Study protocol for a multicentre, prospective cohort study of the association of angiotensin II type 1 receptor blockers on outcomes of coronavirus infection

James A Russell, John C Marshall, Arthur Slutsky, Srinivas Murthy, Dave Sweet, Terry Lee, Joel Singer, David M Patrick, Bin Du, Zhiyong Peng, Matthew Cheng, Kevin D Burns, Michael O Harhay, James A Russell, John C Marshall, Arthur Slutsky, Srinivas Murthy, Dave Sweet, Terry Lee, Joel Singer, David M Patrick, Bin Du, Zhiyong Peng, Matthew Cheng, Kevin D Burns, Michael O Harhay

Abstract

Introduction: The COVID-19 epidemic grows and there are clinical trials of antivirals. There is an opportunity to complement these trials with investigation of angiotensin II type 1 receptor blockers (ARBs) because an ARB (losartan) was effective in murine influenza pneumonia.

Methods and analysis: Our innovative design includes: ARBs; alignment with the WHO Ordinal Scale (primary endpoint) to align with other COVID-19 trials; joint longitudinal analysis; and predictive biomarkers (angiotensins I, 1-7, II and ACE1 and ACE2). Our hypothesis is: ARBs decrease the need for hospitalisation, severity (need for ventilation, vasopressors, extracorporeal membrane oxygenation or renal replacement therapy) or mortality of hospitalised COVID-19 infected adults. Our two-pronged multicentre pragmatic observational cohort study examines safety and effectiveness of ARBs in (1) hospitalised adult patients with COVID-19 and (2) out-patients already on or not on ARBs. The primary outcome will be evaluated by ordinal logistic regression and main secondary outcomes by both joint longitudinal modelling analyses. We will compare rates of hospitalisation of ARB-exposed versus not ARB-exposed patients. We will also determine whether continuing ARBs or not decreases the primary outcome. Based on published COVID-19 cohorts, assuming 15% of patients are ARB-exposed, a total sample size of 497 patients can detect a proportional OR of 0.5 (alpha=0.05, 80% power) comparing WHO scale of ARB-exposed versus non-ARB-exposed patients.

Ethics and dissemination: This study has core institution approval (UBC Providence Healthcare Research Ethics Board) and site institution approvals (Health Research Ethics Board, University of Alberta; Comite d'etique de la recerche, CHU Sainte Justine (for McGill University and University of Sherbrook); Conjoint Health Research Ethics Board, University of Calgary; Queen's University Health Sciences & Affiliated Hospitals Research Ethics Board; Research Ethics Board, Sunnybrook Health Sciences Centre; Veritas Independent Research Board (for Humber River Hospital); Mount Sinai Hospital Research Ethics Board; Unity Health Toronto Research Ethics Board, St. Michael's Hospital). Results will be disseminated by peer-review publication and social media releases.

Trial registration number: NCT04510623.

Keywords: adult intensive & critical care; cardiology; hypertension.

Conflict of interest statement

Competing interests: JR reports patents owned by the University of British Columbia (UBC) that are related to the use of PCSK9 inhibitor(s) in sepsis, and related to the use of vasopressin in septic shock and a patent owned by Ferring for use of selepressin in septic shock. JR is an inventor on these patents. JR was a founder, Director and shareholder in Cyon Therapeutics Inc. and is a shareholder in Molecular You Corp. JR reports receiving consulting fees in the last 3 years from: (1) Asahi Kesai Pharmaceuticals of America (AKPA) (was developing recombinant thrombomodulin in sepsis). (2) SIB Therapeutics LLC (developing a sepsis drug). (3) Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin). JR is no longer actively consulting for the following: (4) La Jolla Pharmaceuticals (developing angiotensin II; JR chaired the DSMB of a trial of angiotensin II from 2015–2017). (5) PAR Pharma (sells prepared bags of vasopressin). JR reports having received an investigator-initiated grant from Grifols (entitled 'Is HBP a mechanism of albumin’s efficacy in human septic shock?') that was provided to and administered by UBC.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Flow chart of patients. ARBs, angiotensin receptor blockers, ACEi, ACE inhibitor; ARB, angiotensin receptor blockers.

References

    1. Yang X, Yu Y, Xu J, et al. . Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020;8:475–81. 10.1016/S2213-2600(20)30079-5
    1. Chen N, Zhou M, Dong X, et al. . Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507–13. 10.1016/S0140-6736(20)30211-7
    1. Huang C, Wang Y, Li X, et al. . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020.
    1. Wang D, Hu B, Hu C, et al. . Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061. 10.1001/jama.2020.1585
    1. Grein J, Ohmagari N, Shin D, et al. . Compassionate use of Remdesivir for patients with severe Covid-19. N Engl J Med 2020.
    1. Fedson DS. Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med 2016;4:421. 10.21037/atm.2016.11.03
    1. Yan Y, Liu Q, Li N, et al. . Angiotensin II receptor blocker as a novel therapy in acute lung injury induced by avian influenza A H5N1 virus infection in mouse. Sci China Life Sci 2015;58:208–11. 10.1007/s11427-015-4814-7
    1. Yang P, Gu H, Zhao Z, et al. . Angiotensin-Converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep 2014;4:7027. 10.1038/srep07027
    1. Kaukonen K-M, Bailey M, Suzuki S, et al. . Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA 2014;311:1308–16. 10.1001/jama.2014.2637
    1. Máca J, Jor O, Holub M, et al. . Past and present ARDS mortality rates: a systematic review. Respir Care 2017;62:113–22. 10.4187/respcare.04716
    1. Wrapp D, Wang N, Corbett KS, et al. . Cryo-Em structure of the 2019-nCoV spike in the prefusion conformation. Science 2020;367:1260–3. 10.1126/science.abb2507
    1. Zhang H, Penninger JM, Li Y, et al. . Angiotensin-Converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 2020;46:586–90. 10.1007/s00134-020-05985-9
    1. Hoffmann M, Kleine-Weber H, Schroeder S, et al. . SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271–80. 10.1016/j.cell.2020.02.052
    1. de Roquetaillade C, Jamme M, Charpentier J, et al. . Hemodynamic impact of cardiovascular antihypertensive medications in patients with sepsis-related acute circulatory failure. Shock 2020;54:315–20. 10.1097/SHK.0000000000001524
    1. Hsieh MS, How CK, Hsieh VC, et al. . Preadmission antihypertensive drug use and sepsis outcome: impact of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (Arbs). Shock 2019.
    1. Hsu W-T, Galm BP, Schrank G, et al. . Effect of renin-angiotensin-aldosterone system inhibitors on short-term mortality after sepsis: a population-based cohort study. Hypertension 2020;75:483–91. 10.1161/HYPERTENSIONAHA.119.13197
    1. Mortensen EM, Restrepo MI, Copeland LA, et al. . Impact of previous statin and angiotensin II receptor blocker use on mortality in patients hospitalized with sepsis. Pharmacotherapy 2007;27:1619–26. 10.1592/phco.27.12.1619
    1. Henry BM, Vikse J, Benoit S, et al. . Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis. Clin Chim Acta 2020;507:167–73. 10.1016/j.cca.2020.04.027
    1. 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;395:1054–62. 10.1016/S0140-6736(20)30566-3
    1. Yin S, Huang M, Li D, et al. . Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2. J Thromb Thrombolysis 2020. 10.1007/s11239-020-02105-8. [Epub ahead of print: 03 Apr 2020].
    1. D'Elia JA, Bayliss G, Gleason RE, et al. . Cardiovascular-renal complications and the possible role of plasminogen activator inhibitor: a review. Clin Kidney J 2016;9:705–12. 10.1093/ckj/sfw080
    1. Koh KK, Chung W-J, Ahn JY, et al. . Angiotensin II type 1 receptor blockers reduce tissue factor activity and plasminogen activator inhibitor type-1 antigen in hypertensive patients: a randomized, double-blind, placebo-controlled study. Atherosclerosis 2004;177:155–60. 10.1016/j.atherosclerosis.2004.07.008
    1. Liu J, Sun N-L, Yang J, et al. . Effects of losartan on fibrinolytic parameters and von Willebrand factor in Chinese subjects with hypertension: a comparative study versus atenolol. J Int Med Res 2009;37:595–600. 10.1177/147323000903700301
    1. Sarzani R, Giulietti F, Di Pentima C, et al. . Disequilibrium between the classic renin-angiotensin system and its opposing arm in SARS-CoV-2-related lung injury. Am J Physiol Lung Cell Mol Physiol 2020;319:L325–36. 10.1152/ajplung.00189.2020
    1. 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;111:2605–10. 10.1161/CIRCULATIONAHA.104.510461
    1. Leung AKK, Genga KR, Topchiy E, et al. . Reduced proprotein convertase subtilisin/kexin 9 (PCSK9) function increases lipoteichoic acid clearance and improves outcomes in gram positive septic shock patients. Sci Rep 2019;9:10588. 10.1038/s41598-019-46745-0
    1. Topchiy E, Cirstea M, Kong HJ, et al. . Lipopolysaccharide is cleared from the circulation by hepatocytes via the low density lipoprotein receptor. PLoS One 2016;11:e0155030. 10.1371/journal.pone.0155030
    1. Walley KR, Francis GA, Opal SM, et al. . The central role of proprotein convertase subtilisin/kexin type 9 in septic pathogen lipid transport and clearance. Am J Respir Crit Care Med 2015;192:1275–86. 10.1164/rccm.201505-0876CI
    1. Genga KR, Trinder M, Kong HJ, et al. . Cetp genetic variant rs1800777 (allele a) is associated with abnormally low HDL-C levels and increased risk of AKI during sepsis. Sci Rep 2018;8:16764. 10.1038/s41598-018-35261-2
    1. Roveran Genga KTM, Kong HJ, Leung AKK, et al. . Cholesterylester transfer protein (CETP) genotype R468Q is associated with increased risk of sepsis-associated acute kidney injury (AKI). Sci Reports 2018.
    1. Trinder M, Genga KR, Kong HJ, et al. . Cholesteryl ester transfer protein influences high-density lipoprotein levels and survival in sepsis. Am J Respir Crit Care Med 2019;199:854–62. 10.1164/rccm.201806-1157OC
    1. Nakada T-aki, Russell JA, Boyd JH, et al. . Association of angiotensin II type 1 receptor-associated protein gene polymorphism with increased mortality in septic shock. Crit Care Med 2011;39:1641–8. 10.1097/CCM.0b013e318218665a
    1. Nakada T-A, Russell JA, Wellman H, et al. . Leucyl/cystinyl aminopeptidase gene variants in septic shock. Chest 2011;139:1042–9. 10.1378/chest.10-2517
    1. Nakada T-A, Russell JA, Boyd JH, et al. . Beta2-Adrenergic receptor gene polymorphism is associated with mortality in septic shock. Am J Respir Crit Care Med 2010;181:143–9. 10.1164/rccm.200903-0332OC
    1. Danser AHJ, Epstein M, Batlle D. Renin-Angiotensin system blockers and the COVID-19 pandemic: at present there is no evidence to abandon renin-angiotensin system blockers. Hypertension 2020;75:1382–5. 10.1161/HYPERTENSIONAHA.120.15082
    1. Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? JAMA 2020;323:1769–70. 10.1001/jama.2020.4812
    1. Vaduganathan M, Vardeny O, Michel T, et al. . Renin-Angiotensin-Aldosterone system inhibitors in patients with Covid-19. N Engl J Med 2020.
    1. Li J, Wang X, Chen J, et al. . 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 Cardiol 2020.
    1. Mehra MR, Desai SS, Kuy S, et al. . Cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med 2020.
    1. Zhang X, Yu J, Pan L-Y, et al. . ACEI/ARB use and risk of infection or severity or mortality of COVID-19: a systematic review and meta-analysis. Pharmacol Res 2020;158:104927. 10.1016/j.phrs.2020.104927
    1. 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. Circ Res 2020.
    1. Feng Y, Ling Y, Bai T, et al. . COVID-19 with different severity: a multi-center study of clinical features.. Am J Respir Crit Care Med 2020.
    1. 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;11:875–9. 10.1038/nm1267
    1. Liu Y, Yang Y, Zhang C, et al. . Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci 2020;63:364–74. 10.1007/s11427-020-1643-8
    1. Huang F, Guo J, Zou Z, et al. . Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients. Nat Commun 2014;5:3595. 10.1038/ncomms4595
    1. Nerenberg KA, Zarnke KB, Leung AA, et al. . Hypertension Canada's 2018 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults and children. Can J Cardiol 2018;34:506–25. 10.1016/j.cjca.2018.02.022
    1. Johansen ME, Yun J, Griggs JM, et al. . Anti-Hypertensive medication combinations in the United States. J Am Board Fam Med 2020;33:143–6. 10.3122/jabfm.2020.01.190134
    1. Murphy DP, Drawz PE, Foley RN. Trends in angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker use among those with impaired kidney function in the United States. J Am Soc Nephrol 2019;30:1314–21. 10.1681/ASN.2018100971
    1. Ibrahim SL, Jiroutek MR, Holland MA, et al. . Utilization of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) in patients diagnosed with diabetes: analysis from the National ambulatory medical care survey. Prev Med Rep 2016;3:166–70. 10.1016/j.pmedr.2016.01.005
    1. Ezekowitz JA, O'Meara E, McDonald MA, et al. . 2017 comprehensive update of the Canadian cardiovascular Society guidelines for the management of heart failure. Can J Cardiol 2017;33:1342–433. 10.1016/j.cjca.2017.08.022
    1. Chiu MH, Miller RJH, Barry R, et al. . Kidney function, ACE-Inhibitor/Angiotensin receptor blocker use, and survival following hospitalization for heart failure: a cohort study. Can J Kidney Health Dis 2018;5:2054358118804838. 10.1177/2054358118804838
    1. Ghimire R, Dhungana SP. Evaluation of drugs used in chronic heart failure at tertiary care centre: a hospital based study. J Cardiovasc Thorac Res 2019;11:79–84. 10.15171/jcvtr.2019.15
    1. Tran RH, Aldemerdash A, Chang P, et al. . Guideline-Directed medical therapy and survival following hospitalization in patients with heart failure. Pharmacotherapy 2018;38:406–16. 10.1002/phar.2091
    1. Walley KR, Russell JA. Protein C -1641 AA is associated with decreased survival and more organ dysfunction in severe sepsis. Crit Care Med 2007;35:12–17. 10.1097/01.CCM.0000249823.44726.4E
    1. Vincent JL, Moreno R, Takala J, et al. . The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the Working group on sepsis-related problems of the European Society of intensive care medicine. Intensive Care Med 1996;22:707–10. 10.1007/BF01709751
    1. Russell JA, Lee T, Singer J, et al. . Days alive and free as an alternative to a mortality outcome in pivotal vasopressor and septic shock trials. J Crit Care 2018;47:333–7. 10.1016/j.jcrc.2018.05.003
    1. Zou Z, Yan Y, Shu Y, et al. . Angiotensin-Converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nat Commun 2014;5:3594. 10.1038/ncomms4594
    1. Wang C, Scharfstein DO, Colantuoni E, et al. . Inference in randomized trials with death and missingness. Biometrics 2017;73:431–40. 10.1111/biom.12594
    1. Colantuoni E, Scharfstein DO, Wang C, et al. . Statistical methods to compare functional outcomes in randomized controlled trials with high mortality. BMJ 2018;360:j5748. 10.1136/bmj.j5748
    1. Hernán MA, Robins JM. Causal inference. Boca Raton: Chapman & Hall/CRC, 2017.
    1. McConnell S, Stuart EA, Devaney B. The truncation-by-death problem: what to do in an experimental evaluation when the outcome is not always defined. Eval Rev 2008;32:157–86. 10.1177/0193841X07309115
    1. Asar Özgür, Ritchie J, Kalra PA, et al. . Joint modelling of repeated measurement and time-to-event data: an introductory tutorial. Int J Epidemiol 2015;44:334–44. 10.1093/ije/dyu262
    1. Ibrahim JG, Chu H, Chen LM. Basic concepts and methods for joint models of longitudinal and survival data. J Clin Oncol 2010;28:2796–801. 10.1200/JCO.2009.25.0654
    1. Henderson R, Diggle P, Dobson A. Joint modelling of longitudinal measurements and event time data. Biostatistics 2000;1:465–80. 10.1093/biostatistics/1.4.465
    1. Hickey GL, Philipson P, Jorgensen A, et al. . joineRML: a joint model and software package for time-to-event and multivariate longitudinal outcomes. BMC Med Res Methodol 2018;18:50. 10.1186/s12874-018-0502-1
    1. Crowther MJ, Abrams KR, Lambert PC. Joint modeling of longitudinal and survival data. Stata Journal 2013;13:165–84.
    1. Zhang D, Chen M-H, Ibrahim JG, et al. . JMFit: a SAS macro for joint models of longitudinal and survival data. J Stat Softw 2016;71:1–3. 10.18637/jss.v071.i03
    1. Little RJ, D'Agostino R, Cohen ML, et al. . The prevention and treatment of missing data in clinical trials. N Engl J Med 2012;367:1355–60. 10.1056/NEJMsr1203730
    1. O'Neill RT, Temple R. The prevention and treatment of missing data in clinical trials: an FDA perspective on the importance of dealing with it. Clin Pharmacol Ther 2012;91:550–4. 10.1038/clpt.2011.340
    1. Hernán MA, Robins JM. Estimating causal effects from epidemiological data. J Epidemiol Community Health 2006;60:578–86. 10.1136/jech.2004.029496
    1. Kasza J, Wolfe R, Schuster T. Assessing the impact of unmeasured confounding for binary outcomes using confounding functions. Int J Epidemiol 2017;46:1303–11. 10.1093/ije/dyx023
    1. VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-Value. Ann Intern Med 2017;167:268–74. 10.7326/M16-2607
    1. Cao B, Wang Y, Wen D, et al. . A trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020;382:1787–99. 10.1056/NEJMoa2001282

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi