Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use prior to medical intensive care unit admission and in-hospital mortality: propensity score-matched cohort study

  • Daiki KobayashiEmail author
  • Nagato Kuriyama
  • Fumitaka Yanase
  • Osamu Takahashi
  • Kazuhiro Aoki
  • Yasuhiro Komatsu
Original Article



The aim of this study was to evaluate whether angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) use prior to medical intensive care unit (ICU) admission was associated with in-hospital mortality and length of ICU stay.


A propensity score-matched cohort study was conducted at single center from 2004 to 2016. We included all adult patients who were admitted to the ICU due to internal medicine-related conditions. We compared patients who had used ACEIs/ARBs prior to ICU admission to patients who had not. Our primary and secondary outcomes were in-hospital mortality and length of stay among survivors and the deceased. Propensity scores were calculated via logistic regression analyses with forward stepwise selection. An odds ratio (OR) for primary outcome was calculated via logistic regression. Sensitivity analyses were performed using conditional logistic regression models including different sets of covariates to confirm our results.


3095 patients were admitted to the ICU. Overall, 693 patients were identified via matching, 231 of whom had used ACEIs/ARBs and 462 of whom had not. None of the baseline characteristics differed significantly between groups. Among them, 131 (18.9%) died. Those who had used ACEIs/ARBs had a lower rate of mortality (p < 0.01). Length of ICU stay did not differ significantly between those with ACEIs/ARBs and those without among survivors (p = 0.43) and the deceased (p = 0.14). The OR for mortality was 0.51 (95% confidence interval 0.32–0.79). The results of the sensitivity analyses confirmed the results (ORs 0.4 6–0.53; all were statistically significant).


Prior ACEI/ARB use may be related to in-hospital mortality among medical ICU patients.


Renin angiotensin-aldosterone system Length of stay Logistic regression 



The authors express sincere thanks to Ms. Aya Oizumi and Ms. Chika Horikawa for data extraction.

Compliance with ethical standards

Conflict of interest

All authors declared that there is no potential conflict of interest.

Ethical approval

Our article is an independent research work. This paper does not contain the results of any other published works by other researchers.

Informed consent

Because this study was retrospective study, the IRB at the hospital waived to obtain informed consent from patients. However, patients who declared not to be used their anonymized data in our study by viewing our public documents were excluded.


  1. 1.
    Sjoding MW, Prescott HC, Wunsch H, Iwashyna TJ, Cooke CR (2016) Longitudinal changes in ICU admissions among elderly patients in the United States. Crit Care Med 44(7):1353–1360Google Scholar
  2. 2.
    Adhikari NK, Fowler RA, Bhagwanjee S, Rubenfeld GD (2010) Critical care and the global burden of critical illness in adults. Lancet 376(9749):1339–1346Google Scholar
  3. 3.
    Suka M, Yoshida K, Takezawa J (2004) Impact of intensive care unit-acquired infection on hospital mortality in Japan: a multicenter cohort study. Environ Health Prev Med 9(2):53–57Google Scholar
  4. 4.
    Woolfson RG, Poston L (1991) Effect of ouabain on endothelium-dependent relaxation of human resistance arteries. Hypertension 17(5):619–625Google Scholar
  5. 5.
    Annane D, Aegerter P, Jars-Guincestre MC, Guidet B (2003) Network CU-R. Current epidemiology of septic shock: the CUB-Rea network. Am J Respir Crit Care Med 168(2):165–172Google Scholar
  6. 6.
    Sanfilippo F, Santonocito C, Morelli A, Foex P (2015) Beta-blocker use in severe sepsis and septic shock: a systematic review. Curr Med Res Opin 31(10):1817–1825Google Scholar
  7. 7.
    Fuchs C, Wauschkuhn S, Scheer C et al (2017) Continuing chronic beta-blockade in the acute phase of severe sepsis and septic shock is associated with decreased mortality rates up to 90 days. Br J Anaesth 119(4):616–625Google Scholar
  8. 8.
    Magder SA (2012) The ups and downs of heart rate. Crit Care Med 40(1):239–245Google Scholar
  9. 9.
    Schmittinger CA, Torgersen C, Luckner G, Schroder DC, Lorenz I, Dunser MW (2012) Adverse cardiac events during catecholamine vasopressor therapy: a prospective observational study. Intensive Care Med 38(6):950–958Google Scholar
  10. 10.
    Sander O, Welters ID, Foex P, Sear JW (2005) Impact of prolonged elevated heart rate on incidence of major cardiac events in critically ill patients with a high risk of cardiac complications. Crit Care Med 33(1):81–88 (discussion 241–242) Google Scholar
  11. 11.
    Mochizuki M, Yano M, Oda T et al (2007) Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure. J Am Coll Cardiol 49(16):1722–1732Google Scholar
  12. 12.
    Rudiger A, Singer M (2007) Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med 35(6):1599–1608Google Scholar
  13. 13.
    Cohen RI (2010) Sepsis-induced myocardial dysfunction: linking physiology and genomics. Crit Care Med 38(3):1001–1002Google Scholar
  14. 14.
    Park JH, Kang SJ, Song JK et al (2005) Left ventricular apical ballooning due to severe physical stress in patients admitted to the medical ICU. Chest 128(1):296–302Google Scholar
  15. 15.
    Shen JI, Saxena AB, Montez-Rath ME, Leng L, Chang TI, Winkelmayer WC (2017) Comparative effectiveness of angiotensin receptor blockers vs. angiotensin-converting enzyme inhibitors on cardiovascular outcomes in patients initiating peritoneal dialysis. J Nephrol 30(2):281–288Google Scholar
  16. 16.
    Schmidt M, Mansfield KE, Bhaskaran K et al (2017) Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study. BMJ 356:j791Google Scholar
  17. 17.
    Heidenreich PA, Zhao X, Hernandez AF, Yancy CW, Fonarow GC (2012) Patient and hospital characteristics associated with traditional measures of inpatient quality of care for patients with heart failure. Am Heart J. 163(2):239–245.e233Google Scholar
  18. 18.
    Elder DH, Wei L, Szwejkowski BR et al (2011) The impact of renin-angiotensin-aldosterone system blockade on heart failure outcomes and mortality in patients identified to have aortic regurgitation: a large population cohort study. J Am Coll Cardiol 58(20):2084–2091Google Scholar
  19. 19.
    Kasama S, Toyama T, Kumakura H et al (2005) Effects of candesartan on cardiac sympathetic nerve activity in patients with congestive heart failure and preserved left ventricular ejection fraction. J Am Coll Cardiol 45(5):661–667Google Scholar
  20. 20.
    Evans M, Carrero JJ, Szummer K et al (2016) Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in myocardial infarction patients with renal dysfunction. J Am Coll Cardiol 67(14):1687–1697Google Scholar
  21. 21.
    White CM, Kluger J, Lertsburapa K, Faheem O, Coleman CI (2007) Effect of preoperative angiotensin converting enzyme inhibitor or angiotensin receptor blocker use on the frequency of atrial fibrillation after cardiac surgery: a cohort study from the atrial fibrillation suppression trials II and III. Eur J Cardiothorac Surg 31(5):817–820Google Scholar
  22. 22.
    Mortensen EM, Restrepo MI, Anzueto A, Pugh J (2005) The impact of prior outpatient ACE inhibitor use on 30-day mortality for patients hospitalized with community-acquired pneumonia. BMC Pulm Med 5:12Google Scholar
  23. 23.
    Mortensen EM, Copeland LA, Pugh MJ et al (2009) Impact of statins and ACE inhibitors on mortality after COPD exacerbations. Respir Res 10:45Google Scholar
  24. 24.
    Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40(5):373–383Google Scholar
  25. 25.
    Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13(10):818–829Google Scholar
  26. 26.
    Vincent JL, Moreno R, Takala J et al (1996) 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 22(7):707–710Google Scholar
  27. 27.
    Sykes L, Nipah R, Kalra P, Green D (2018) A narrative review of the impact of interventions in acute kidney injury. J Nephrol 31(4):523–535Google Scholar
  28. 28.
    Kellum JA, Lameire N, Aspelin P et al (2012) Kidney disease: Improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2(1):1–138Google Scholar
  29. 29.
    Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Sturmer T (2006) Variable selection for propensity score models. Am J Epidemiol 163(12):1149–1156Google Scholar
  30. 30.
    Austin PC (2010) Statistical criteria for selecting the optimal number of untreated subjects matched to each treated subject when using many-to-one matching on the propensity score. Am J Epidemiol 172(9):1092–1097Google Scholar
  31. 31.
    Kelly JG, O’Malley K (1990) Clinical pharmacokinetics of the newer ACE inhibitors. A review. Clin Pharmacokinet 19(3):177–196Google Scholar
  32. 32.
    British Hypertension Society (2008) Angiotensin Receptor Blockers (ARBs). Accessed 25 March 2017
  33. 33.
    Ahmed AK, Kamath NS, El Kossi M, El Nahas AM (2010) The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease. Nephrol Dial Transplant 25(12):3977–3982Google Scholar
  34. 34.
    Doerschug KC, Delsing AS, Schmidt GA, Ashare A (2010) Renin-angiotensin system activation correlates with microvascular dysfunction in a prospective cohort study of clinical sepsis. Crit Care 14(1):R24Google Scholar
  35. 35.
    Correa TD, Takala J, Jakob SM (2015) Angiotensin II in septic shock. Crit Care 19:98Google Scholar
  36. 36.
    Fani F, Regolisti G, Delsante M et al (2018) Recent advances in the pathogenetic mechanisms of sepsis-associated acute kidney injury. J Nephrol 31(3):351–359Google Scholar
  37. 37.
    Cave AC, Brewer AC, Narayanapanicker A et al (2006) NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal 8(5–6):691–728Google Scholar
  38. 38.
    Negi SI, Jeong EM, Shukrullah I et al (2015) Renin-angiotensin activation and oxidative stress in early heart failure with preserved ejection fraction. Biomed Res Int 2015:825027Google Scholar
  39. 39.
    The SOLVD Investigators (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325(5):293–302Google Scholar
  40. 40.
    Santos-Gallego CG, Vahl TP, Goliasch G et al (2016) Sphingosine-1-phosphate receptor agonist fingolimod increases myocardial salvage and decreases adverse postinfarction left ventricular remodeling in a porcine model of ischemia/reperfusion. Circulation 133(10):954–966Google Scholar
  41. 41.
    Stiefel P, Vallejo-Vaz AJ, Garcia Morillo S, Villar J (2011) Role of the Renin-Angiotensin system and aldosterone on cardiometabolic syndrome. Int J Hypertens 2011:685238Google Scholar
  42. 42.
    Kuriyama N, Mizuno T, Niwa F, Watanabe Y, Nakagawa M (2010) Autonomic nervous dysfunction during acute cerebral infarction. Neurol Res 32(8):821–827Google Scholar
  43. 43.
    Johansson P, Stensballe J, Ostrowski S (2017) Shock induced endotheliopathy (SHINE) in acute critical illness—a unifying pathophysiologic mechanism. Crit Care 21(1):25Google Scholar
  44. 44.
    Chawla LS, Busse L, Brasha-Mitchell E et al (2014) Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care 18(5):534Google Scholar
  45. 45.
    Vallejos A, Olivares P, Varela D et al (2018) Preventive leptin administration protects against sepsis through improving hypotension, tachycardia, oxidative stress burst, multiple organ dysfunction, and increasing survival. Front Physiol 9:1800Google Scholar
  46. 46.
    Yamada T, Shojima N, Noma H, Yamauchi T, Kadowaki T (2017) Glycemic control, mortality, and hypoglycemia in critically ill patients: a systematic review and network meta-analysis of randomized controlled trials. Intensive Care Med 43(1):1–15Google Scholar
  47. 47.
    Orban JC, Walrave Y, Mongardon N et al (2017) Causes and characteristics of death in intensive care units: a prospective multicenter study. Anesthesiology 126(5):882–889Google Scholar
  48. 48.
    Hill AB (1965) The environment and disease: association or causation? Proc R Soc Med 58:295–300Google Scholar
  49. 49.
    Diez J, Querejeta R, Lopez B, Gonzalez A, Larman M, Martinez Ubago JL (2002) Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 105(21):2512–2517Google Scholar
  50. 50.
    Mottram PM, Haluska B, Leano R, Cowley D, Stowasser M, Marwick TH (2004) Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 110(5):558–565Google Scholar

Copyright information

© Italian Society of Nephrology 2019

Authors and Affiliations

  1. 1.Division of General Internal Medicine, Department of MedicineSt. Luke’s International HospitalTokyoJapan
  2. 2.Fujita Health UniversityToyoakeJapan
  3. 3.Department of Epidemiology for Community Health and MedicineKyoto Prefectural University of MedicineKyotoJapan
  4. 4.Department of Intensive Care UnitSaitama Medical Center Jichi Medical UniversityOmiyaJapan
  5. 5.Department of Anesthesia and Intensive Care UnitSt. Luke’s International HospitalTokyoJapan
  6. 6.Division of Nephrology, Department of MedicineSt. Luke’s International HospitalTokyoJapan

Personalised recommendations