Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality | Cardiology | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality

Educational Objective
To understand the association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality
1 Credit CME
Key Points

Question  Is angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use associated with greater susceptibility to coronavirus disease 2019 (COVID-19) and with worse outcomes after COVID-19 diagnosis?

Findings  In a retrospective cohort study of 4480 patients diagnosed as having COVID-19, prior ACEI/ARB use, compared with no use, was not significantly associated with mortality (adjusted hazard ratio, 0.83). In a nested case-control study of a cohort of 494 170 patients with hypertension, use of ACEI/ARB, compared with use of other antihypertensive medications, was not significantly associated with COVID-19 diagnosis (adjusted hazard ratio, 1.05).

Meaning  Prior use of ACEI/ARB was not significantly associated with COVID-19 diagnosis or with mortality among patients diagnosed as having COVID-19.

Abstract

Importance  It has been hypothesized that angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) may make patients more susceptible to coronavirus disease 2019 (COVID-19) and to worse outcomes through upregulation of the functional receptor of the virus, angiotensin-converting enzyme 2.

Objective  To examine whether use of ACEI/ARBs was associated with COVID-19 diagnosis and worse outcomes in patients with COVID-19.

Design, Setting, and Participants  To examine outcomes among patients with COVID-19, a retrospective cohort study using data from Danish national administrative registries was conducted. Patients with COVID-19 from February 22 to May 4, 2020, were identified using ICD-10 codes and followed up from day of diagnosis to outcome or end of study period (May 4, 2020). To examine susceptibility to COVID-19, a Cox regression model with a nested case-control framework was used to examine the association between use of ACEI/ARBs vs other antihypertensive drugs and the incidence rate of a COVID-19 diagnosis in a cohort of patients with hypertension from February 1 to May 4, 2020.

Exposures  ACEI/ARB use was defined as prescription fillings 6 months prior to the index date.

Main Outcomes and Measures  In the retrospective cohort study, the primary outcome was death, and a secondary outcome was a composite outcome of death or severe COVID-19. In the nested case-control susceptibility analysis, the outcome was COVID-19 diagnosis.

Results  In the retrospective cohort study, 4480 patients with COVID-19 were included (median age, 54.7 years [interquartile range, 40.9-72.0]; 47.9% men). There were 895 users (20.0%) of ACEI/ARBs and 3585 nonusers (80.0%). In the ACEI/ARB group, 18.1% died within 30 days vs 7.3% in the nonuser group, but this association was not significant after adjustment for age, sex, and medical history (adjusted hazard ratio [HR], 0.83 [95% CI, 0.67-1.03]). Death or severe COVID-19 occurred in 31.9% of ACEI/ARB users vs 14.2% of nonusers by 30 days (adjusted HR, 1.04 [95% CI, 0.89-1.23]). In the nested case-control analysis of COVID-19 susceptibility, 571 patients with COVID-19 and prior hypertension (median age, 73.9 years; 54.3% men) were compared with 5710 age- and sex-matched controls with prior hypertension but not COVID-19. Among those with COVID-19, 86.5% used ACEI/ARBs vs 85.4% of controls; ACEI/ARB use compared with other antihypertensive drugs was not significantly associated with higher incidence of COVID-19 (adjusted HR, 1.05 [95% CI, 0.80-1.36]).

Conclusions and Relevance  Prior use of ACEI/ARBs was not significantly associated with COVID-19 diagnosis among patients with hypertension or with mortality or severe disease among patients diagnosed as having COVID-19. These findings do not support discontinuation of ACEI/ARB medications that are clinically indicated in the context of the COVID-19 pandemic.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Emil L. Fosbøl, MD, PhD, The Heart Center, University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, 2100 KBH Ø, Copenhagen, Denmark (elf@heart.dk).

Published Online: June 19, 2020. doi:10.1001/jama.2020.11301

Author Contributions: Drs Fosbøl and Gerds had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Fosbøl, Selmer, Gislason, Torp-Pedersen, Køber.

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

Drafting of the manuscript: Fosbøl, Østergaard.

Critical revision of the manuscript for important intellectual content: Butt, Østergaard, Andersson, Selmer, Kragholm, Schou, Phelps, Gislason, Gerds, Torp-Pedersen, Køber.

Statistical analysis: Fosbøl, Østergaard, Selmer, Schou, Gislason, Gerds, Torp-Pedersen, Køber.

Administrative, technical, or material support: Fosbøl, Butt, Phelps, Gislason, Torp-Pedersen, Køber.

Supervision: Selmer, Torp-Pedersen, Køber.

Conflict of Interest Disclosures: Dr Schou reported receiving speaker fees from Novartis, Novo Nordisk, AstraZeneca, and Boehringer Ingelheim. Dr Torp-Pedersen reported receiving grants from Bayer and Novo Nordisk. Dr Køber reported receiving speaker honoraria from Novartis, AstraZeneca, and Boehringer Ingelheim. No other disclosures were reported.

References
1.
Diaz  JH .  Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19.   J Travel Med. 2020;27(3):taaa041. doi:10.1093/jtm/taaa041 PubMedGoogle Scholar
2.
Esler  M , Esler  D .  Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?   J Hypertens. 2020;38(5):781-782. doi:10.1097/HJH.0000000000002450 PubMedGoogle ScholarCrossref
3.
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)30116-8 PubMedGoogle Scholar
4.
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. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032 PubMedGoogle ScholarCrossref
5.
Sommerstein  R , Kochen  MM , Messerli  FH , Gräni  C .  Coronavirus disease 2019 (COVID-19): do angiotensin-converting enzyme inhibitors/angiotensin receptor blockers have a biphasic effect?   J Am Heart Assoc. 2020;9(7):e016509. doi:10.1161/JAHA.120.016509 PubMedGoogle Scholar
6.
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(2):271-280.e8. doi:10.1016/j.cell.2020.02.052PubMedGoogle ScholarCrossref
7.
Li  W , Moore  MJ , Vasilieva  N ,  et al.  Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.   Nature. 2003;426(6965):450-454. doi:10.1038/nature02145 PubMedGoogle ScholarCrossref
8.
Bozkurt  B , Kovacs  R , Harrington  R . HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. Published 2020. Accessed May 2, 2020. https://professional.heart.org/professional/ScienceNews/UCM_505836_HFSAACCAHA-statement-addresses-concerns-re-using-RAAS-antagonists-in-COVID-19.jsp
9.
European Society of Cardiology. Position statement of the ESC council on hypertension on ACE-inhibitors and angiotensin receptor blockers. Published March 13, 2020. Accessed June 12, 2020. https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang
10.
Vaduganathan  M , Vardeny  O , Michel  T , McMurray  JJV , Pfeffer  MA , Solomon  SD .  Renin-angiotensin-aldosterone system inhibitors in patients with COVID-19.   N Engl J Med. 2020;382(17):1653-1659. doi:10.1056/NEJMsr2005760 PubMedGoogle ScholarCrossref
11.
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 Cardiol. Published online April 23, 2020. doi:10.1001/jamacardio.2020.1624 PubMedGoogle Scholar
12.
Mancia  G , Rea  F , Ludergnani  M , Apolone  G , Corrao  G .  Renin-angiotensin-aldosterone system blockers and the risk of COVID-19.   N Engl J Med. Published online May 1, 2020. doi:10.1056/NEJMoa2006923 PubMedGoogle Scholar
13.
Mehta  N , Kalra  A , Nowacki  AS ,  et al.  Association of use of angiotensin-converting enzyme inhibitors and angiotensin ii receptor blockers with testing positive for coronavirus disease 2019 (COVID-19).   JAMA Cardiol. Published online May 5, 2020. doi:10.1001/jamacardio.2020.1855 PubMedGoogle Scholar
14.
Reynolds  HR , Adhikari  S , Pulgarin  C ,  et al.  Renin-angiotensin-aldosterone system inhibitors and risk of COVID-19.   N Engl J Med. Published online May 1, 2020. doi:10.1056/NEJMoa2008975 PubMedGoogle Scholar
15.
Schmidt  M , Schmidt  SAJ , Adelborg  K ,  et al.  The Danish health care system and epidemiological research: from health care contacts to database records.   Clin Epidemiol. 2019;11:563-591. doi:10.2147/CLEP.S179083 PubMedGoogle ScholarCrossref
16.
Sundbøll  J , Adelborg  K , Munch  T ,  et al.  Positive predictive value of cardiovascular diagnoses in the Danish National Patient Registry: a validation study.   BMJ Open. 2016;6(11):e012832. doi:10.1136/bmjopen-2016-012832 PubMedGoogle Scholar
17.
Olesen  JB , Lip  GY , Hansen  ML ,  et al.  Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.   BMJ. 2011;342:d124. doi:10.1136/bmj.d124 PubMedGoogle ScholarCrossref
18.
Ozenne  BMH , Scheike  TH , Staerk  L , Gerds  TA .  On the estimation of average treatment effects with right-censored time to event outcome and competing risks.   Biom J. 2020;62(3):751-763.Google ScholarCrossref
19.
Borgan  O , Samuelsen  SO . Nested case-control and case-cohort studies. In: Klein  JP , van Houwelingen  HC , Ibrahim  JG , Scheike  TH , eds.  Handbook of Survival Analysis. Chapman and Hall/CRC; 2013.
20.
Burchill  LJ , Velkoska  E , Dean  RG , Griggs  K , Patel  SK , Burrell  LM .  Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions.   Clin Sci (Lond). 2012;123(11):649-658. doi:10.1042/CS20120162 PubMedGoogle ScholarCrossref
21.
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.104.510461 PubMedGoogle ScholarCrossref
22.
Hamming  I , Timens  W , Bulthuis  ML , Lely  AT , Navis  G , van Goor  H .  Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus: a first step in understanding SARS pathogenesis.   J Pathol. 2004;203(2):631-637. doi:10.1002/path.1570 PubMedGoogle ScholarCrossref
23.
Lakshmanan  AP , Thandavarayan  RA , Watanabe  K ,  et al.  Modulation of AT-1R/MAPK cascade by an olmesartan treatment attenuates diabetic nephropathy in streptozotocin-induced diabetic mice.   Mol Cell Endocrinol. 2012;348(1):104-111. doi:10.1016/j.mce.2011.07.041 PubMedGoogle ScholarCrossref
24.
Ocaranza  MP , Godoy  I , Jalil  JE ,  et al.  Enalapril attenuates downregulation of angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat.   Hypertension. 2006;48(4):572-578. doi:10.1161/01.HYP.0000237862.94083.45 PubMedGoogle ScholarCrossref
25.
Sukumaran  V , Veeraveedu  PT , Gurusamy  N ,  et al.  Olmesartan attenuates the development of heart failure after experimental autoimmune myocarditis in rats through the modulation of ANG 1-7 mas receptor.   Mol Cell Endocrinol. 2012;351(2):208-219. doi:10.1016/j.mce.2011.12.010 PubMedGoogle ScholarCrossref
26.
Sukumaran  V , Veeraveedu  PT , Lakshmanan  AP ,  et al.  Olmesartan medoxomil treatment potently improves cardiac myosin-induced dilated cardiomyopathy via the modulation of ACE-2 and ANG 1-7 mas receptor.   Free Radic Res. 2012;46(7):850-860. doi:10.3109/10715762.2012.684878 PubMedGoogle ScholarCrossref
27.
Zhong  JC , Ye  JY , Jin  HY ,  et al.  Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression.   Regul Pept. 2011;166(1-3):90-97. doi:10.1016/j.regpep.2010.09.005 PubMedGoogle ScholarCrossref
28.
Cohn  JN , Tognoni  G ; Valsartan Heart Failure Trial Investigators.  A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.   N Engl J Med. 2001;345(23):1667-1675. doi:10.1056/NEJMoa010713 PubMedGoogle ScholarCrossref
29.
Group  CTS ; CONSENSUS Trial Study Group.  Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).   N Engl J Med. 1987;316(23):1429-1435. doi:10.1056/NEJM198706043162301 PubMedGoogle ScholarCrossref
30.
Køber  L , Torp-Pedersen  C , Carlsen  JE ,  et al; Trandolapril Cardiac Evaluation (TRACE) Study Group.  A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction.   N Engl J Med. 1995;333(25):1670-1676. doi:10.1056/NEJM199512213332503 PubMedGoogle ScholarCrossref
31.
Halliday  BP , Wassall  R , Lota  AS ,  et al.  Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.   Lancet. 2019;393(10166):61-73. doi:10.1016/S0140-6736(18)32484-X PubMedGoogle ScholarCrossref
32.
Pflugfelder  PW , Baird  MG , Tonkon  MJ , DiBianco  R , Pitt  B ; The Quinapril Heart Failure Trial Investigators.  Clinical consequences of angiotensin-converting enzyme inhibitor withdrawal in chronic heart failure: a double-blind, placebo-controlled study of quinapril.   J Am Coll Cardiol. 1993;22(6):1557-1563. doi:10.1016/0735-1097(93)90578-O PubMedGoogle ScholarCrossref
33.
ClinicalTrials.gov. Coronavirus (COVID-19) ACEi/ARB investigation (CORONACION). ClinicalTrials.gov identifier: NCT04330300. Accessed June 10, 2020. https://clinicaltrials.gov/ct2/show/NCT04330300
34.
ClinicalTrials.gov. ACE inhibitors or ARBs discontinuation in context of SARS-CoV-2 pandemic (ACORES-2). ClinicalTrials.gov identifier: NCT04329195. Accessed June 10, 2020. https://clinicaltrials.gov/ct2/show/NCT04329195
35.
ClinicalTrials.gov. Losartan for Patients With COVID-19 Not Requiring Hospitalization. ClinicalTrials.gov identifier: NCT04311177. Accessed June 10, 2020. https://clinicaltrials.gov/ct2/show/NCT04311177
36.
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)30566-3 PubMedGoogle ScholarCrossref
37.
Messerli  FH , Siontis  GCM , Rexhaj  E .  COVID-19 and renin angiotensin blockers: current evidence and recommendations.   Circulation. Published online April 13, 2020. doi:10.1161/CIRCULATIONAHA.120.047022 PubMedGoogle Scholar
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close