Effects of Intravenous Nicorandil on the Mid-Term Prognosis of Patients

Home , Nesiritide

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 ventricular 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. Covariates in the model included tistical significance in the univariate analysis (P<0.05). age, sex, comorbidities, vital signs, NYHA class, LVEF, intra- After the data were initially analyzed, we performed a pro- venous drugs, and laboratory findings at baseline Table( 1). pensity-matched analysis to minimize selection bias.12 Based Patients in the Nicorandil and Control groups were matched by on a multivariate logistic regression model, each patient was 2-digit in a 1:1 ratio, based on the estimated propensity score for treatment with intravenous nicorandil. P<0.05 was considered significant. Statistical analysis was performed using JMP Table 2. Changes in Hemodynamic Parameters of All Study 8.0.1 (SAS Institute Inc, Cary, NC, USA). Patients Nicorandil Control P value Results Systolic BP (mmHg) A total of 402 consecutive patients with AHFS were registered. At admission 147.0 (32.2) 141.9 (32.5) 0.2119 The mean age was 79.1±10.4 years, and 189 patients (47.0%) 3 h 125.8 (22.7) 127.1 (24.7) 0.6718 were male (Table 1). During the 180-day follow-up, the pri- 24 h 116.4 (17.2) 121.5 (22.0) 0.0569 mary endpoint occurred in 82 patients (20.4%: death from all 72 h 113.8 (17.2) 120.3 (21.2) 0.0145 causes, 42 patients; rehospitalization for HF, 40 patients). Diastolic BP (mmHg) At admission 81.0 (18.9) 79.5 (21.2) 0.5697 Comparison of the Clinical Characteristics, Hemodynamic 3 h 67.6 (14.4) 71.0 (16.3) 0.0908 and Prognosis Between the Nicorandil and Control Groups 24 h 60.2 (11.7) 68.0 (15.0) <0.0001 Table 1 shows the baseline clinical characteristics of all study 72 h 58.4 (11.1) 67.5 (14.3) <0.0001 participants, those receiving nicorandil (n=78), and those not Heart rate (beats/min) receiving nicorandil (n=324). The prevalence of hypertension, At admission 93.0 (21.0) 89.1 (26.9) 0.2259 diabetes mellitus, dyslipidemia and ischemic heart disease was 3 h 85.4 (17.2) 82.7 (20.6) 0.2907 24 h 80.5 (14.4) 79.0 (16.8) 0.4769 Multivariate Cox Hazard Regression Analysis of Events: 72 h 80.8 (14.5) 76.4 (15.0) 0.0211 Table 3. Death or Rehospitalization for Heart Failure Proportional pulse pressure HR 95%CI P value At admission 0.44 (0.12) 0.44 (0.11) 0.8166 Age (years) 1.066 1.036–1.100 <0.0001 3 h 0.46 (0.10) 0.44 (0.11) 0.1195 Systolic BP (mmHg) 0.983 0.972–0.994 0.0023 24 h 0.48 (0.09) 0.44 (0.11) 0.0007 NYHA class III/IV 6.55 3.161–15.910 <0.0001 72 h 0.48 (0.10) 0.43 (0.10) 0.0002 Log creatinine 3.866 1.382–10.227 0.0106 Intravenous of nicorandil 0.179 0.073–0.378 <0.0001 Data are mean (SD). BP, blood pressure; Proportional pulse pressure, pulse pressure/ HR, hazard ratio; CI, confidence interval. Other abbreviations see in systolic BP. Tables 1,2.

Figure 1. Kaplan-Meier analysis of cumulative event-free rates. Event, death from all causes or rehospitalization for heart failure.

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Figure 2. Kaplan-Meier analysis of cumulative event-free rates in the subanaly- ses of patients with SBP <140 mmHg (A), NYHA ≥III (B), and serum creatinine ≥1.3 mg/dl (C). NYHA, New York Heart As- sociation; SBP, systolic blood pressure.

significantly higher in the Nicorandil group, but the prevalence groups for mean baseline SBP (147.0 mmHg vs. 141.9 mmHg, of atrial fibrillation was significantly lower. The percentage of P=0.2119). A comparison of the use of intravenous drugs for the patients in NYHA class III or IV (97.4% vs. 68.9%, P<0.0001) treatment of HF during hospitalization revealed that the percent- and the median BNP level (940 pg/ml vs. 520 pg/ml, P<0.0001) age of patients receiving loop diuretics was significantly higher were significantly higher in the Nicorandil group than in the in the Nicorandil group (96.2% vs. 86.4%, P=0.0163), but no Control group, and mean LVEF (46.5% vs. 54.7%, P=0.0005) significant difference was observed between groups in the per- was significantly lower in the Nicorandil group than in the Con- centage of patients receiving dobutamine or dopamine (7.7% vs. trol group. There were no significant differences between the 2 7.1% and 3.9 vs. 5.3%, respectively). A comparison of the use

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Table 4. Baseline Characteristics of the Propensity-Matched Patients Nicorandil (n=67) Control (n=67) P value Age (years) 79.0 (10.3) 77.5 (11.0) 0.4432 Male 28 (41.8) 29 (43.3) 0.8613 Medical history Hypertension 51 (76.1) 42 (62.7) 0.0916 Diabetes 27 (40.3) 18 (26.9) 0.0997 Dyslipidemia 25 (37.3) 21 (31.3) 0.4668 Smoker 21 (31.3) 21 (31.3) 1.0000 Cerebrovascular disease 15 (22.4) 14 (20.9) 0.8338 Atrial fibrillation 19 (28.4) 16 (23.9) 0.5552 Ischemic heart disease 28 (41.8) 31 (46.3) 0.6016 Vital signs at admission Systolic BP (mmHg) 147.4 (32.9) 143.8 (31.4) 0.5169 Diastolic BP (mmHg) 82.4 (18.8) 79.5 (21.1) 0.4006 Heart rate (beats/min) 93.4 (21.9) 95.1 (26.7) 0.6848 NYHA class III/IV 65 (97.0) 65 (97.0) 1.0000 LVEF (%) 46.9 (16.3) 44.7 (16.8) 0.4405 Laboratory findings Creatinine (mg/dl) 1.1 (0.9–1.4) 1.0 (0.8–1.5) 0.9395 Hemoglobin (g/dl) 11.3 (2.4) 11.2 (2.2) 0.6915 BNP (pg/ml) 938 (579–1,692) 793 (431–1,510) 0.1848 IV medications during hospitalization Loop diuretics 64 (95.5) 64 (95.5) 1.0000 Carperitide 23 (34.3) 17 (25.4) 0.2573 Nitroglycerin 5 (7.5) 6 (9.0) 0.7530 Dobutamine 5 (7.5) 10 (14.9) 0.1707 Dopamine 2 (3.0) 8 (11.9) 0.0962 Oral medications at discharge ACEI and/or ARB 50 (75.8) 36 (57.1) 0.0250 β-blocker 39 (59.1) 27 (42.9) 0.0652 Aldosterone antagonist 26 (39.4) 26 (41.3) 0.8281 Data are number (%), mean (SD) or median (interquartile range). Abbreviations see in Tables 1,2. of oral medications at discharge revealed that the percentage tion for HF during the 180-day follow-up, age (P<0.001), SBP of patients receiving angiotensin-converting enzyme inhibitors (P<0.001), DBP (P<0.001), heart rate (P<0.01), NYHA class or angiotensin-receptor II antagonists and beta-blockers were (P<0.001), serum creatinine (P<0.001), hemoglobin (P<0.01), significantly higher in the Nicorandil group (76.6% vs. 56.5%, the use of intravenous nicorandil (P<0.01), and the use of P=0.0012; 59.7% vs. 32.2%, P<0.0001, respectively). intravenous nitroglycerin (P<0.05) were found to be significant Nicorandil was administered for a mean of 4.4±1.2 days, at factors. The multivariate Cox hazard analysis of these factors a mean maximum dose of 0.13±0.04 mg · kg–1 · h−1. The time revealed that age (hazard ratio (HR)=1.066, 95% confidence course of the hemodynamics is shown in Table 2. SBP at 72 h interval (CI) 1.036–1.100, P<0.0001), SBP (HR=0.983, 95%CI in the Nicorandil group was significantly lower than the Control 0.972–0.994, P=0.0023), NYHA class III or more severe symp- group. DBP at both 24 h and 72 h in the Nicorandil group was toms (HR=6.550, 95%CI 3.161–15.910, P<0.0001), log cre- significantly lower than the Control group. Proportional pulse atinine (HR=3.866, 95%CI 1.382–10.227, P=0.0106), and use pressure was calculated as (SBP−DBP)/SBP. Proportional of intravenous nicorandil (HR=0.179, 95%CI 0.073–0.378, pulse pressure was significantly higher in patients in the Nicor- P<0.0001) were significant predictive factors for the occur- andil group than in those in the Control group at 24 h and 72 h. rence of death or rehospitalization for HF (Table 3). There were no significant differences between the 2 groups in heart rate during the 72 h. Kaplan-Meier Survival Analysis During the 180-day follow-up, 7 patients in the Nicorandil Figure 1 shows that the event-free survival rates were signifi- group (9.0%) and 75 patients (23.2%) in the Control group died cantly higher in patients in the Nicorandil group than in those or were rehospitalized for HF; the rate of occurrence was sig- in the Control group (P=0.006). Event-free survival rates were nificantly lower in the Nicorandil group (P=0.0053). The rate significantly lower in patients with more severe NYHA class of death or rehospitalization for HF within 30 days was also symptoms (≥III vs.

Circulation Journal Vol.76, May 2012 1174 ISHIHARA S et al.

Figure 3. Kaplan-Meier analysis of cumulative event-free rates in propensity-matched patients.

in the Nicorandil group than in those in the Control group. well-balanced decrease in both preload and afterload it in- duces, nicorandil improves the hemodynamics of patients with Propensity-Matched Patient Analysis AHFS.7,16 It is recommended that intravenous nicorandil ther- Estimated propensity scores were used to match 67 patients apy be initiated with a bolus injection to ensure prompt im- each from the Nicorandil and Control groups. The baseline provement of hemodynamics. Although prompt improvement clinical characteristics of the patients did not differ between of hemodynamics should improve the prognosis of patients groups (Table 4). According to the propensity-matched patient with AHFS,4 it has been reported that treatment with the natri- analysis, death or rehospitalization for HF occurred in 7 patients uretic peptide analog, nesiritide, may cause deterioration of of the Nicorandil group (10.5%) and 22 patients of the Control renal function and thus the prognosis of patients with decom- group (32.8%). During the 180-day follow-up, the incidence of pensated HF, possibly via induction of hypotension by bolus death or rehospitalization for HF was significantly lower in the administration or continuous infusion of a high dose.15,17 In Nicorandil group than in the Control group (HR=0.276, 95%CI studies in which intravenous bolus injections of nicorandil 0.109–0.614, P=0.0012). Figure 3 shows that event-free sur- were given at doses of 0.251 mg/kg18 and 0.2 mg/kg,7 nicor- vival rates were significantly higher in propensity-matched andil induced prompt and substantial decreases in pulmonary patients of the Nicorandil group than in those of the Control capillary wedge pressure and systemic vascular resistance, as group (P=0.0015). well as marked increases in the cardiac index without causing an excessive decrease in BP or significant changes in heart rate. In a study of 99 patients with AHFS treated with a bolus Discussion injection of nicorandil 0.2 mg/kg followed by continuous infu- Patients with AHFS often receive intravenous drugs such as sion at 0.05–0.2 mg · kg–1 · h−1, Tanaka et al reported that hemo- loop diuretics, nitrates, and natriuretic peptide analogs and dynamics was stable throughout the treatment with nicorandil inotropic agents. It has been reported in large-scale registry in all patients except 1 (1%) who exhibited a decrease in BP studies such as ADHERE that the use of inotropic agents that did not require discontinuation of the nicorandil infusion.7 increases in-hospital mortality.13 The effects of vasodilators on Several reports6,7,19 have noted that nicorandil significant de- the prognosis of patients with AHFS are still being debated.14,15 creased SBP in patients with high baseline SBP but not in The results of the present study suggest that starting treatment those with low to normal baseline SBP, indicating that nicor- with nicorandil, an intravenous vasodilator, in the urgent phase andil treatment is safe and efficacious. In this study, all patients of AHFS may have decreased the incidence of death or rehos- in the Nicorandil group received a bolus injection of nicorandil pitalization for HF during the 180-day follow-up in 402 con- at 0.1–0.2 mg/kg followed by continuous nicorandil infusion at secutive patients with AHFS. 0.1 mg · kg–1 · h−1 for at least 3 days, during which time the infu- Nicorandil differs from classical nitrates, such as nitroglyc- sion rate of nicorandil was adjusted at the discretion of each erin, in its function as a KATP channel activator.5 Nicorandil physician according to SBP, symptoms or clinical signs. In exerts a vasodilative effect mainly on the systemic veins, as do consequence, nicorandil was administered for a mean of 4.4±1.2 conventional nitrates, but it also dilates arteries, including days, at a mean maximum dose of 0.13±0.04 mg · kg–1 · h−1. peripheral arteries, by opening KATP channels. By virtue of the Hemodynamics in the Nicorandil group improved promptly

Circulation Journal Vol.76, May 2012 Nicorandil and Prognosis in AHFS 1175 without causing an excessive decrease in BP. Above all, DBP line SBP, NYHA class III or more severe symptoms of HF, and and proportional pulse pressure at 24 h and 72 h in the Nicor- baseline creatinine level were independent predictive factors andil group were more improved than those in the Control for death or rehospitalization for HF during a 180-day period. group, suggesting that nicorandil predominantly dilated periph- These predictive factors for our study population have also eral resistant vessels subsequent to increasing cardiac output.20 been reported to predict the prognosis of patients with AHFS Tanaka et al reported that nicorandil can reduce preload in lower in other studies.30,31 infusion rates of <0.1 mg · kg–1 · h−1, but for further improvement in the afterload and cardiac output via KATP channel opening, a Study Limitations higher infusion rate of 0.2 mg · kg–1 · h−1 would be more appropri- This study was retrospective and conducted in a single institu- ate.7 However, their study was monotherapy of nicorandil, tion, and there were significant differences in the baseline whereas continuous nicorandil infusion at 0.1–0.15 mg · kg–1 · h−1 patient characteristics of the Nicorandil and Control groups. as in the present study may be able to improve preload and af- Although statistical techniques were used to decrease the terload in clinical use (ie, combined therapy with diuretics or effects of these differences on the results, we cannot rule out other vasodilators). No pronounced hypotension occurred with the possibility that unspecified factors affected the results of this nicorandil regimen. All patients could thus receive nicor- our analysis. There was a difference in the percentage of andil safely. In a subanalysis of the SURVIVE study, the 180- patients receiving angiotensin-converting enzyme inhibitors or day mortality of patients with severe acutely decompensated HF angiotensin-receptor II antagonists at discharge after propensity was 22.5% among those with a ≥30% decrease in BNP level analysis. This difference may affect the mid-term prognosis, during the first 24 h of treatment, and significantly lower than their use at discharge was not associated with the occurrence of that in patients with a <30% decrease, 30.3% (HR=0.692, death or rehospitalization for HF during the 180-day follow-up. P=0.001).21 On the other hand, Minami et al6 and Shirakabe et In addition, because the rate of death or rehospitalization for al19 reported that during the first 48 h of nicorandil treatment the HF within 30 days was also significantly lower in the Nicor- median plasma BNP level was reduced from 1,639 pg/ml to andil group, intravenous nicorandil treatment should improve 623 pg/ml (62% decrease) and from 1,397 pg/ml to 502 pg/ml the prognosis of patients with AHFS. (65% decrease), respectively. The prompt improvement in he- In this study, the percentage of patients receiving intrave- modynamics by nicorandil might thus have contributed to the nous vasodilators in the Control group was 31% and might be improved prognosis of patients with AHFS. low, although the hemodynamic status of the patients at admis- Ischemic heart disease is the most significant disease in sion was relatively maintained. Several guidelines for the treat- patients with AHFS, and patients with it have a worse progno- ment of AHFS have recommend pharmacotherapy with vaso- sis than those with nonischemic etiologies.22,23 Ischemic heart dilators in patients without excessively low BP. Prospective disease was present in 32.1% of the present patients (it should randomized studies in a large number of patients should there- be noted that patients with acute coronary syndrome were fore be conducted confirm our findings. However, although excluded from the study); this prevalence was similar to that our study was retrospective, its findings are significant because in the ATTEND registry study currently underway in Japan.24 it is difficult to prospectively evaluate the benefits of drug In patients with AHFS, high left ventricular diastolic pressure treatment in the urgent phase in patients with AHFS. may induce subendocardial ischemia, which may increase the rate of progression of myocardial damage. Maintaining coronary perfusion may thus play an important role in preventing Conclusions myocardial injury in patients with AHFS. Nicorandil dilates Our findings suggest that intravenous nicorandil treatment epicardial conduit arteries through its nitrate-like effect, and started in the urgent phase of AHFS may improve the progno- dilates coronary resistance vessels by opening KATP chan- sis of patients with AHFS. nels.25 Okamura et al have reported that nicorandil is more effective in increasing anterograde coronary blood flow than nitroglycerin alone, without causing the coronary steal phe- References nomenon in patients with ischemic heart disease.26 A recent 1. Zannad F, Adamopoulos C, Mebazaa A, Gheorghiade M. The challenge of acute decompensated heart failure. Heart Fail Rev 2006; 11: report noted that nicorandil improves microvascular dysfunc- 135 – 139. tion (as assessed by the index of microcirculatory resistance) 2. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski after primary percutaneous coronary intervention.27 Nicorandil P, Poole-Wilson PA, et al. ESC guidelines for the diagnosis and treat- also exhibits cardioprotective effects in the ischemic myocar- ment of acute and chronic heart failure 2008: The Task Force for the dium, similar to those of ischemic preconditioning, via activa- Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 8,28 of the European Society of Cardiology: Developed in collaboration tion of mitochondrial KATP channels. Ishii et al have dem- with the Heart Failure Association of the ESC (HFA) and endorsed onstrated that nicorandil can reduce reperfusion injury and by the European Society of Intensive Care Medicine (ESICM). Eur improve clinical outcomes after acute myocardial infarction Heart J 2008; 29: 2388 – 2442. when administered in adjunctively with coronary interven- 3. Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, 11 Ganiats TG, et al. 2009 focused update: ACCF/AHA guidelines for tion. These findings support the usefulness of nicorandil in the diagnosis and management of heart failure in adults: A report of improving coronary circulation and alleviating myocardial the American College of Cardiology Foundation/American Heart damage in patients with AHFS related to ischemia. Association Task Force on Practice Guidelines. Circulation 2009; It has also been reported by many studies that intravenous 119: 1977 – 2016. 4. Mebazaa A, Gheorghiade M, Piña IL, Harjola VP, Hollenberg SM, nicorandil administration results in significantly less develop- Follath F, et al. Practical recommendations for prehospital and early ment of hemodynamic tolerance than nitroglycerin.29 Because in-hospital management of patients presenting with acute heart failure it is important in the treatment of AHFS to decrease cardiac syndromes. Crit Care Med 2008; 36: S129 – S139. load for a long period of time without causing hemodynamic 5. Taira N. Nicorandil as a hybrid between nitrates and potassium channel activators. Am J Cardiol 1989; 63: 18J – 24J. tolerance, the potential of nicorandil in the treatment of AHFS 6. Minami Y, Nagashima M, Kajimoto K, Shiga T, Hagiwara N. Acute can thus be considered quite high. efficacy and safety of intravenous administration of nicorandil in patients In this study, we found that nicorandil treatment, age, base- with acute heart failure syndromes: Usefulness of noninvasive echocar-

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