Circulation Journal ORIGINAL ARTICLE Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Heart Failure Effects of Intravenous Nicorandil on the Mid-Term Prognosis of Patients With Acute Heart Failure Syndrome Shiro Ishihara, MD; Tokushi Koga, MD; Shigeru Kaseda, MD; Eiji Nyuta, MD; Yoshie Haga, MD; Shinichiro Fujishima, MD; Takao Ishitsuka, MD; Seizo Sadoshima, MD Background: Acute heart failure syndrome (AHFS) remains a major clinical challenge because of its poor prognosis. Nicorandil, a hybrid compound of a potassium-channel opener and nitric oxide donor, has been reported to improve the prognosis of ischemic heart disease. We sought to evaluate the effect of intravenous nicorandil on the mid-term prognosis of AHFS. Methods and Results: A total of 402 consecutive patients who were hospitalized for AHFS were divided into 2 groups according to the use of intravenous nicorandil: 78 patients in the Nicorandil group and 324 patients in the Control group. During the 180-day follow-up, death or rehospitalization for heart failure occurred in 7 patients in the Nicorandil group (9.0%) and in 75 patients (23.2%) in the Control group. Event-free survival rates were significantly higher in the Nicorandil group than in the Control group (P=0.006). Multivariate Cox hazard analysis revealed that age (hazard ratio (HR)=1.066, P<0.0001), systolic blood pressure (HR=0.983, P=0.0023), New York Heart Association class III/IV (HR=6.550, P<0.0001), log creatinine (HR=3.866, P=0.0106), and use of intravenous nicorandil (HR=0.179, P<0.0001) were significant predictive factors for the occurrence of death or rehospitalization for heart failure. Conclusions: Intravenous nicorandil treatment from the urgent phase of AHFS may improve the prognosis. (Circ J 2012; 76: 1169 – 1176) Key Words: Acute heart failure syndrome; Nicorandil; Prognosis cute heart failure syndrome (AHFS) is a clinical syn- afterload reduction.6,7 Nicorandil also exhibits cardioprotec- drome associated with a variety of underlying dis- tive effects in the ischemic myocardium, similar to those of A eases, and remains a major clinical challenge, with a ischemic preconditioning, via activation of mitochondrial KATP high and increasing incidence and substantial morbidity and channels.8 Several studies have demonstrated that nicorandil mortality.1 Large, controlled trials of chronic heart failure can reduce infarct size and improve functional and clinical (HF) have identified treatments that improve clinical out- outcomes after acute myocardial infarction when administered comes, whereas the management and outcome of AHFS have adjunctively with coronary intervention.9–11 However, there not changed over the past 2 decades. The Guidelines of the are no reports of the effects on clinical outcome of nicorandil European Society of Cardiology and American Heart Asso- treatment in the urgent phase of AHFS. This study was con- ciation and the practical recommendation of a consensus ducted to evaluate the effect of intravenous nicorandil on the workshop for the treatment of AHFS are that pharmacotherapy mid-term prognosis of patients with AHFS. with vasodilators is preferable to inotropic agents in patients without excessively low blood pressure (BP).2–4 Nicorandil has nitrate-like properties and activates the ATP- Methods sensitive potassium (KATP) channels, resulting in balanced Data Sources venous and arterial vasodilation.5 Intravenous administration This was a single center, retrospective and observational study. of nicorandil by bolus injection followed by continuous infu- A total of 428 consecutive patients who were hospitalized for sion improves the pulmonary capillary wedge pressure and AHFS (including acute exacerbation of chronic HF) for the first cardiac index in patients with AHFS immediately and con- time between January 2005 and December 2009 were evalu- tinuously as a potent vasodilator with combined preload and ated; 28 patients were excluded because they had acute coro- Received October 2, 2011; revised manuscript received December 26, 2011; accepted January 13, 2012; released online March 14, 2012 Time for primary review: 10 days Department of Cardiology, Steel Memorial Yawata Hospital, Kitakyushu, Japan Mailing address: Shiro Ishihara, MD, Department of Cardiology, Steel Memorial Yawata Hospital, 1-1-1 Harunomachi, Yahatahigashi-ku, Kitakyushu 805-0050, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-11-1110 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.76, May 2012 1170 ISHIHARA S et al. Table 1. Baseline Characteristics of All Study Patients All patients Nicorandil Control P value (n=402) (n=78) (n=324) Age (years) 79.1 (10.4) 79.6 (9.8) 78.9 (10.6) 0.6290 Male 189 (47.0) 31 (39.7) 158 (48.8) 0.1518 Medical history Hypertension 263 (65.4) 59 (75.6) 204 (63.0) 0.0346 Diabetes 113 (28.1) 33 (42.3) 80 (24.7) 0.0019 Dyslipidemia 75 (18.7) 33 (42.3) 42 (13.0) <0.0001 Smoker 106 (26.4) 24 (31.2) 82 (25.3) 0.2946 Cerebrovascular disease 78 (19.5) 21 (26.9) 57 (17.7) 0.0632 Atrial fibrillation 141 (35.1) 19 (24.4) 122 (37.7) 0.0272 Ischemic heart disease 129 (32.1) 35 (44.9) 94 (29.0) 0.0071 NYHA class III/IV 297 (74.4) 76 (97.4) 221 (68.9) <0.0001 LVEF (%) 53.0 (18.3) 46.5 (16.2) 54.7 (18.5) 0.0005 Laboratory findings Creatinine (mg/dl) 1.0 (0.8–1.4) 1.1 (0.9–1.4) 1.0 (0.8–1.4) 0.1844 Hemoglobin (g/dl) 11.4 (2.3) 11.1 (2.5) 11.5 (2.2) 0.1501 BNP (pg/ml) 597 (312–1,220) 940 (556–1,529) 520 (262–1,050) <0.0001 IV medications during hospitalization Loop diuretics 355 (88.3) 75 (96.2) 280 (86.4) 0.0163 Carperitide 107 (26.6) 27 (34.6) 80 (24.7) 0.0750 Nitroglycerin 38 (9.5) 6 (7.7) 32 (9.9) 0.5439 Dobutamine 29 (7.2) 5 (7.7) 23 (7.1) 0.8557 Dopamine 20 (5.0) 3 (3.9) 17 (5.3) 0.6095 Oral medications at discharge ACEI and/or ARB 229 (60.1) 59 (76.6) 170 (56.5) 0.0012 β-blocker 143 (37.5) 46 (59.7) 97 (32.2) <0.0001 Aldosterone antagonist 138 (36.2) 30 (39.0) 108 (35.9) 0.6163 Data are number (%), mean (SD) or median (interquartile ranges). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BNP, brain natriuretic peptide; IV, intravenous; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association. nary syndrome (n=26) or right HF (n=2). Thus, 402 patients natriuretic peptide (BNP)) were performed using blood samples were finally included in this study. obtained at arrival at the emergency department. Left ventricu- lar ejection fraction (LVEF) was calculated using either the left Patients and Nicorandil Administration ventricular long-axis view on M-mode images or the Simpson After hospital admission, nicorandil was administered at the method. All participants provided informed consent, and the discretion of the physician caring for the patient. A total of 402 institutional ethics committee approved the study. patients were divided into a Nicorandil group (n=78; 19.4%) who received intravenous administration of nicorandil and a Study Endpoints Control group (n=324) who did not receive nicorandil during The primary endpoint of this study was the occurrence of death hospitalization. Intravenous administration of nicorandil was from all causes or rehospitalization for HF during the 180-day started in the emergency department within 1 h of hospitaliza- follow-up analyzed by time to first event. Clinical endpoint tion with a bolus injection of 0.1–0.2 mg/kg, followed by con- information during the 180-day period following the first hos- tinuous infusion of 0.1 mg · kg–1 · h–1 for >3 days, during which pitalization was obtained from medical records when the sub- time the infusion rate of nicorandil was adjusted at the discre- jects were inpatients or outpatients during the study period, or tion of each physician according to systolic blood pressure obtained via telephone interviews when they were visiting (SBP), symptoms or clinical signs. The infusion of nicorandil other hospitals. was stopped when it was judged by each physician that HF had improved. Clinical data were obtained from the medical records Statistical Analysis of in- and outpatients. Patients were evaluated for severity of Data are the mean ± standard deviation, percentages, or medians HF at the time of hospitalization according to the New York (interquartile range). The unpaired t-test or Mann-Whitney test Heart Association (NYHA) classification of HF symptoms. was used for unpaired comparisons as appropriate. The Fisher’s SBP, diastolic blood pressure (DBP), and heart rate at the time exact or chi-square test was used to examine differences be- of arrival at the emergency department were used as the base- tween categorical variables. The cumulative incidence of death line values. Determination of ischemic heart disease was made or rehospitalization for HF was estimated according to the on the basis of clinical criteria, including a history of myocar- Kaplan-Meier method, and the log-rank statistic was used for dial infarction, angina, or myocardial revascularization, or the comparisons. The Cox proportional hazards regression model results of exercise testing and/or noninvasive imaging. Clinical was used to determine which variables were related signifi- laboratory tests (including hemoglobin, creatinine, and brain cantly to death or rehospitalization for HF during the follow-up. Circulation Journal Vol.76, May 2012 Nicorandil and Prognosis in AHFS 1171 Variable selection in multivariate modeling was based on sta- assigned a propensity score.