Clinical benefit of spironolactone in patients with acute decompensated heart failure and severe renal dysfunction: Data from the Korean Heart Failure (KorHF) Registry Jaewon Oh MD, Seok-Min Kang MD, PhD, Mi Kyung Song MS, Namki Hong MD, Jong-Chan Youn MD, PhD, Seongwoo Han MD, PhD, Eun-Seok Jeon MD, PhD, Myeong-Chan Cho MD, PhD, Jae-Joong Kim MD, PhD, Byung-Su Yoo MD, PhD, Shung Chull Chae MD, PhD, Byung-Hee Oh MD, PhD, Dong-Ju Choi MD, PhD, Myung-Mook Lee MD, PhD, Kyu-Hyung Ryu MD, PhD PII: DOI: Reference:

S0002-8703(15)00110-6 doi: 10.1016/j.ahj.2015.01.014 YMHJ 4825

To appear in:

American Heart Journal

Received date: Accepted date:

23 August 2014 17 January 2015

Please cite this article as: Oh Jaewon, Kang Seok-Min, Song Mi Kyung, Hong Namki, Youn Jong-Chan, Han Seongwoo, Jeon Eun-Seok, Cho Myeong-Chan, Kim Jae-Joong, Yoo Byung-Su, Chae Shung Chull, Oh Byung-Hee, Choi Dong-Ju, Lee Myung-Mook, Ryu Kyu-Hyung, Clinical benefit of spironolactone in patients with acute decompensated heart failure and severe renal dysfunction: Data from the Korean Heart Failure (KorHF) Registry, American Heart Journal (2015), doi: 10.1016/j.ahj.2015.01.014

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Clinical benefit of spironolactone in patients with acute

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decompensated heart failure and severe renal dysfunction:

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Data from the Korean Heart Failure (KorHF) Registry

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Oh, Spironolactone in ADHF with severe renal dysfunction

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Jaewon Oh MD1, Seok-Min Kang MD, PhD1, Mi Kyung Song, MS2, Namki Hong, MD1, Jong-Chan Youn, MD, PhD1, Seongwoo Han, MD, PhD3, Eun-Seok Jeon, MD,

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PhD4, Myeong-Chan Cho, MD, PhD5, Jae-Joong Kim, MD, PhD6, Byung-Su Yoo, MD, PhD7, Shung Chull Chae, MD, PhD8, Byung-Hee Oh, MD, PhD9, Dong-Ju Choi,

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MD, PhD10, Myung-Mook Lee, MD, PhD11, and Kyu-Hyung Ryu, MD, PhD12

Cardiology, Severance Cardiovascular Hospital and Cardiovascular Research Institute,

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Department of Research Affairs, Biostatistics Collaboration Unit, Yonsei University

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College of Medicine, Seoul, 3Cardiology, Korea University Hospital, Seoul, 4Cardiology, Sungkyunkwan University Samsung Medical Center, Seoul, 5Cardiology, Chungbuk National University Hospital, Cheongju, 6Cardiology, Ulsan University Asan Medical Center, Seoul, 7Cardiology, Yonsei University Wonju Christian Hospital, Wonju, 8

Cardiology, Kyung Pook National University Hospital, Daegu, 9Cardiology, Seoul

National University Hospital, Seoul,10Cardiology, Seoul National University Bundang Hospital, Seongnam,11Cardiology,Dongguk University Ilsan Hospital, Goyang, 12

Cardiology, Konkuk University Medical Center, Seoul, Korea

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Corresponding Author:

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Seok-Min Kang, MD, PhD,

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Professor, Cardiology Division, Department of Internal Medicine, Yonsei University College of Medicine

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134 Shinchon-dong Seodaemun-gu, Seoul, 120-752, Korea;

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Tel: 82-2-2228-8450

E-mail address: [email protected]

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Fax: 82-2-2227-7722

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Total Words : 5214 words including references, figure legends and tables

ABSTRACT Backgrounds: We investigated the relationship between spironolactone use and all-cause

ACCEPTED MANUSCRIPT Oh Page 3 mortality in acute decompensated heart failure (ADHF) patients with severe renal dysfunction. The clinical benefit of spironolactone in the treatment of heart failure (HF)

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has been described in several large randomized clinical trials. However, its clinical

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benefits have not been studied in hospitalized ADHF patients with severe renal dysfunction (estimated glomerular filtration rate, eGFR 60 mL/min/1.73m2)8. In addition, current HF guidelines suggest that

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MRA is contraindicated when creatinine is >2.5 mg/dL or creatinine clearance is < 30

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mL/min9-11. In recent study regarding HF outpatients with severe renal dysfunction (eGFR < 45 mL/min/1.73m2), baseline anemia, a well-known prognostic marker is not an independent predictor for all-cause mortality 12. This implies that different pathophysiologic mechanisms affect the prognosis of HF patients with or without severe renal dysfunction. Therefore, we examined the clinical effectiveness of MRA with spironolactone (only available in Korea) in real-world acute decompensated heart failure (ADHF) patients with severe renal dysfunction from a large cohort of the Korean Heart Failure (KorHF) Registry.

ACCEPTED MANUSCRIPT Oh Page 5 METHODS Study sample and design

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The KorHF Registry is a nationwide, prospective, observational, multicentre,

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online registry that includes the etiologies, clinical characteristics, treatment modalities, morbidity, mortality, and prognostic markers of patients hospitalised for ADHF. We

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studied 3,200 ADHF patients that were admitted to 24 Korean tertiary hospitals within 24

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hours of symptom onset between June 2004 and April 200913-16. The ADHF diagnoses were based on specific symptoms in patient medical histories and signs upon physical

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examination, according to current guidelines. Detailed data regarding patient characteristics, in-hospital course, and discharge medications were collected from

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electronic case reports recorded using a web-based electronic data capture system. The

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Ethics Committee at each participating hospital approved the study protocol, which conformed to the tenets of the Declaration of Helsinki. From the initial 3,200 patients,

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357 patients without available echocardiographic data and 54 patients without other

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baseline laboratory data were excluded, as were 1,754 patients without severe renal dysfunction (eGFR > 45mL/min/1.73m2). Thus, the final analysis included 1,035 patients. The clinical endpoint, all-cause mortality after discharge from the hospital was collected by reviewing the medical records and by telephone interviews at the study end. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses and drafting and editing of the paper.

Statistical analysis

ACCEPTED MANUSCRIPT Oh Page 6 We calculated estimated GFR (eGFR) using the Modification of Diet in Renal Disease (MDRD) equation 17,18. Continuous variables were described using means and

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standard deviations and categorical variables were described using numbers or

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percentages. We compared inter-group differences using Student’s t-test, chi-square, and paired t-tests. To adjust for selection bias, we had propensity scores matching. A

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propensity score for the predicted probability of spironolactone use in each patient was

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estimated with the use of a logistic-regression model fit with all the variables in Table 1. We created a propensity-score matched cohort by attempting to match each patient who

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used spironolactone with one who did not use spironolactone (a 1:1 match) 19,20. In greedy nearest-neighbour matching (10 to 2 digit matching), a patient who used

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spironolactone (n=105) was randomly selected and matching was attempted with the

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‘nearest’ patient who did not use spironolactone (n=105). This process was repeated pair was unique, and data for unmatched patients in either group were not used in subsequent

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analyses. The scores performances in logistic-regression model were evaluated in terms

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of calibration and discrimination. From the perspective of goodness-of-fit, calibration evaluates the degree of correspondence between the estimated probabilities produced by a model and the actual observation. Discrimination is the probability that the score will assign higher values of risk to patients who will go on to have events compared with those who will not. It was measured with areas under the receiver-operator characteristic curves (AUCs), which range from 0.50 (no discrimination) to 1.0 (perfect discrimination). Our model was well-calibrated (Hosmer-Lemeshow test p=0.3179) and showed a good discrimination (c-statistic = 0.883). We also assessed the degree of balance in measured covariates between spironolactone users and non-users. The balance of covariates was

ACCEPTED MANUSCRIPT Oh Page 7 measured by their absolute standardized differences (ASD) in means. An ASD of means below 0.10 indicates a small imbalance. In our study, the absolute standardized difference

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of means was decreased from 26.67% to 6.21%. We further adjusted the parameters

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whose ASD was over 0.10 in final Cox regression analysis like as previous analysis21. Survival was evaluated by Kaplan–Meier analysis with a log-rank test. Independent

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effects of variables on clinical events were calculated using a Cox multivariate

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proportional hazards regression analysis, incorporating covariates with p-values < 0.05 in unadjusted analysis. Clinical event risks were represented by hazard ratio (HR) with 95%

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confidence interval (CI). P-values< 0.05 were considered statistically significant and all reported probability values were two-tailed. Propensity score-matching was performed

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with SAS version 9.2 (SAS Inc. Cary, NC, USA); other analyses were conducted using

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RESULTS

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SPSS version 21.0 (SPSS/IBM Corp., Chicago, IL, USA).

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The baseline characteristics and laboratory findings of ADHF patients with severe renal dysfunction are illustrated in Table 1 according to mortality. Mean eGFR, creatinine, BUN, and blood urea nitrogen:creatinine ratio (BCR) were 30.011.2 mL/min/1.73m2, 2.331.76 mg/dL, 34.818.8 mg/dL, and 15.67.2, respectively. Compared with surviving patients, deceased patients had a significantly higher age, BUN, BCR, potassium, heart failure admission history, and furosemide and hemofiltration use, and lower body mass index (BMI), systolic blood pressure (SBP), hemoglobin, cholesterol, sodium, eGFR, and use of angiotensin converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), beta blockers and spironolactone at discharge. However left

ACCEPTED MANUSCRIPT Oh Page 8 ventricular ejection fraction (LVEF), and frequency of hypertension (HTN), diabetes mellitus (DM), atrial fibrillation and chronic renal dysfunction were not significantly

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different between the two groups.

Effect of spironolactone on clinical outcomes

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The clinical endpoint of our study was all-cause mortality. During the median

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407-day follow-up period (IQR 108–905 days), 239 patients (23.1%) died and 347 patients (33.5%) had spironolactone therapy at discharge. Median dose of spironolactone

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at discharge was 25mg (IQR 12.5-25mg) per day. In Kaplan-Meier survival analysis, allcause mortality in the spironolactone group was significantly lower than that in the non-

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spironolactone group (18.7% vs. 25.3%, respectively; log rank p=0.013; Fig. 1A). In

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unadjusted Cox proportional hazards analysis, spironolactone use was an independent predictor of all-cause mortality (HR:0.698, 95% CI:0.525-0.928, p=0.013). However,

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after adjusting for gender, age, BMI, SBP, hemoglobin, sodium, potassium, BUN, eGFR,

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heart failure admission history, chronic renal dysfunction, furosemide, ACEIs/ARBs or beta blockers use, spironolactone use was not an independent predictor (HR:0.974, 95 % CI:0.681-1.392, p=0.884) (Table 2). To further validate the clinical benefit of spironolactone use on all-cause mortality, we performed propensity score-matching between spironolactone users and non-users. Supplementary Table 1 shows baseline characteristics and laboratory findings of ADHF patients with severe renal dysfunction in a propensity score-matched cohort. In the matched cohort, all-cause mortality was not significantly different between spironolactone users and non-users (19.0% vs. 25.7% for spironolactone vs. non-

ACCEPTED MANUSCRIPT Oh Page 9 spironolactone groups, respectively; log rank p=0.115; Fig. 1B). In Cox regression analysis, spironolactone use was not related to all-cause mortality in matched cohort with

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neither no adjustment (HR 0.631, 95% CI 0.354-1.125, p=0.119) nor adjustment for

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gender, age, heart failure admission history, hypertension and RAAS blockers (HR 0.646, 95% CI 0.352-1.185, p=0.158) which showed imbalance in post-matching balance test.

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Regarding rehospitalization as a clinical endpoint, we could not find any significant

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clinical benefit of spironolactone in total (32.3% vs. 28.9% for spironolactone vs. nonspironolactone groups, respectively, log rank p=0.673) and matched (39.5% vs. 35.7%

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for spironolactone vs. non-spironolactone groups, respectively, long rank p=0.724) patients. And the incidence of hyperkalemia (serum potassium ≥ 5.5mmol/L) was 11.9%

Subgroup analysis

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at admission, 3.6% at discharge and 10.3% at 1 month after discharge.

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Subgroup analyses within all the ADHF patients are shown in Figure 2. We

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found some subgroups whose interaction with spironolactone use was significant. Firstly, the clinical benefit of spironolactone was only significant in women (20.9% vs. 29.9% for spironolactone vs. non-spironolactone groups, respectively, long rank p=0.032, n=300) not in men (18.0% vs. 23.2% for spironolactone vs. non-spironolactone groups, respectively, long rank p=0.158, n=735, p for interaction=0.021). Secondly, in terms of pre-hospital spironolactone use, spironolactone was only beneficial in patients undergoing pre-hospital spironolactone use (17.0% vs. 39.5% for spironolactone vs. nonspironolactone groups, respectively, long rank p

Clinical benefit of spironolactone in patients with acute decompensated heart failure and severe renal dysfunction: Data from the Korean Heart Failure Registry.

We investigated the relationship between spironolactone use and all-cause mortality in acute decompensated heart failure (ADHF) patients with severe r...
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