ORIGINAL ARTICLE Korean J Intern Med 2021;36:371-381 https://doi.org/10.3904/kjim.2019.262 Effect of angiotensin converting enzyme inhibitor and angiotensin II receptor blocker on the patients with sepsis Hyun Woo Lee1,*,†, Jae Kyung Suh2,*, Eunjin Jang3, and Sang-Min Lee1 1Division of Pulmonary and Critical Background/Aims: Inhibitors of the renin-angiotensin system, angiotensin-con- Care Medicine, Department of verting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), Internal Medicine, Seoul National University Hospital, Seoul; 2National reportedly have anti-inflammatory effects. This study assessed the association of Evidence-Based Healthcare prior use of ACE inhibitors and ARBs with sepsis-related clinical outcomes. Collaborating Agency, Seoul; 3 Methods: A population-based observational study was conducted using the Department of Information Statistics, Andong National University, Andong, Health Insurance Review and Assessment Service claims data. Among the adult Korea patients hospitalized with new onset of sepsis in 2012, patients who took ARBs or ACE inhibitors at least 30 days prior to hospitalization were analyzed. Generalized linear models and logistic regression were used to examine the relation between the prior use of medication and clinical outcomes, such as in-hospital mortality, mechanical ventilation, and length of stay. Results: Of a total of 27,628 patients who were hospitalized for sepsis, the ACE in- Received : August 8, 2019 hibitor, ARB, and non-user groups included 1,214 (4.4%), 3,951 (14.4%), and 22,463 Revised : October 19, 2019 (82.1%) patients, respectively. As the patients in the ACE inhibitor and ARB groups Accepted : November 25, 2019 had several comorbid conditions, higher rates of intensive care unit admission, Correspondence to hemodialysis, and mechanical ventilation were observed. However, after covariate Sang-Min Lee, Ph.D. adjustment, the use of ACE inhibitor (odds ratio [OR], 0.752; 95% confidence inter- Division of Pulmonary and val [CI], 0.661 to 0.855) or ARB (OR, 0.575; 95% CI, 0.532 to 0.621) was significantly Critical Care Medicine, Depart- associated with a lower rate of in-hospital mortality. ment of Internal Medicine, Seoul National University Hospital, Conclusions: Pre-hospitalization use of ACE inhibitors or ARBs for sepsis was an 101 Daehak-ro, Jongno-gu, Seoul independent factor for a lower rate of in-hospital mortality. 03080, Korea Tel: +82-2-2072-0833 Fax: +82-2-764-2199 Keywords: Angiotensin-converting enzyme inhibitors; Angiotensin II; Angioten- E-mail: [email protected] sin receptor antagonists; Mortality; Sepsis https://orcid.org/0000-0002- 1388-9318 *These authors contributed INTRODUCTION ume [1]. The RAS is known to be phys- equally to this work. iologically activated in rodents [1] and The renin-angiotensin system (RAS) humans [2] during sepsis. Deficiency in †Current affiliation: Division of Pulmonary and is a complex endocrine system with a the expression of angiotensin-convert- Critical Care Medicine, Depart- multi-dimensional enzymatic cascade ing enzyme (ACE) and angiotensin II is ment of Internal Medicine, Seoul to keep arterial blood pressure con- associated with high mortality rates in Metropolitan Government Seoul National University Boramae stant, which in turn helps maintain patients with severe sepsis [3]. Experi- Medical Center, Seoul, Korea tissue perfusion and extracellular vol- mental studies have demonstrated the Copyright © 2021 The Korean Association of Internal Medicine pISSN 1226-3303 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ eISSN 2005-6648 by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. http://www.kjim.org The Korean Journal of Internal Medicine Vol. 36, No. 2, March 2021 effectiveness of angiotensin II in restoring blood pres- METHODS sure and cardiac output in sheep [4] and pigs [5] during septic shock. In a recent randomized controlled trial for Study design, setting, and data sources patients with vasodilatory shock, of which approximately We referred to The Strengthening the Reporting of Ob- 80% cases were due to sepsis, administration of angio- servational Studies in Epidemiology (STROBE) state- tensin II elevated blood pressure in patients resistant to ment to report the results of our study [19]. A retro- conventional catecholamines as well as permitted dose spective, population-based cohort study was conducted reduction of other vasopressors [6]. using the Health Insurance Review and Assessment Ser- Although RAS activation is a physiological reaction vice (HIRA) annual claims data of the total population in counteracting septic shock, excessive activation may South Korea from 2009 to 2013. The HIRA database con- further aggravate pro-inflammatory responses and vas- sists of six domains: (1) general information, (2) health- cular dysfunction, resulting in worse clinical outcomes. care services, (3) diagnosis, (4) outpatient prescription, In particular, a high degree of RAS activation was asso- (5) drug master, and (6) providers information. Detailed ciated with micro-vascular dysfunction and organ fail- information concerning HIRA data was published pre- ure in patients with sepsis [2]. Conversely, inactivation viously [20]. Sepsis patients who were hospitalized in a of RAS showed protective effects on acute pulmonary or tertiary care center or general hospital in 2012 were iden- renal injury [7,8] and decreased endotoxin-induced oxi- tified using the International Classification of Diseases dative stress and endothelial dysfunction [9]. In animal 10th Revision (ICD-10) codes (A40 and A41). Considering models, the inhibition of angiotensin II improved mor- that the definition of sepsis was revised in 2003 [21] and tality due to sepsis [10]. Accordingly, chronic suppres- 2016 [22], the most recent delineation was applied to all sion of RAS prior to an event of sepsis may be beneficial patients in this study. No major epidemiological event for clinical outcomes. In fact, one human observation- or considerable change to nationwide policies was re- al study reported that the 30-day mortality rate due to ported during this study period. sepsis was reduced in elderly male patients who ever received angiotensin II receptor blockers (ARBs) [11]. Participants However, there is a lack of evidence evaluating the rela- We identified all patients aged≥ 18 years who experienced tionship between RAS suppression prior to an event of a new event of sepsis from January 01, 2012 to Decem- sepsis, and clinical prognoses. ber 31, 2012. Patients with recent use of ACE inhibitors ACE inhibitors or ARBs have been used to suppress or ARBs before a new event of sepsis were operationally RAS in patients with hypertension [12], cardiovascular defined as the ACE inhibitor or ARB groups, respectively. diseases [13], and renal diseases [14]. ACE inhibitors in- Patients who did not use ACE inhibitors or ARBs were terrupt ACE which catalyzes cleavage of angiotensin I to operationally defined as the non-user group. Recent use angiotensin II, while ARBs inhibit angiotensin II from of ACE inhibitors or ARBs was defined as a prescription binding to the angiotensin II receptor type I. There have given at least 30 days or more prior to the onset of sepsis. been several studies to evaluate whether ACE inhibitors Medications used by the ACE inhibitor group included or ARBs can be beneficial in sepsis, but contradictory alacepril, captopril, cilazapril, enalapril, fosinopril, im- results have been reported [15-18]. idapril, lisinopril, moexipril, perindopril, ramipril, and The present study was conducted to determine the temocapril. Medications used by the ARB group included impact of prior RAS inhibition on the clinical prognosis candesartan, eprosartan, fimasartan, irbesartan, losartan, during sepsis. The purpose of this study was to eluci- olmesartan, telmisartan, and valsartan. date the effects of prior ACE inhibitor or ARB use on the in-hospital mortality rate in patients who were diag- Measurement of variables nosed with new onset of sepsis. We evaluated demographic characteristics such as age and sex, baseline comorbidities, Charlson comorbidity index (CCI), and current medications of hospitalized sepsis patients. Baseline comorbidities included hy- 372 www.kjim.org https://doi.org/10.3904/kjim.2019.262 Lee HW, et al. Angiotensin inhibition and sepsis pertension, diabetes mellitus, cerebrovascular disorder 200,354 Patients with sepsis in claim data from 2009 to 2013 (CVD), chronic obstructive pulmonary disorder (COPD), congestive heart failure (CHF), coronary artery disease (CAD), liver cirrhosis, chronic kidney disease (CKD), pul- 32,168 Patients who were hospitalized for sepsis in 2012 monary tuberculosis, and malignancy. Comorbidities were identified by reviewing the diagnosis code (ICD- 10 code) up to 3 years before sepsis occurrence. Current 27,628 Patientis who were hospitalized for a new onset of sepsis medications other than ACE inhibitors and ARBs used within 30 days prior to the onset of sepsis, such as statins and beta-blockers, were identified. Clinical outcomes 1,214 ACE inhibitor group 3,951 ARB group 22,463 Non-user group included the following events: intensive care unit (ICU) (4.4%) (14.4%) (82.1%) admission, mechanical ventilation, acute renal failure with hemodialysis, duration of mechanical ventilation, Figure