidney disease: Improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2:1–138. doi: 10.1038/kisup.2012.1.
    1. Gando S, Wada H, Thachil J Scientific and Standardization Committee on DIC of the International Society on Thrombosis and Haemostasis (ISTH) Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS). J Thromb Haemost. 2013;11:826–835. doi: 10.1111/jth.12190.
    1. Waljee AK, Mukherjee A, Singal AG, Zhang Y, Warren J, Balis U, Marrero J, Zhu J, Higgins PD. Comparison of imputation methods for missing laboratory data in medicine. BMJ Open. 2013;3:e002847. doi: 10.1136/bmjopen-2013-002847.
    1. VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-Value. Ann Intern Med. 2017;167:268–274. doi: 10.7326/M16-2607.
    1. Mathur MB, Ding P, Riddell CA, VanderWeele TJ. Web site and R Package for computing E-values. Epidemiology. 2018;29:e45–e47. doi: 10.1097/EDE.0000000000000864.
    1. Haneuse S, VanderWeele TJ, Arterburn D. Using the E-Value to assess the potential effect of unmeasured confounding in observational studies. JAMA. 2019;321:602–603. doi: 10.1001/jama.2018.21554.
    1. American Heart Association (AHA), Heart Failure Society of America (HFSA) and American College of Cardiology (ACC) Patients taking ACE-i and ARBs who contract COVID-19 should continue treatment, unless otherwise advised by their physician. 2020. Available at: . Accessed March 19, 2020.
    1. International Society of Hypertension. A statement from the International Society of Hypertension on COVID-19. 2020. Available at: . Accessed March 5, 2020.
    1. Morra ME, Van Thanh L, Kamel MG, Ghazy AA, Altibi AMA, Dat LM, Thy TNX, Vuong NL, Mostafa MR, Ahmed SI, et al. Clinical outcomes of current medical approaches for Middle East respiratory syndrome: a systematic review and meta-analysis. Rev Med Virol. 2018;28:e1977. doi:10.1002/rmv.1977.
    1. Matsuyama R, Nishiura H, Kutsuna S, Hayakawa K, Ohmagari N. Clinical determinants of the severity of Middle East respiratory syndrome (MERS): a systematic review and meta-analysis. BMC Public Health. 2016;16:1203. doi: 10.1186/s12889-016-3881-4.
    1. Chen M, Yang ZD, Smith KM, Carter JD, Nadler JL. Activation of 12-lipoxygenase in proinflammatory cytokine-mediated beta cell toxicity. Diabetologia. 2005;48:486–495. doi: 10.1007/s00125-005-1673-y.
    1. Rodriguez-Iturbe B, Pons H, Johnson RJ. Role of the immune system in hypertension. Physiol Rev. 2017;97:1127–1164. doi: 10.1152/physrev.00031.2016.
    1. Zhang Y, Murugesan P, Huang K, Cai H. NADPH oxidases and oxidase crosstalk in cardiovascular diseases: novel therapeutic targets. Nat Rev Cardiol. 2020;17:170–194. doi: 10.1038/s41569-019-0260-8.
    1. Dhaun N, Webb DJ. Endothelins in cardiovascular biology and therapeutics. Nat Rev Cardiol. 2019;16:491–502. doi: 10.1038/s41569-019-0176-3.
    1. Kuba K, Imai Y, Penninger JM. Angiotensin-converting enzyme 2 in lung diseases. Curr Opin Pharmacol. 2006;6:271–276. doi: 10.1016/j.coph.2006.03.001.
    1. Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436:112–116. doi: 10.1038/nature03712.
    1. Henry C, Zaizafoun M, Stock E, Ghamande S, Arroliga AC, White HD. Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia. Proc (Bayl Univ Med Cent) 2018;31:419–423. doi: 10.1080/08998280.2018.1499293.
    1. Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, Wang Z, Li J, Li J, Feng C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63:364–374. doi: 10.1007/s11427-020-1643-8.
    1. Lai CC, Wang YH, Wang CY, Wang HC, Yu CJ, Chen L. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on the risk of pneumonia and severe exacerbations in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2018;13:867–874. doi:10.2147/COPD.S158634.
    1. Te Riet L, van Esch JH, Roks AJ, van den Meiracker AH, Danser AH. Hypertension: renin-angiotensin-aldosterone system alterations. Circ Res. 2015;116:960–975. doi: 10.1161/CIRCRESAHA.116.303587.
    1. Kozhuharov N, Goudev A, Flores D, Maeder MT, Walter J, Shrestha S, Gualandro DM, de Oliveira Junior MT, Sabti Z, Müller B, et al. GALACTIC Investigators. Effect of a strategy of comprehensive vasodilation vs usual care on mortality and heart failure rehospitalization among patients with acute heart failure: the GALACTIC Randomized Clinical Trial. JAMA. 2019;322:2292–2302. doi: 10.1001/jama.2019.18598.
    1. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62:263–271. doi: 10.1016/j.jacc.2013.02.092.
    1. Wang TZ, Kodiyanplakkal RPL, Calfee DP. Antimicrobial resistance in nephrology. Nat Rev Nephrol. 2019;15:463–481. doi: 10.1038/s41581-019-0150-7.

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