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Acute effects of intravenous nicorandil on hemodynamics in patients hospitalized with acute decompensated heart failure
Journal of Cardiology (2010) 56, 291—299
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Original article
Acute effects of intravenous nicorandil on hemodynamics in patients hospitalized with acute decompensated heart failure Keiji Tanaka (MD, FJCC) a,∗, Kazuzo Kato (MD) b,1, Teruo Takano (MD, FJCC) c,2, Takashi Katagiri (MD, FJCC) d,3, Hidetsugu Asanoi (MD, FJCC) e,4, Jun Nejima (MD) a,5, Mitsuyoshi Nakashima (MD) f, Takeshi Kamijo (PhD) g, Matao Sakanashi (MD) h,6 a
Division of Intensive and Coronary Care Unit, Nippon Medical School Hospital, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113 8603, Japan The Cardiovascular Institute Hospital, Tokyo, Japan c First Internal Medicine, Nippon Medical School Hospital, Tokyo, Japan d Third Department of Internal Medicine, Division of Cardiology, Showa University School of Medicine, Tokyo, Japan e Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan f Hamamatsu Institute of Clinical Pharmacology and Therapeutics, Hamamatsu, Japan g Chugai Pharmaceutical Co., Ltd., Tokyo, Japan h Department of Pharmacology, School of Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan b
Received 11 March 2010; received in revised form 15 June 2010; accepted 24 June 2010 Available online 14 August 2010
KEYWORDS Heart failure; Treatment; Vasodilator agents; Nicorandil; KATP channel opener; Acute decompensated heart failure ∗ 1 2 3 4 5 6
Summary Background: Nicorandil injection, a potent vasodilator with KATP channel opening action and nitrate-like action, has been used for treatment of unstable angina. In the present investigation, we examined the effect of intravenous nicorandil on hemodynamics in patients with acute decompensated heart failure (ADHF). Methods: ADHF patients admitted to hospital with pulmonary artery wedge pressure (PAWP) ≥ 18 mm Hg were enrolled. Patients received nicorandil by an intravenous bolus injection of 0.2 mg/kg/5 min followed by continuous infusion at a rate of 0.05, 0.10, or 0.20 mg/kg/h for 6 h.
Corresponding author. Tel.: +81 3 3822 2131; fax: +81 3 5814 6235. E-mail address: [email protected] (K. Tanaka). Present address: Keiwa Clinic, Tokyo, Japan. Present address: Nippon Medical School Foundation, Tokyo, Japan. Present address: Showa University, Tokyo, Japan. Present address: Imizu City Hospital, Imizu, Japan. Present address: Department of Internal Medicine, Tsurumi University Dental Hospital, Yokohama, Japan. Present address: University of the Ryukyus, Okinawa, Japan.
0914-5087/$ — see front matter © 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jjcc.2010.06.009
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K. Tanaka et al. Results: Nicorandil administration caused a significant decrease in PAWP and increase in the cardiac index (CI) that began immediately after the injection and were maintained during the continuous infusion. After 6 h, nicorandil administration at 0.2 mg/kg/5 min followed by 0.20 mg/kg/h resulted in a decrease in PAWP (26.5%, p < 0.01), an increase in CI (15.8%, p < 0.05), and a decrease in total peripheral resistance (13.8%, p < 0.01) in a dose-dependent manner. Nicorandil decreased blood pressure significantly, without an excessive decrease or negative impact even in patients with lower systolic blood pressure. Conclusion: Intravenous administration of nicorandil, by bolus injection followed by continuous infusion, improves PAWP and CI in ADHF patients immediately and continuously as a potent vasodilator with combined preload and afterload reduction. These results demonstrate that nicorandil is a safe and effective new medication for the treatment of ADHF. © 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
Introduction Acute heart failure is a clinical syndrome with a variety of underlying diseases, and the number of patients with acute decompensated heart failure (ADHF) is increasing rapidly. However, the pathophysiology of ADHF and its treatment are still incompletely understood, and, therefore, optimal treatment for this condition remains somewhat controversial. Guidelines for the treatment of ADHF were published by the Japanese Circulation Society in 2006 [1], by the European Society of Cardiology (ESC) in 2008 [2], and by the American Heart Association in 2009 [3], and practical recommendations for prehospital and early management of patients with ADHF have also been released [4]. In those guidelines and practical recommendations, vasodilators are in general currently considered to be a cardinal form of therapy. However, because both the underlying diseases and effects of different vasodilators are quite available, the strategy for vasodilator therapy for ADHF has not yet become fully established. Nicorandil is a vasodilator that combines KATP channel opening action and nitrate-like action [5] and has been used for the treatment of angina pectoris (tablet formula) and unstable angina (injection formula). The KATP channel opening action of nicorandil exerts a vasodilating effect by hyperpolarizing vascular smooth muscle membranes, thereby inhibiting calcium influx into cells [6]. Nitrate-like action mainly dilates venous vessels via guanylate cyclase activation. In ischemic heart disease, nicorandil has been reported to improve coronary circulation by dilating coronary resistance vessels in addition to large coronary arteries [7,8]. Nicorandil has also been reported to have a myocardial protective effect from reperfusion injury following percutaneous coronary interventional procedures [9—11]. In chronic congestive heart failure in patients with a relatively stable hemodynamic condition, nicorandil has been reported to improve hemodynamics by reducing the preload and afterload and increasing cardiac output when administered orally [12,13], as a single intravenous injection [14], or as a continuous infusion [15,16]. However, we are not aware of any report of the evaluation of the effects of intravenous nicorandil on hemodynamics in patients with ADHF. The purpose of the present investigation was to establish the adequate clinical dosage of
nicorandil based upon efficacy and safety in patients with ADHF.
Materials and methods Two Phase 2 studies were conducted between March 1995 and February 2000 in 26 medical institutions throughout Japan to support the application for approval of ADHF as an additional indication for nicorandil. These studies were approved by the institutional review board of each participating medical institution and conducted in compliance with the principles of the Declaration of Helsinki and Japanese Good Clinical Practice (GCP). Voluntary written informed consent to participate in the study was obtained from all study patients or from their legally acceptable representatives.
Patients Study subjects were patients with ADHF who met all of the following inclusion criteria: (1) placement of a SwanGanz catheter was possible throughout the study period; (2) age 20 years or older; (3) pulmonary artery wedge pressure (PAWP) or diastolic pulmonary artery pressure ≥ 18 mm Hg; and (4) written informed consent provided by patient or representative. Exclusion criteria were: (1) serious arrhythmia; (2) cardiogenic shock or severe hypotension with systolic blood pressure (SBP) below 90 mm Hg; (3) contraindications for nicorandil injection; and (4) considered inappropriate as a participant by an investigator. Nicorandil (Sigmart® Injection, Chugai, Tokyo, Japan, 12 mg or 48 mg, lyophilized injection containing 12 mg or 48 mg of nicorandil per vial) was used as the study drug, which was dissolved in physiological saline or 5% glucose solution. Each patient group in the two studies received an initial bolus injection of nicorandil followed by an infusion lasting 6 h. The composition of the groups according to dosage in the two studies used in the analysis is described below. Early Phase 2 study: The study had a multicenter, open-label, group comparison design and included the following five groups according to dosage: 0.2 mg/kg/5 min + 0.05 mg/kg/h, 0.2 mg/kg/5 min + 0.10 mg/kg/h, 0.2 mg/kg/
lNicorandil in acute decompensated heart failure 5 min + 0.15 mg/kg/h, 0.2 mg/kg/5 min + 0.20 mg/kg/h, and 0.2 mg/kg/5 min + 0.25 mg/kg/h. Late Phase 2 study: The study had a randomized, double-blind, parallel-group design and included the following three groups according to dosage: 0.2 mg/kg/5 min + 0.05 mg/kg/h, 0.2 mg/kg/5 min + 0.10 mg/kg/h, and 0.2 mg/ kg/5 min + 0.20 mg/kg/h. Subjects were assigned to the treatment group by a controller according to key codes using permuted block randomization with a block size of three (three subjects per block). Fig. 1 shows the distribution of the patients. For the two studies, we obtained consent from a total of 128 patients, 99 of which were included in the analysis. Twenty-nine patients were excluded for the following reasons: use of study drug dosages that were not included in this analysis (0.2 mg/kg/5 min + 0.15 mg/kg/h or 0.2 mg/kg/5 min + 0.25 mg/kg/h; all the excluded patients were from the early Phase 2 study), violation of inclusion or exclusion criteria or concomitant use of a prohibited drug.
Study procedures Baseline hemodynamic parameters were measured and treatment with nicorandil was initiated if these parameters were stable for at least 15 min. In both studies, a single 0.2 mg/kg dose of nicorandil was intravenously administered over a 5-min period, after which the designated dose for that patient’s group was intravenously administered continuously for 6 h. Concomitant use of the following classes of drugs that could affect evaluation of the efficacy of nicorandil was prohibited at least 3 h before and during continuous infusion of the study drug: vasodilators, diuretics, inotropic agents (except for digitalis), sulfonylurea hypoglycemic agents, human atrial natriuretic peptide agents, -blockers, antiarrhythmic agents, and morphine and other such opioids. However, use of digitalis, intravenous fluids, and agents used for treatment for non-cardiovascular diseases were permitted during the nicorandil administration provided the dosage remained stable. The following baseline characteristics were determined: gender, age, height, body weight, and underlying disease. Hemodynamic parameters measured were heart rate (HR), SBP, and diastolic blood pressure (DBP). The following parameters were measured using a Swan-Ganz catheter or were calculated: PAWP, cardiac index (CI), stroke volume index (SVI), mean right atrial pressure (RAP), and total peripheral resistance (TPR). Each parameter was measured before, at 15 and 30 min, and at 1, 2, 4, and 6 h after the start of nicorandil administration. Adverse events were also monitored.
Statistical analysis Patients in the two studies who received nicorandil as a 0.2 mg/kg/5 min bolus injection followed by continuous infusion of 0.05, 0.10, or 0.20 mg/kg/h were included in the analysis. Statistics are presented as mean ± standard deviation (SD) or mean ± standard error (SE). The baseline characteristics of each group were analyzed using the 2 test or one-way analysis of variance (one-way ANOVA). Hemodynamic parameters were analyzed by compiling the changes
293 over time for each dosage and performing one-way repeated measures ANOVA followed by the Least-Squares Means (LSMeans) Tukey Honestly Significantly Different (HSD) test. Percent changes in hemodynamic parameters at 6 h after administration of nicorandil were analyzed using the paired t-test and the Jonckheere trend test. Intergroup comparison of percent change in PAWP by baseline characteristics was performed using one-way ANOVA. The relationships of percent changes at 6 h after administration of 0.20 mg/kg/h nicorandil between CI and SVI, and CI and TPR were analyzed using Pearson’s correlation analysis. Changes in blood pressure at 15 min were analyzed after dividing all the patients according to increments of 20 mm Hg of SBP before nicorandil administration (baseline SBP) using the paired t-test. There was no statistical difference in distribution of each dose among the baseline SBP levels, and it was demonstrated that the peripheral vasodilating effect of nicorandil with bolus injection lasted for 15 min (data are not shown). Therefore, all the data were pooled to evaluate the influence of bolus injection on blood pressure for subanalysis. An adverse reaction was defined as an adverse event for which a causal relationship with the study drug could not be ruled out. The number of occurrences and the incidence were determined for each adverse reaction. A two-sided significance level of 15% was used for the analyses of patient characteristics, and a two-sided significance level of 5% was used for the other analyses. Statistical analyses were performed using JMP (JMP version 7.0.1, SAS Institute Japan, Tokyo, Japan).
Results Patient baseline characteristics Table 1 shows baseline characteristics of the study patients. Of the 99 patients eligible for analysis, 31 were females, the mean age was 67.1 ± 11.0 years, and 35 patients had new-onset of acute heart failure. The principal underlying diseases were as follows: ischemic heart disease, 40 patients; valvular disease, 22 patients; hypertension, 15 patients; and dilated cardiomyopathy, 18 patients. Intergroup differences were observed for gender, body weight, and number of patients with valvular disease, but no significant difference among the groups was observed for any of the other characteristics. Before the initiation of nicorandil administration, all the patients in all three groups had received early treatment for heart failure including oxygen inhalation therapy, and 81.8% had been treated with drugs. Baseline values for hemodynamic parameters are presented in Table 2. PAWP and CI values for the entire patient group were 25.7 ± 6.4 mm Hg and 2.47 ± 0.94 L/min/m2 , respectively. An intergroup difference was observed for RAP, but not for any of the other parameters.
Changes in pulmonary artery wedge pressure and cardiac index over time The time course of PAWP is plotted in Fig. 2, and the percent changes in PAWP at 6 h are shown in Table 3. When nicorandil was administered as a 0.2 mg/kg/5 min
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Figure 1
Table 1
Distribution of patients.
Baseline characteristics of study population. Mean ± SD/total (%)
Bolus (mg/kg/5 min)
0.2
p Value
Infusion (mg/kg/h)
0.05
0.10
0.20
N Gender Female Body weight (kg) (Mean ± SD) Age (y) (Mean ± SD) Principal underlying disease Ischemic heart disease Valvular disease Hypertension Dilated cardiomyopathy Other diseases Type of heart failure New-onset of acute heart failure Forrester subset II/IV Previous medications ACEI/ARB Calcium antagonists -Blockers Nitrates Human atrial natriuretic peptide Digitalis Catecholamines Other inotropic agents Diuretics Concomitant drugs Absent Present Baseline SBP (mm Hg) ≤100 101—120 121—140 141—160 161<
28
37
34
99 (100)
12
5
14
31 (31.3)
0.013
55.8 ± 11.4
62.0 ± 12.2
57.3 ± 12.0
58.6 ± 12.1
0.090
67.5 ± 11.4
65.9 ± 12.6
68.1 ± 9.0
67.1 ± 11.0
0.692
14 3 4 6 1
16 7 5 9 0
10 12 6 3 3
40 (40.4) 22 (22.2) 15 (15.2) 18 (18.2) 4 (4.0)
0.234 0.057 0.879 0.208 0.167
8
14
13
35 (35.4)
0.675
14/14
19/18
21/13
54/45
0.577
9 7 0 12 1 8 1 3 18
6 7 3 15 1 11 3 3 24
9 5 1 12 1 14 2 1 19
24 (24.2) 19 (19.2) 4 (4.0) 39 (39.4) 3 (3.0) 33 (33.3) 6 (6.1) 7 (7.1) 61 (61.6)
0.310 0.591 0.239 0.819 0.979 0.486 0.749 0.470 0.697
2 26
8 29
8 26
18 (18.2) 81 (81.8)
0.198
1 6 7 9 5
3 12 9 9 4
4 8 9 10 3
8 (8.2) 25 (25.5) 25 (25.5) 28 (28.6) 12 (12.2)
0.885
Each value represents the number of patients or mean ± SD. ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor antagonists; SBP, systolic blood pressure. Statistical analyses were performed by ANOVA or the 2 test.
lNicorandil in acute decompensated heart failure Table 2
295
Baseline hemodynamics in patients with acute decompensated heart failure.
Bolus (mg/kg/5 min)
0.2
Infusion (mg/kg/h)
0.05
0.10
0.20
N PAWP (mm Hg) CI (L/min/m2 ) SVI (mL/beat/m2 ) SBP (mm Hg) DBP (mm Hg) TPR (dyn s cm−5 ) HR (beat/min) RAP (mm Hg) PRP (mm Hg beat/min)
28 27.1 ± 6.3 2.36 ± 0.67 27.0 ± 8.3 142 ± 27 82 ± 13 2141 ± 681 91 ± 18 8.26 ± 3.63 12944 ± 3901
37 25.0 ± 6.6 2.45 ± 0.96 28.9 ± 12.7 134 ± 31 77 ± 16 1803 ± 618 89 ± 21 11.03 ± 5.84 12000 ± 4159
34 25.3 ± 6.3 2.57 ± 1.12 29.9 ± 17.4 131 ± 22 75 ± 14 1894 ± 916 93 ± 24 9.97 ± 5.70 12217 ± 4239
Total
p Value
99 25.7 ± 6.4 2.47 ± 0.94 28.7 ± 13.5 135 ± 27 77 ± 15 1928 ± 755 91 ± 21 9.90 ± 5.34 12341 ± 4093
0.403 0.681 0.701 0.297 0.158 0.200 0.772 0.122 0.643
Each value represents the mean ± SD. Statistical analyses were performed by ANOVA. PAWP, pulmonary artery wedge pressure; CI, cardiac index; SVI, stroke volume index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TPR, total peripheral resistance; HR, heart rate; RAP, mean right atrial pressure; PRP, pressure rate product.
bolus injection followed by continuous infusion of 0.05, 0.10, or 0.20 mg/kg/h, PAWP was significantly decreased compared to the baseline from 15 min to 6 h at all three doses. With 0.20 mg/kg/h, the post-bolus PAWP decrease was maintained until 6 h. At doses of 0.05, 0.10, and 0.20 mg/kg/h, the percent change in PAWP at 6 h was −16.7 ± 16.0% (p < 0.001), −20.5 ± 17.4% (p < 0.001), and −26.5 ± 21.9% (p < 0.001), respectively, which represented dose-dependent decreases (p = 0.023). The course of CI over time is plotted in Fig. 2, and the percent changes in CI at 6 h are shown in Table 3. CI was increased immediately after a nicorandil bolus injec-
Figure 2 Effect of nicorandil on pulmonary artery wedge pressure (PAWP) and cardiac index (CI) in patients with acute decompensated heart failure. Each point and bar represents the mean ± SE. : 0.2 mg/kg/5 min + 0.05 mg/kg/h, 䊉: 0.2 mg/kg/5 min + 0.10 mg/kg/h, : 0.2 mg/kg/5 min + 0.20 mg/kg/h. *p < 0.05 vs pre-value (repeated measures ANOVA and LSMeans Tukey HSD test).
tion of 0.2 mg/kg/5 min in every group, but the change was maintained thereafter only with 0.20 mg/kg/h. At doses of 0.05, 0.10, and 0.20 mg/kg/h, the percent increase in CI at 6 h was 6.8 ± 34.6%, 8.3 ± 20.9% (p = 0.026), and 15.8 ± 32.1% (p = 0.010), respectively, which represented dose-dependent increases (p = 0.032).
Changes in other hemodynamic parameters over time The time course of the other hemodynamic parameters is also plotted in Fig. 3, and the percent changes at 6 h are given in Table 3. SBP was significantly decreased at 15 min, and this decrease was maintained for 6 h with 0.10 mg/kg/h and 0.20 mg/kg/h. Mean changes in SBP were −5.9 ± 7.3 mm Hg and −7.4 ± 11.0 mm Hg at 15 min and 6 h with 0.10 mg/kg/h, and −6.3 ± 12.8 mm Hg and −11.5 ± 14.6 mm Hg at 15 min and 6 h with 0.20 mg/kg/h, respectively. There was no clinically excessive decrease in SBP throughout the administration. DBP, TPR and RAP had significant decreases at 15 min, and these changes were maintained for 6 h with 0.10 mg/kg/h and 0.20 mg/kg/h. HR did not change significantly in any group during the administration. Pressure rate product (PRP) decreased significantly at 6 h with 0.10 mg/kg/h and 0.20 mg/kg/h. The percent changes in SVI, SBP, TPR, and PRP at 6 h were significantly dose-dependent as were those of PAWP and CI. However, there was no significant dose-dependent change in RAP, since the change reached a plateau at 0.10 mg/kg/h (Table 3). The relationships of percent changes between CI and SVI, and CI and TPR at 6 h with 0.20 mg/kg/h of nicorandil are shown in Fig. 4. Positive significant correlation between CI and SVI (R = 0.901, p < 0.001), and negative correlation between CI and TRP (R = −0.806, p < 0.001) were observed.
Changes in blood pressure at 15 min Fig. 5 shows changes in SBP and DBP at 15 min in patients divided according to increments of 20 mm Hg in the baseline SBP. There was no significant decrease in SBP at
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Table 3 Percent change in hemodynamic parameters at 6 h after administration of nicorandil in patients with acute decompensated heart failure. Bolus (mg/kg/5 min)
0.2
p Value
Infusion (mg/kg/h)
0.05
0.10
0.20
PAWP CI SVI SBP DBP TPR HR RAP PRP
−16.7 ± 16.0** 6.8 ± 34.6 4.9 ± 31.7 −1.6 ± 8.1 −2.3 ± 11.9 −1.6 ± 21.0 2.0 ± 11.4 −5.6 ± 23.6 0.3 ± 12.7
−20.5 ± 17.4** 8.3 ± 20.9* 13.1 ± 25.5** −5.1 ± 7.8** −8.0 ± 17.5* −9.9 ± 19.7** −2.7 ± 13.3 −13.5 ± 40.6 −7.8 ± 14.5**
−26.5 ± 21.9** 15.8 ± 32.1* 18.6 ± 37.3** −7.9 ± 10.6** −8.8 ± 10.8** −13.8 ± 27.5** −1.0 ± 9.4 −11.6 ± 45.9 −8.9 ± 13.6**
0.023 0.032 0.039 0.003 0.053 0.009 0.294 0.089 0.005
Each value represents the mean ± SD of percent change. ‘‘p value’’ obtained by Jonckheere analysis. Abbreviations are defined in Table 2. * p < 0.05 vs pre-value (paired t-test). ** p < 0.01 vs pre-value (paired t-test).
15 min when the baseline SBP was 120 mm Hg or below, while a significant decrease was detected with baseline SBP values over 120 mm Hg. The mean change in SBP in patients with baseline SBP greater than 160 mm Hg was
−22.7 ± 20.3 mm Hg (p = 0.003). In contrast, DBP decreased significantly in patients with baseline SBP below 100 mm Hg to over 160 mm Hg, with the exception of 121—140 mm Hg baseline SBP.
Figure 3 Effect of nicorandil on hemodynamic parameters in patients with acute decompensated heart failure. Each point and bar represents the mean ± SE. : 0.2 mg/kg/5 min + 0.05 mg/kg/h, 䊉: 0.2 mg/kg/5 min + 0.10 mg/kg/h, : 0.2 mg/kg/5 min + 0.20 mg/kg/h. *p < 0.05 vs pre-value (repeated measures ANOVA and LSMeans Tukey HSD test). SBP, systolic blood pressure; HR, heart rate; DBP, diastolic blood pressure; SVI, stroke volume index; TPR, total peripheral resistance; PRP, pressure rate product; RAP, mean right atrial pressure.
lNicorandil in acute decompensated heart failure
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Figure 5 Acute effect of nicorandil on blood pressure according to baseline systolic blood pressure (SBP) in patients with acute decompensated heart failure. Each point and bar represents the mean ± SD. *p < 0.05, **p < 0.01 vs pre-value (paired t-test). DBP, diastolic blood pressure.
Figure 4 Regression analyses between cardiac index (CI) and stroke volume index (SVI) (A), and CI and total peripheral resistance (TPR) (B) using Pearson’s correlation analysis. Each point represents the percent change at 6 h with 0.20 mg/kg/h of nicorandil.
Safety There were 8 adverse reactions, including headache in 5 patients (5.1%) and decreased blood pressure, premature ventricular contraction, and ventricular tachycardia in one patient (1.0%) each. None of the adverse reactions was considered severe. Nicorandil treatment was not discontinued in any patient because of adverse reactions. No complications were caused by a Swan-Ganz catheter. No death during nicorandil administration was reported.
Discussion Results of the present investigation showed that intravenous nicorandil given to patients with ADHF as a bolus injection followed by continuous infusion reduced the preload and afterload immediately after the initiation of treatment and rapidly improved and stabilized hemodynamics in a dosedependent manner. Nicorandil was also administered safely in all patients during the study period without any severe adverse reactions. Because vasodilators rapidly improve hemodynamics, they are widely used along with diuretics to treat acute
heart failure [17]. In the ESC guidelines [2], use of vasodilators to treat ADHF is recommended when pulmonary congestion is present and if SBP is greater than 90 mm Hg. The ESC guidelines also suggest that early reperfusion treatment may be effective in ADHF in patients with underlying acute coronary syndrome. Three dosage groups were included in the present analysis; in those groups, nicorandil was administered as a 0.2 mg/kg/5 min bolus injection followed by continuous infusion of 0.05, 0.10, or 0.20 mg/kg/h. Significant differences among the three dosage groups were observed for gender, body weight, and number of patients with valvular disease. However, differences in response attributable to gender were not observed (data not shown). Differences in body weight were inconsequential, since the dosages were specified according to body weight. Furthermore, the percent decrease in PAWP in patients with underlying valvular heart disease did not differ significantly from the percent decrease in other patients. Accordingly, the influence of the differences in baseline characteristics was thought to be small. In the current investigation, bolus injection of nicorandilinduced rapid improvement in PAWP and CI; with continuous infusion, particularly at 0.20 mg/kg/h, these changes were maintained throughout the treatment. As stated earlier, nicorandil monotherapy has been reported to improve hemodynamics in chronic congestive heart failure when administered as a single intravenous injection [14] or as a continuous infusion [15,16]. Giles et al. [14] reported that single intravenous doses of nicorandil improved hemodynamics immediately after administration. Because rapid hemodynamic improvement in the acute phase is essential in the treatment of ADHF, loading of nicorandil with bolus intravenous administration would be favored in this clinical setting. Nicorandil significantly increased CI and SVI, and decreased TPR, while nicorandil did not change HR. The change in CI was significantly positively correlated with that of SVI, and significantly negatively correlated with that of TPR. In a canine acute heart failure model, nicorandil increased stroke volume, which was accompanied by a marked decrease in left ventricular end-systolic volume
298 [18]. Therefore, it is suggested that the nicorandil-induced increases in CI and SVI were mainly associated with afterload reduction. Nicorandil has been found to act by two mechanisms, a KATP channel opening action and a nitrate-like action in a canine heart failure model [19]. KATP channel opening agents mainly dilate arteries but do not affect veins [19,20], and their direct action on cardiac function is weak [6,21]. It is reported that the KATP channel opening action of nicorandil is considered to be predominant in dilating arteries, since the effects of nicorandil in decreasing peripheral resistance and increasing cardiac output were inhibited by the KATP channel blocker glibenclamide in a canine heart failure model [18]. However, which mechanisms lead to improvement in CI are unknown in ADHF patients, and further investigations are needed to clarify this issue. Nicorandil improves hemodynamics as a potent balanced vasodilator with combined dilation of both arterial and venous systems via both KATP channel opening and nitrate-like actions, thus increasing CI and reducing PAWP. A decrease in PAWP was observed with the lowest infusion rate of nicorandil (0.05 mg/kg/h), and RAP decreased and reached a plateau with the middle infusion rate (0.10 mg/kg/h), suggesting that there is a component of nitrate-like action at lower doses of nicorandil as reported by Giles et al. [14]. A decrease in TPR and increases in CI and SVI were observed at the higher infusion rate of nicorandil (0.20 mg/kg/h). In addition, secondary changes in cardiac function caused by preload and afterload reduction could contribute to the hemodynamic improvement. Therefore, it is apparent that nicorandil can reduce preload in lower infusion rates of 0.05—0.10 mg/kg/h, but for further improvement in the afterload and CI, a higher infusion rate of 0.20 mg/kg/h would be more appropriate. Nicorandil significantly decreased blood pressure immediately with bolus injection. This decrease was maintained during the infusion while an excessive decrease in blood pressure did not occur. Decreased blood pressure was reported as an adverse reaction in only one patient in this investigation, and it was not severe. Therefore, we evaluated the effect of nicorandil on blood pressure, dividing the baseline SBP according to increments of 20 mm Hg. Nicorandil did not decrease SBP significantly in patients with low to normal SBP, while it did decrease SBP remarkably in patients with an elevated baseline SBP. In addition, nicorandil also decreased DBP significantly in patients over almost all the SBP range including lower SBP, suggesting that nicorandil predominantly dilates peripheral resistant vessels subsequent to maintaining cardiac output and SBP. These results coincide well with the report by Minami et al. [22] that nicorandil decreased blood pressure in subjects with a high baseline blood pressure. Elevated blood pressure in patients with ADHF generated by excessively high vessel tone, which is activated by the sympathetic nervous system and renin—angiotensin—aldosterone system, may be involved in the pathology of ADHF. In such cases, nicorandil could lead the relaxation of vascular smooth muscle and could decrease blood pressure. To clarify the precise mechanism of nicorandil on blood pressure in ADHF, further study is needed. Nicorandil decreased PRP significantly at 6 h in the present investigation, suggesting that decreased myocar-
K. Tanaka et al. dial oxygen consumption may contribute to improvement in heart failure. Miura et al. [23] reported that nicorandil inhibits the release of norepinephrine from ischemic myocardium, and Giles et al. [14] reported that a single intravenous administration of nicorandil improved hemodynamics without concomitant tachycardia or an increase in plasma catecholamines. Whether or not nicorandil similarly affects release of catecholamines with continuous infusion in ADHF is a subject for future investigation.
Study limitations The present investigation consisted of two separate protocols. One of the two studies was conducted in an open manner, and thus the bias of patient selection is not fully excluded. Since the studies were conducted to evaluate the efficacy of nicorandil in any type of ADHF, no limitation for a principal underlying disease or cardiac function was established in patient enrollment. Therefore, the number of patients was not sufficient to analyze the efficacy of nicorandil on hemodynamics for each principal underlying disease. The prescription rates of ACE inhibitors/ARBs and -blockers were 24.2% and 4.0% respectively since the studies were conducted between 1995 and 2000 when these drugs were not fully established treatments for chronic heart failure. It is recommended that future studies be carried out in a large number of ADHF patients, which would include a control group, measurement of neurohormones, evaluation of effects on coronary perfusion and myocardial injury, and assessment of outcomes such as mortality and rehospitalization.
Conclusions In patients with ADHF, intravenous administration of nicorandil by bolus injection followed by continuous infusion improves PAWP and CI immediately and continuously as a potent vasodilator with combined preload and afterload reduction, via the dual mechanism of KATP channel opening and nitrate-like actions. These findings indicate that nicorandil could be an effective and beneficial new medication for the treatment of ADHF.
Acknowledgments The clinical studies were conducted to support the supplementary approval of nicorandil for acute heart failure in Japan and were sponsored by Chugai Pharmaceutical Co. Ltd.
Appendix A. Institutes and investigators that participated in the clinical studies: Asahikawa City Hospital (Kunihiko Hirasawa), Iwate Medical University Memorial Heart Center (Kenichi Fukami), Iwate Medical University (Katsuhiko Hiramori), Nippon Medical School Chiba Hokusoh Hospital (Keiji Tanaka), Jichi Medical School Omiya Medical Center (Nobuhiro Ohmura), Nihon University School of Medicine Itabashi Hospital (Katsuo
lNicorandil in acute decompensated heart failure Kanmatsuse, Satoshi Saito), Nippon Medical School Hospital (Teruo Takano, Keiji Tanaka), The Cardiovascular Institute Hospital (Kazuo Kato, Haruki Ito), Tokyo Women’s Medical University Heart Institute of Japan (Hiroshi Kasanuki), Sakakibara Heart Institute (Tetsuya Sumiyoshi), Showa University Hospital (Mikitaka Murakami, Takashi Katagiri), Showa University Fujigaoka Hospital (Youichi Takeyama), St. Marianna University School of Medicine Hospital (Masayoshi Sakakibara), Tokai University Hospital (Shunnosuke Handa), Toyama Medical and Pharmaceutical University Hospital (Hiroshi Inoue, Hidetsugu Asanoi), Shiga University of Medical Science Hospital (Masahiko Kinoshita), Kyoto University Hospital (Shigetake Sasayama, Hideo Otani), Osaka Police Hospital (Kazuhisa Kodama), Osaka City General Hospital (Kazuo Haze), Sakurabashi Watanabe Hospital (Kenshi Fujii), National Cardiovascular Center (Hiroshi Nonogi), Komatsushima Red Cross Hospital (Yoshikazu Hiasa), Yamaguchi University Hospital (Masunori Matsuzaki), Saiseikai Fukuoka General Hospital (Yusuke Yamamoto), Saiseikai Kumamoto Hospital (Kazuya Hayasaki, Takashi Honda), and Ryukyu University Hospital (Hisashi Yoshida).
References [1] Guidelines for treatment of acute heart failure (JCS); 2006. http://www.j-circ.or.jp/guideline/pdf/JCS2006 maruyama h. pdf. [2] Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, Strömberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail 2008;10:933—89. [3] Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG, Konstam MA, Mancini DM, Rahko PS, Silver MA, Stevenson LW, Yancy CW. 2009 focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119:1977—2016. [4] Mebazaa A, Gheorghiade M, Pi˜ na IL, Harjola VP, Hollenberg SM, Follath F, Rhodes A, Plaisance P, Roland E, Nieminen M, Komajda M, Parkhomenko A, Masip J, Zannad F, Filippatos G. Practical recommendations for prehospital and early inhospital management of patients presenting with acute heart failure syndromes. Crit Care Med 2008;36(1 (Suppl.)):S129—39. [5] Taira N. Nicorandil as a hybrid between nitrates and potassium channel activators. Am J Cardiol 1989;63:18J—24J. [6] Sakai K, Shiraki Y, Nabata H. Cardiovascular effects of a new coronary vasodilator N-(2-hydroxyethyl) nicotinamide nitrate (SG-75): comparison with nitroglycerin and diltiazem. J Cardiovasc Pharmacol 1981;3:139—50. [7] Nakae I, Matsumoto T, Horie H, Yokohama H, Omura T, Minai K, Matsui T, Nozawa M, Takahashi M, Sugimoto Y, Ito M, Izumi M, Nakamura Y, Mitsunami K, Kinoshita M. Effects of intravenous nicorandil on coronary circulation in humans: plasma concentration and action mechanism. J Cardiovasc Pharmacol 2000;35:919—25.
299 [8] Okamura A, Rakugi H, Ohishi M, Yanagitani Y, Shimizu M, Nishii T, Taniyama Y, Asai T, Takiuchi S, Moriguchi K, Ohkuro M, Komai N, Yamada K, Inamoto N, Otsuka A, et al. Additive effects of nicorandil on coronary blood flow during continuous administration of nitroglycerin. J Am Coll Cardiol 2001;37:719—25. [9] Ito H, Taniyama Y, Iwakura K, Nishikawa N, Masuyama T, Kuzuya T, Hori M, Higashino Y, Fujii K, Minamino T. Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction. J Am Coll Cardiol 1999;33:654—60. [10] Ishii H, Ichimiya S, Kanashiro M, Amano T, Imai K, Murohara T, Matsubara T. Impact of a single intravenous administration of nicorandil before reperfusion in patients with ST-segmentelevation myocardial infarction. Circulation 2005;112:1284—8. [11] Iwakura K, Ito H, Okamura A, Koyama Y, Date M, Higuchi Y, Inoue K, Kimura R, Nagai H, Imai M, Toyoshima Y, Ozawa M, Ito N, Okazaki Y, Shibuya M, et al. Nicorandil treatment in patients with acute myocardial infarction: a meta-analysis. Circ J 2009;73:925—31. [12] Solal AC, Jaeger P, Bouthier J, Juliard JM, Dahan M, Gourgon R. Hemodynamic action of nicorandil in chronic congestive heart failure. Am J Cardiol 1989;63:44J—8J. [13] Tice FD, Binkley PF, Cody RJ, Moeschberger ML, Mohrland JS, Wolf DL, Leier CV. Hemodynamic effects of oral nicorandil in congestive heart failure. Am J Cardiol 1990;65:1361—7. [14] Giles TD, Pina IL, Quiroz AC, Roffidal L, Zaleski R, Porter RS, Karalis DG, Mohrland JS, Wolf DL, Hearron AE, Sander GE. Hemodynamic and neurohumoral responses to intravenous nicorandil in congestive heart failure in humans. J Cardiovasc Pharmacol 1992;20:572—8. [15] Tsutamoto T, Kinoshita M, Nakae I, Maeda Y, Wada A, Yabe T, Horie H. Absence of hemodynamic tolerance to nicorandil in patients with severe congestive heart failure. Am Heart J 1994;127:866—73. [16] Larsen AI, Goransson L, Aarsland T, Tamby JF, Dickstein K. Comparison of the degree of hemodynamic tolerance during intravenous infusion of nitroglycerin versus nicorandil in patients with congestive heart failure. Am Heart J 1997;134:435—41. [17] Metra M, Teerlink JR, Voors AA, Felker GM, Milo-Cotter O, Weatherley B, Dittrich H, Cotter G. Vasodilators in the treatment of acute heart failure: what we know, what we don’t. Heart Fail Rev 2009;14:299—307. [18] Kamijo T, Tomaru T, Miwa AY, Nakamura F, Kido H, Uchida Y. Hemodynamic effects of nicorandil on acute congestive heart failure in dogs. Asia Pacific J Pharmacol 1996;11:141—8. [19] Kamijo T, Kamei K, Sugo I, Kamiyama T, Sudo H, Ohba Y. Hemodynamic and hormonal responses to nicorandil in a canine model of acute ischemic heart failure: a comparison with cromakalim and nitroglycerin. J Cardiovasc Pharmacol 1999;33:93—101. [20] Gotanda K, Yokoyama H, Satoh K, Taira N. Cardiohemodynamic effects of cromakalim and pinacidil, potassium-channel openers, in the dog, special reference to venous return. Cardiovasc Drugs Ther 1989;3:507—15. [21] Yanagisawa T, Hashimoto H, Taira N. Interaction of potassium channel openers and blockers in canine atrial muscle. Br J Pharmacol 1989;97:753—62. [22] Minami Y, Nagashima M, Kajimoto K, Shiga T, Hagiwara N. Acute efficacy and safety of intravenous administration of nicorandil in patients with acute heart failure syndromes: usefulness of noninvasive echocardiographic hemodynamic evaluation. J Cardiovasc Pharmacol 2009;54:335—40. [23] Miura T, Kawamura S, Tatsuno H, Ikeda Y, Mikami S, Iwamoto H, Okamura T, Iwatate M, Kimura M, Dairaku Y, Maekawa T, Matsuzaki M. Ischemic preconditioning attenuates cardiac sympathetic nerve injury via ATP-sensitive potassium channels during myocardial ischemia. Circulation 2001;104:1053—8.
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Original article
Acute effects of intravenous nicorandil on hemodynamics in patients hospitalized with acute decompensated heart failure Keiji Tanaka (MD, FJCC) a,∗, Kazuzo Kato (MD) b,1, Teruo Takano (MD, FJCC) c,2, Takashi Katagiri (MD, FJCC) d,3, Hidetsugu Asanoi (MD, FJCC) e,4, Jun Nejima (MD) a,5, Mitsuyoshi Nakashima (MD) f, Takeshi Kamijo (PhD) g, Matao Sakanashi (MD) h,6 a
Division of Intensive and Coronary Care Unit, Nippon Medical School Hospital, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113 8603, Japan The Cardiovascular Institute Hospital, Tokyo, Japan c First Internal Medicine, Nippon Medical School Hospital, Tokyo, Japan d Third Department of Internal Medicine, Division of Cardiology, Showa University School of Medicine, Tokyo, Japan e Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan f Hamamatsu Institute of Clinical Pharmacology and Therapeutics, Hamamatsu, Japan g Chugai Pharmaceutical Co., Ltd., Tokyo, Japan h Department of Pharmacology, School of Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan b
Received 11 March 2010; received in revised form 15 June 2010; accepted 24 June 2010 Available online 14 August 2010
KEYWORDS Heart failure; Treatment; Vasodilator agents; Nicorandil; KATP channel opener; Acute decompensated heart failure ∗ 1 2 3 4 5 6
Summary Background: Nicorandil injection, a potent vasodilator with KATP channel opening action and nitrate-like action, has been used for treatment of unstable angina. In the present investigation, we examined the effect of intravenous nicorandil on hemodynamics in patients with acute decompensated heart failure (ADHF). Methods: ADHF patients admitted to hospital with pulmonary artery wedge pressure (PAWP) ≥ 18 mm Hg were enrolled. Patients received nicorandil by an intravenous bolus injection of 0.2 mg/kg/5 min followed by continuous infusion at a rate of 0.05, 0.10, or 0.20 mg/kg/h for 6 h.
Corresponding author. Tel.: +81 3 3822 2131; fax: +81 3 5814 6235. E-mail address: [email protected] (K. Tanaka). Present address: Keiwa Clinic, Tokyo, Japan. Present address: Nippon Medical School Foundation, Tokyo, Japan. Present address: Showa University, Tokyo, Japan. Present address: Imizu City Hospital, Imizu, Japan. Present address: Department of Internal Medicine, Tsurumi University Dental Hospital, Yokohama, Japan. Present address: University of the Ryukyus, Okinawa, Japan.
0914-5087/$ — see front matter © 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jjcc.2010.06.009
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K. Tanaka et al. Results: Nicorandil administration caused a significant decrease in PAWP and increase in the cardiac index (CI) that began immediately after the injection and were maintained during the continuous infusion. After 6 h, nicorandil administration at 0.2 mg/kg/5 min followed by 0.20 mg/kg/h resulted in a decrease in PAWP (26.5%, p < 0.01), an increase in CI (15.8%, p < 0.05), and a decrease in total peripheral resistance (13.8%, p < 0.01) in a dose-dependent manner. Nicorandil decreased blood pressure significantly, without an excessive decrease or negative impact even in patients with lower systolic blood pressure. Conclusion: Intravenous administration of nicorandil, by bolus injection followed by continuous infusion, improves PAWP and CI in ADHF patients immediately and continuously as a potent vasodilator with combined preload and afterload reduction. These results demonstrate that nicorandil is a safe and effective new medication for the treatment of ADHF. © 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
Introduction Acute heart failure is a clinical syndrome with a variety of underlying diseases, and the number of patients with acute decompensated heart failure (ADHF) is increasing rapidly. However, the pathophysiology of ADHF and its treatment are still incompletely understood, and, therefore, optimal treatment for this condition remains somewhat controversial. Guidelines for the treatment of ADHF were published by the Japanese Circulation Society in 2006 [1], by the European Society of Cardiology (ESC) in 2008 [2], and by the American Heart Association in 2009 [3], and practical recommendations for prehospital and early management of patients with ADHF have also been released [4]. In those guidelines and practical recommendations, vasodilators are in general currently considered to be a cardinal form of therapy. However, because both the underlying diseases and effects of different vasodilators are quite available, the strategy for vasodilator therapy for ADHF has not yet become fully established. Nicorandil is a vasodilator that combines KATP channel opening action and nitrate-like action [5] and has been used for the treatment of angina pectoris (tablet formula) and unstable angina (injection formula). The KATP channel opening action of nicorandil exerts a vasodilating effect by hyperpolarizing vascular smooth muscle membranes, thereby inhibiting calcium influx into cells [6]. Nitrate-like action mainly dilates venous vessels via guanylate cyclase activation. In ischemic heart disease, nicorandil has been reported to improve coronary circulation by dilating coronary resistance vessels in addition to large coronary arteries [7,8]. Nicorandil has also been reported to have a myocardial protective effect from reperfusion injury following percutaneous coronary interventional procedures [9—11]. In chronic congestive heart failure in patients with a relatively stable hemodynamic condition, nicorandil has been reported to improve hemodynamics by reducing the preload and afterload and increasing cardiac output when administered orally [12,13], as a single intravenous injection [14], or as a continuous infusion [15,16]. However, we are not aware of any report of the evaluation of the effects of intravenous nicorandil on hemodynamics in patients with ADHF. The purpose of the present investigation was to establish the adequate clinical dosage of
nicorandil based upon efficacy and safety in patients with ADHF.
Materials and methods Two Phase 2 studies were conducted between March 1995 and February 2000 in 26 medical institutions throughout Japan to support the application for approval of ADHF as an additional indication for nicorandil. These studies were approved by the institutional review board of each participating medical institution and conducted in compliance with the principles of the Declaration of Helsinki and Japanese Good Clinical Practice (GCP). Voluntary written informed consent to participate in the study was obtained from all study patients or from their legally acceptable representatives.
Patients Study subjects were patients with ADHF who met all of the following inclusion criteria: (1) placement of a SwanGanz catheter was possible throughout the study period; (2) age 20 years or older; (3) pulmonary artery wedge pressure (PAWP) or diastolic pulmonary artery pressure ≥ 18 mm Hg; and (4) written informed consent provided by patient or representative. Exclusion criteria were: (1) serious arrhythmia; (2) cardiogenic shock or severe hypotension with systolic blood pressure (SBP) below 90 mm Hg; (3) contraindications for nicorandil injection; and (4) considered inappropriate as a participant by an investigator. Nicorandil (Sigmart® Injection, Chugai, Tokyo, Japan, 12 mg or 48 mg, lyophilized injection containing 12 mg or 48 mg of nicorandil per vial) was used as the study drug, which was dissolved in physiological saline or 5% glucose solution. Each patient group in the two studies received an initial bolus injection of nicorandil followed by an infusion lasting 6 h. The composition of the groups according to dosage in the two studies used in the analysis is described below. Early Phase 2 study: The study had a multicenter, open-label, group comparison design and included the following five groups according to dosage: 0.2 mg/kg/5 min + 0.05 mg/kg/h, 0.2 mg/kg/5 min + 0.10 mg/kg/h, 0.2 mg/kg/
lNicorandil in acute decompensated heart failure 5 min + 0.15 mg/kg/h, 0.2 mg/kg/5 min + 0.20 mg/kg/h, and 0.2 mg/kg/5 min + 0.25 mg/kg/h. Late Phase 2 study: The study had a randomized, double-blind, parallel-group design and included the following three groups according to dosage: 0.2 mg/kg/5 min + 0.05 mg/kg/h, 0.2 mg/kg/5 min + 0.10 mg/kg/h, and 0.2 mg/ kg/5 min + 0.20 mg/kg/h. Subjects were assigned to the treatment group by a controller according to key codes using permuted block randomization with a block size of three (three subjects per block). Fig. 1 shows the distribution of the patients. For the two studies, we obtained consent from a total of 128 patients, 99 of which were included in the analysis. Twenty-nine patients were excluded for the following reasons: use of study drug dosages that were not included in this analysis (0.2 mg/kg/5 min + 0.15 mg/kg/h or 0.2 mg/kg/5 min + 0.25 mg/kg/h; all the excluded patients were from the early Phase 2 study), violation of inclusion or exclusion criteria or concomitant use of a prohibited drug.
Study procedures Baseline hemodynamic parameters were measured and treatment with nicorandil was initiated if these parameters were stable for at least 15 min. In both studies, a single 0.2 mg/kg dose of nicorandil was intravenously administered over a 5-min period, after which the designated dose for that patient’s group was intravenously administered continuously for 6 h. Concomitant use of the following classes of drugs that could affect evaluation of the efficacy of nicorandil was prohibited at least 3 h before and during continuous infusion of the study drug: vasodilators, diuretics, inotropic agents (except for digitalis), sulfonylurea hypoglycemic agents, human atrial natriuretic peptide agents, -blockers, antiarrhythmic agents, and morphine and other such opioids. However, use of digitalis, intravenous fluids, and agents used for treatment for non-cardiovascular diseases were permitted during the nicorandil administration provided the dosage remained stable. The following baseline characteristics were determined: gender, age, height, body weight, and underlying disease. Hemodynamic parameters measured were heart rate (HR), SBP, and diastolic blood pressure (DBP). The following parameters were measured using a Swan-Ganz catheter or were calculated: PAWP, cardiac index (CI), stroke volume index (SVI), mean right atrial pressure (RAP), and total peripheral resistance (TPR). Each parameter was measured before, at 15 and 30 min, and at 1, 2, 4, and 6 h after the start of nicorandil administration. Adverse events were also monitored.
Statistical analysis Patients in the two studies who received nicorandil as a 0.2 mg/kg/5 min bolus injection followed by continuous infusion of 0.05, 0.10, or 0.20 mg/kg/h were included in the analysis. Statistics are presented as mean ± standard deviation (SD) or mean ± standard error (SE). The baseline characteristics of each group were analyzed using the 2 test or one-way analysis of variance (one-way ANOVA). Hemodynamic parameters were analyzed by compiling the changes
293 over time for each dosage and performing one-way repeated measures ANOVA followed by the Least-Squares Means (LSMeans) Tukey Honestly Significantly Different (HSD) test. Percent changes in hemodynamic parameters at 6 h after administration of nicorandil were analyzed using the paired t-test and the Jonckheere trend test. Intergroup comparison of percent change in PAWP by baseline characteristics was performed using one-way ANOVA. The relationships of percent changes at 6 h after administration of 0.20 mg/kg/h nicorandil between CI and SVI, and CI and TPR were analyzed using Pearson’s correlation analysis. Changes in blood pressure at 15 min were analyzed after dividing all the patients according to increments of 20 mm Hg of SBP before nicorandil administration (baseline SBP) using the paired t-test. There was no statistical difference in distribution of each dose among the baseline SBP levels, and it was demonstrated that the peripheral vasodilating effect of nicorandil with bolus injection lasted for 15 min (data are not shown). Therefore, all the data were pooled to evaluate the influence of bolus injection on blood pressure for subanalysis. An adverse reaction was defined as an adverse event for which a causal relationship with the study drug could not be ruled out. The number of occurrences and the incidence were determined for each adverse reaction. A two-sided significance level of 15% was used for the analyses of patient characteristics, and a two-sided significance level of 5% was used for the other analyses. Statistical analyses were performed using JMP (JMP version 7.0.1, SAS Institute Japan, Tokyo, Japan).
Results Patient baseline characteristics Table 1 shows baseline characteristics of the study patients. Of the 99 patients eligible for analysis, 31 were females, the mean age was 67.1 ± 11.0 years, and 35 patients had new-onset of acute heart failure. The principal underlying diseases were as follows: ischemic heart disease, 40 patients; valvular disease, 22 patients; hypertension, 15 patients; and dilated cardiomyopathy, 18 patients. Intergroup differences were observed for gender, body weight, and number of patients with valvular disease, but no significant difference among the groups was observed for any of the other characteristics. Before the initiation of nicorandil administration, all the patients in all three groups had received early treatment for heart failure including oxygen inhalation therapy, and 81.8% had been treated with drugs. Baseline values for hemodynamic parameters are presented in Table 2. PAWP and CI values for the entire patient group were 25.7 ± 6.4 mm Hg and 2.47 ± 0.94 L/min/m2 , respectively. An intergroup difference was observed for RAP, but not for any of the other parameters.
Changes in pulmonary artery wedge pressure and cardiac index over time The time course of PAWP is plotted in Fig. 2, and the percent changes in PAWP at 6 h are shown in Table 3. When nicorandil was administered as a 0.2 mg/kg/5 min
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Figure 1
Table 1
Distribution of patients.
Baseline characteristics of study population. Mean ± SD/total (%)
Bolus (mg/kg/5 min)
0.2
p Value
Infusion (mg/kg/h)
0.05
0.10
0.20
N Gender Female Body weight (kg) (Mean ± SD) Age (y) (Mean ± SD) Principal underlying disease Ischemic heart disease Valvular disease Hypertension Dilated cardiomyopathy Other diseases Type of heart failure New-onset of acute heart failure Forrester subset II/IV Previous medications ACEI/ARB Calcium antagonists -Blockers Nitrates Human atrial natriuretic peptide Digitalis Catecholamines Other inotropic agents Diuretics Concomitant drugs Absent Present Baseline SBP (mm Hg) ≤100 101—120 121—140 141—160 161<
28
37
34
99 (100)
12
5
14
31 (31.3)
0.013
55.8 ± 11.4
62.0 ± 12.2
57.3 ± 12.0
58.6 ± 12.1
0.090
67.5 ± 11.4
65.9 ± 12.6
68.1 ± 9.0
67.1 ± 11.0
0.692
14 3 4 6 1
16 7 5 9 0
10 12 6 3 3
40 (40.4) 22 (22.2) 15 (15.2) 18 (18.2) 4 (4.0)
0.234 0.057 0.879 0.208 0.167
8
14
13
35 (35.4)
0.675
14/14
19/18
21/13
54/45
0.577
9 7 0 12 1 8 1 3 18
6 7 3 15 1 11 3 3 24
9 5 1 12 1 14 2 1 19
24 (24.2) 19 (19.2) 4 (4.0) 39 (39.4) 3 (3.0) 33 (33.3) 6 (6.1) 7 (7.1) 61 (61.6)
0.310 0.591 0.239 0.819 0.979 0.486 0.749 0.470 0.697
2 26
8 29
8 26
18 (18.2) 81 (81.8)
0.198
1 6 7 9 5
3 12 9 9 4
4 8 9 10 3
8 (8.2) 25 (25.5) 25 (25.5) 28 (28.6) 12 (12.2)
0.885
Each value represents the number of patients or mean ± SD. ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor antagonists; SBP, systolic blood pressure. Statistical analyses were performed by ANOVA or the 2 test.
lNicorandil in acute decompensated heart failure Table 2
295
Baseline hemodynamics in patients with acute decompensated heart failure.
Bolus (mg/kg/5 min)
0.2
Infusion (mg/kg/h)
0.05
0.10
0.20
N PAWP (mm Hg) CI (L/min/m2 ) SVI (mL/beat/m2 ) SBP (mm Hg) DBP (mm Hg) TPR (dyn s cm−5 ) HR (beat/min) RAP (mm Hg) PRP (mm Hg beat/min)
28 27.1 ± 6.3 2.36 ± 0.67 27.0 ± 8.3 142 ± 27 82 ± 13 2141 ± 681 91 ± 18 8.26 ± 3.63 12944 ± 3901
37 25.0 ± 6.6 2.45 ± 0.96 28.9 ± 12.7 134 ± 31 77 ± 16 1803 ± 618 89 ± 21 11.03 ± 5.84 12000 ± 4159
34 25.3 ± 6.3 2.57 ± 1.12 29.9 ± 17.4 131 ± 22 75 ± 14 1894 ± 916 93 ± 24 9.97 ± 5.70 12217 ± 4239
Total
p Value
99 25.7 ± 6.4 2.47 ± 0.94 28.7 ± 13.5 135 ± 27 77 ± 15 1928 ± 755 91 ± 21 9.90 ± 5.34 12341 ± 4093
0.403 0.681 0.701 0.297 0.158 0.200 0.772 0.122 0.643
Each value represents the mean ± SD. Statistical analyses were performed by ANOVA. PAWP, pulmonary artery wedge pressure; CI, cardiac index; SVI, stroke volume index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TPR, total peripheral resistance; HR, heart rate; RAP, mean right atrial pressure; PRP, pressure rate product.
bolus injection followed by continuous infusion of 0.05, 0.10, or 0.20 mg/kg/h, PAWP was significantly decreased compared to the baseline from 15 min to 6 h at all three doses. With 0.20 mg/kg/h, the post-bolus PAWP decrease was maintained until 6 h. At doses of 0.05, 0.10, and 0.20 mg/kg/h, the percent change in PAWP at 6 h was −16.7 ± 16.0% (p < 0.001), −20.5 ± 17.4% (p < 0.001), and −26.5 ± 21.9% (p < 0.001), respectively, which represented dose-dependent decreases (p = 0.023). The course of CI over time is plotted in Fig. 2, and the percent changes in CI at 6 h are shown in Table 3. CI was increased immediately after a nicorandil bolus injec-
Figure 2 Effect of nicorandil on pulmonary artery wedge pressure (PAWP) and cardiac index (CI) in patients with acute decompensated heart failure. Each point and bar represents the mean ± SE. : 0.2 mg/kg/5 min + 0.05 mg/kg/h, 䊉: 0.2 mg/kg/5 min + 0.10 mg/kg/h, : 0.2 mg/kg/5 min + 0.20 mg/kg/h. *p < 0.05 vs pre-value (repeated measures ANOVA and LSMeans Tukey HSD test).
tion of 0.2 mg/kg/5 min in every group, but the change was maintained thereafter only with 0.20 mg/kg/h. At doses of 0.05, 0.10, and 0.20 mg/kg/h, the percent increase in CI at 6 h was 6.8 ± 34.6%, 8.3 ± 20.9% (p = 0.026), and 15.8 ± 32.1% (p = 0.010), respectively, which represented dose-dependent increases (p = 0.032).
Changes in other hemodynamic parameters over time The time course of the other hemodynamic parameters is also plotted in Fig. 3, and the percent changes at 6 h are given in Table 3. SBP was significantly decreased at 15 min, and this decrease was maintained for 6 h with 0.10 mg/kg/h and 0.20 mg/kg/h. Mean changes in SBP were −5.9 ± 7.3 mm Hg and −7.4 ± 11.0 mm Hg at 15 min and 6 h with 0.10 mg/kg/h, and −6.3 ± 12.8 mm Hg and −11.5 ± 14.6 mm Hg at 15 min and 6 h with 0.20 mg/kg/h, respectively. There was no clinically excessive decrease in SBP throughout the administration. DBP, TPR and RAP had significant decreases at 15 min, and these changes were maintained for 6 h with 0.10 mg/kg/h and 0.20 mg/kg/h. HR did not change significantly in any group during the administration. Pressure rate product (PRP) decreased significantly at 6 h with 0.10 mg/kg/h and 0.20 mg/kg/h. The percent changes in SVI, SBP, TPR, and PRP at 6 h were significantly dose-dependent as were those of PAWP and CI. However, there was no significant dose-dependent change in RAP, since the change reached a plateau at 0.10 mg/kg/h (Table 3). The relationships of percent changes between CI and SVI, and CI and TPR at 6 h with 0.20 mg/kg/h of nicorandil are shown in Fig. 4. Positive significant correlation between CI and SVI (R = 0.901, p < 0.001), and negative correlation between CI and TRP (R = −0.806, p < 0.001) were observed.
Changes in blood pressure at 15 min Fig. 5 shows changes in SBP and DBP at 15 min in patients divided according to increments of 20 mm Hg in the baseline SBP. There was no significant decrease in SBP at
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Table 3 Percent change in hemodynamic parameters at 6 h after administration of nicorandil in patients with acute decompensated heart failure. Bolus (mg/kg/5 min)
0.2
p Value
Infusion (mg/kg/h)
0.05
0.10
0.20
PAWP CI SVI SBP DBP TPR HR RAP PRP
−16.7 ± 16.0** 6.8 ± 34.6 4.9 ± 31.7 −1.6 ± 8.1 −2.3 ± 11.9 −1.6 ± 21.0 2.0 ± 11.4 −5.6 ± 23.6 0.3 ± 12.7
−20.5 ± 17.4** 8.3 ± 20.9* 13.1 ± 25.5** −5.1 ± 7.8** −8.0 ± 17.5* −9.9 ± 19.7** −2.7 ± 13.3 −13.5 ± 40.6 −7.8 ± 14.5**
−26.5 ± 21.9** 15.8 ± 32.1* 18.6 ± 37.3** −7.9 ± 10.6** −8.8 ± 10.8** −13.8 ± 27.5** −1.0 ± 9.4 −11.6 ± 45.9 −8.9 ± 13.6**
0.023 0.032 0.039 0.003 0.053 0.009 0.294 0.089 0.005
Each value represents the mean ± SD of percent change. ‘‘p value’’ obtained by Jonckheere analysis. Abbreviations are defined in Table 2. * p < 0.05 vs pre-value (paired t-test). ** p < 0.01 vs pre-value (paired t-test).
15 min when the baseline SBP was 120 mm Hg or below, while a significant decrease was detected with baseline SBP values over 120 mm Hg. The mean change in SBP in patients with baseline SBP greater than 160 mm Hg was
−22.7 ± 20.3 mm Hg (p = 0.003). In contrast, DBP decreased significantly in patients with baseline SBP below 100 mm Hg to over 160 mm Hg, with the exception of 121—140 mm Hg baseline SBP.
Figure 3 Effect of nicorandil on hemodynamic parameters in patients with acute decompensated heart failure. Each point and bar represents the mean ± SE. : 0.2 mg/kg/5 min + 0.05 mg/kg/h, 䊉: 0.2 mg/kg/5 min + 0.10 mg/kg/h, : 0.2 mg/kg/5 min + 0.20 mg/kg/h. *p < 0.05 vs pre-value (repeated measures ANOVA and LSMeans Tukey HSD test). SBP, systolic blood pressure; HR, heart rate; DBP, diastolic blood pressure; SVI, stroke volume index; TPR, total peripheral resistance; PRP, pressure rate product; RAP, mean right atrial pressure.
lNicorandil in acute decompensated heart failure
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Figure 5 Acute effect of nicorandil on blood pressure according to baseline systolic blood pressure (SBP) in patients with acute decompensated heart failure. Each point and bar represents the mean ± SD. *p < 0.05, **p < 0.01 vs pre-value (paired t-test). DBP, diastolic blood pressure.
Figure 4 Regression analyses between cardiac index (CI) and stroke volume index (SVI) (A), and CI and total peripheral resistance (TPR) (B) using Pearson’s correlation analysis. Each point represents the percent change at 6 h with 0.20 mg/kg/h of nicorandil.
Safety There were 8 adverse reactions, including headache in 5 patients (5.1%) and decreased blood pressure, premature ventricular contraction, and ventricular tachycardia in one patient (1.0%) each. None of the adverse reactions was considered severe. Nicorandil treatment was not discontinued in any patient because of adverse reactions. No complications were caused by a Swan-Ganz catheter. No death during nicorandil administration was reported.
Discussion Results of the present investigation showed that intravenous nicorandil given to patients with ADHF as a bolus injection followed by continuous infusion reduced the preload and afterload immediately after the initiation of treatment and rapidly improved and stabilized hemodynamics in a dosedependent manner. Nicorandil was also administered safely in all patients during the study period without any severe adverse reactions. Because vasodilators rapidly improve hemodynamics, they are widely used along with diuretics to treat acute
heart failure [17]. In the ESC guidelines [2], use of vasodilators to treat ADHF is recommended when pulmonary congestion is present and if SBP is greater than 90 mm Hg. The ESC guidelines also suggest that early reperfusion treatment may be effective in ADHF in patients with underlying acute coronary syndrome. Three dosage groups were included in the present analysis; in those groups, nicorandil was administered as a 0.2 mg/kg/5 min bolus injection followed by continuous infusion of 0.05, 0.10, or 0.20 mg/kg/h. Significant differences among the three dosage groups were observed for gender, body weight, and number of patients with valvular disease. However, differences in response attributable to gender were not observed (data not shown). Differences in body weight were inconsequential, since the dosages were specified according to body weight. Furthermore, the percent decrease in PAWP in patients with underlying valvular heart disease did not differ significantly from the percent decrease in other patients. Accordingly, the influence of the differences in baseline characteristics was thought to be small. In the current investigation, bolus injection of nicorandilinduced rapid improvement in PAWP and CI; with continuous infusion, particularly at 0.20 mg/kg/h, these changes were maintained throughout the treatment. As stated earlier, nicorandil monotherapy has been reported to improve hemodynamics in chronic congestive heart failure when administered as a single intravenous injection [14] or as a continuous infusion [15,16]. Giles et al. [14] reported that single intravenous doses of nicorandil improved hemodynamics immediately after administration. Because rapid hemodynamic improvement in the acute phase is essential in the treatment of ADHF, loading of nicorandil with bolus intravenous administration would be favored in this clinical setting. Nicorandil significantly increased CI and SVI, and decreased TPR, while nicorandil did not change HR. The change in CI was significantly positively correlated with that of SVI, and significantly negatively correlated with that of TPR. In a canine acute heart failure model, nicorandil increased stroke volume, which was accompanied by a marked decrease in left ventricular end-systolic volume
298 [18]. Therefore, it is suggested that the nicorandil-induced increases in CI and SVI were mainly associated with afterload reduction. Nicorandil has been found to act by two mechanisms, a KATP channel opening action and a nitrate-like action in a canine heart failure model [19]. KATP channel opening agents mainly dilate arteries but do not affect veins [19,20], and their direct action on cardiac function is weak [6,21]. It is reported that the KATP channel opening action of nicorandil is considered to be predominant in dilating arteries, since the effects of nicorandil in decreasing peripheral resistance and increasing cardiac output were inhibited by the KATP channel blocker glibenclamide in a canine heart failure model [18]. However, which mechanisms lead to improvement in CI are unknown in ADHF patients, and further investigations are needed to clarify this issue. Nicorandil improves hemodynamics as a potent balanced vasodilator with combined dilation of both arterial and venous systems via both KATP channel opening and nitrate-like actions, thus increasing CI and reducing PAWP. A decrease in PAWP was observed with the lowest infusion rate of nicorandil (0.05 mg/kg/h), and RAP decreased and reached a plateau with the middle infusion rate (0.10 mg/kg/h), suggesting that there is a component of nitrate-like action at lower doses of nicorandil as reported by Giles et al. [14]. A decrease in TPR and increases in CI and SVI were observed at the higher infusion rate of nicorandil (0.20 mg/kg/h). In addition, secondary changes in cardiac function caused by preload and afterload reduction could contribute to the hemodynamic improvement. Therefore, it is apparent that nicorandil can reduce preload in lower infusion rates of 0.05—0.10 mg/kg/h, but for further improvement in the afterload and CI, a higher infusion rate of 0.20 mg/kg/h would be more appropriate. Nicorandil significantly decreased blood pressure immediately with bolus injection. This decrease was maintained during the infusion while an excessive decrease in blood pressure did not occur. Decreased blood pressure was reported as an adverse reaction in only one patient in this investigation, and it was not severe. Therefore, we evaluated the effect of nicorandil on blood pressure, dividing the baseline SBP according to increments of 20 mm Hg. Nicorandil did not decrease SBP significantly in patients with low to normal SBP, while it did decrease SBP remarkably in patients with an elevated baseline SBP. In addition, nicorandil also decreased DBP significantly in patients over almost all the SBP range including lower SBP, suggesting that nicorandil predominantly dilates peripheral resistant vessels subsequent to maintaining cardiac output and SBP. These results coincide well with the report by Minami et al. [22] that nicorandil decreased blood pressure in subjects with a high baseline blood pressure. Elevated blood pressure in patients with ADHF generated by excessively high vessel tone, which is activated by the sympathetic nervous system and renin—angiotensin—aldosterone system, may be involved in the pathology of ADHF. In such cases, nicorandil could lead the relaxation of vascular smooth muscle and could decrease blood pressure. To clarify the precise mechanism of nicorandil on blood pressure in ADHF, further study is needed. Nicorandil decreased PRP significantly at 6 h in the present investigation, suggesting that decreased myocar-
K. Tanaka et al. dial oxygen consumption may contribute to improvement in heart failure. Miura et al. [23] reported that nicorandil inhibits the release of norepinephrine from ischemic myocardium, and Giles et al. [14] reported that a single intravenous administration of nicorandil improved hemodynamics without concomitant tachycardia or an increase in plasma catecholamines. Whether or not nicorandil similarly affects release of catecholamines with continuous infusion in ADHF is a subject for future investigation.
Study limitations The present investigation consisted of two separate protocols. One of the two studies was conducted in an open manner, and thus the bias of patient selection is not fully excluded. Since the studies were conducted to evaluate the efficacy of nicorandil in any type of ADHF, no limitation for a principal underlying disease or cardiac function was established in patient enrollment. Therefore, the number of patients was not sufficient to analyze the efficacy of nicorandil on hemodynamics for each principal underlying disease. The prescription rates of ACE inhibitors/ARBs and -blockers were 24.2% and 4.0% respectively since the studies were conducted between 1995 and 2000 when these drugs were not fully established treatments for chronic heart failure. It is recommended that future studies be carried out in a large number of ADHF patients, which would include a control group, measurement of neurohormones, evaluation of effects on coronary perfusion and myocardial injury, and assessment of outcomes such as mortality and rehospitalization.
Conclusions In patients with ADHF, intravenous administration of nicorandil by bolus injection followed by continuous infusion improves PAWP and CI immediately and continuously as a potent vasodilator with combined preload and afterload reduction, via the dual mechanism of KATP channel opening and nitrate-like actions. These findings indicate that nicorandil could be an effective and beneficial new medication for the treatment of ADHF.
Acknowledgments The clinical studies were conducted to support the supplementary approval of nicorandil for acute heart failure in Japan and were sponsored by Chugai Pharmaceutical Co. Ltd.
Appendix A. Institutes and investigators that participated in the clinical studies: Asahikawa City Hospital (Kunihiko Hirasawa), Iwate Medical University Memorial Heart Center (Kenichi Fukami), Iwate Medical University (Katsuhiko Hiramori), Nippon Medical School Chiba Hokusoh Hospital (Keiji Tanaka), Jichi Medical School Omiya Medical Center (Nobuhiro Ohmura), Nihon University School of Medicine Itabashi Hospital (Katsuo
lNicorandil in acute decompensated heart failure Kanmatsuse, Satoshi Saito), Nippon Medical School Hospital (Teruo Takano, Keiji Tanaka), The Cardiovascular Institute Hospital (Kazuo Kato, Haruki Ito), Tokyo Women’s Medical University Heart Institute of Japan (Hiroshi Kasanuki), Sakakibara Heart Institute (Tetsuya Sumiyoshi), Showa University Hospital (Mikitaka Murakami, Takashi Katagiri), Showa University Fujigaoka Hospital (Youichi Takeyama), St. Marianna University School of Medicine Hospital (Masayoshi Sakakibara), Tokai University Hospital (Shunnosuke Handa), Toyama Medical and Pharmaceutical University Hospital (Hiroshi Inoue, Hidetsugu Asanoi), Shiga University of Medical Science Hospital (Masahiko Kinoshita), Kyoto University Hospital (Shigetake Sasayama, Hideo Otani), Osaka Police Hospital (Kazuhisa Kodama), Osaka City General Hospital (Kazuo Haze), Sakurabashi Watanabe Hospital (Kenshi Fujii), National Cardiovascular Center (Hiroshi Nonogi), Komatsushima Red Cross Hospital (Yoshikazu Hiasa), Yamaguchi University Hospital (Masunori Matsuzaki), Saiseikai Fukuoka General Hospital (Yusuke Yamamoto), Saiseikai Kumamoto Hospital (Kazuya Hayasaki, Takashi Honda), and Ryukyu University Hospital (Hisashi Yoshida).
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