ORIGINAL R ESEARCH AR TICLE
Effect of Nicorandil in Patients with Heart Failure: A Systematic Review and Meta-Analysis Fujie Zhao, Sandip Chaugai, Peng Chen, Yan Wang & Dao Wen Wang Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Keywords Hypertension; Ischemic heart disease; Molecular cardio-biology; Vascular biology. Correspondence Dao Wen Wang, M.D., Ph.D., Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China Tel.: (86-27)8366-2826 Fax: (86-27)8366-2826 E-mail: [email protected]
doi: 10.1111/1755-5922.12097
SUMMARY Background and purpose: It is unclear whether nicorandil, a metabolic therapeutic drug, can be applied clinically to therapy of heart failure (HF). This meta-analysis evaluated therapeutic effects of nicorandil on HF patients. Experimental approach: We performed a systematic review and meta-analysis of published studies evaluating effect of nicorandil on HF patients. Studies were stratified according to controlled versus uncontrolled designs and analyzed using random-effects meta-analysis models. Key results: We identified a total of 20 studies with a total of 1222 patients. In five randomized controlled studies, nicorandil treatment resulted in reduction in all-cause mortality and hospitalization for cardiac causes (HR: 0.35, P < 0.001) and improved cardiac pump function (SMD: 0.31, P = 0.02). In 15 observational studies, nicorandil therapy increases cardiac pump function (SMD: 0.75, P < 0.001), improves NYHA functional class (WMD: 1.33, P < 0.001), decreases PCWP (WMD: 6.86 mm Hg, P < 0.001), and pulmonary arterial pressure (SMD: 0.84, P < 0.001). Conclusions and implications: The use of nicorandil in HF patients exerts substantial beneficial effects, suggesting that it may be an additional therapeutic agent for HF.
Introduction Heart Failure (HF) represents a raising health care concern in developed and developing countries, reaching epidemic proportions [1]. About 1–2% of adult population in developed countries suffers HF, with ≥10% prevalence among elderly (>70 years) [2]. Heart failure is generally a chronic condition but can present acutely with pulmonary edema, cardiogenic shock, or decompensation of CHF requiring emergency care. Vasodilators remain the conventional treatment for urgent care of patients with heart failure. Nicorandil, a nicotinamide derivative, is a recently developed vasodilator with potent coronary and peripheral vascular activity and has been used as a novel antianginal agent. It has a nitrate component and it is also a sarcolemmal ATP-sensitive potassium channels (K-ATP) opener. Nicorandil thus has a dual mechanism of vasodilation, which increases coronary blood flow and reduces preload and afterload, and has been shown to have antianginal efficacy similar to other traditional drugs. Besides, experimental studies have shown that nicorandil exerted cardioprotective effects through opening mitochondrial ATP-dependent potassium channels by reducing oxidative damage [3,4], preserving ATP production [4], preventing cytochrome c release [4], modulating neutrophil properties [5], enhancing the production of prostacyclin (PGI2) [6], accelerating Na+ recovery [7], and attenuating the mitochondrial Ca2+ overload with accompanying depolarization of the mitochondrial membrane [8]. On the other hand, opening of
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sarcolemmal ATP-dependent potassium channels may also show cardioprotective effects by abbreviating excitability such that calcium overload and energy consumption would be attenuated [9]. In addition, many other effects of nicorandil on cardiovascular system have been investigated, such as anti-inflammatory and antiproliferative effects [10], antiapoptosis [4,11–14], antiischemic and antiinfract [15–17], antiarrhythmic [18–20], improving microvascular circulation [21,22], protecting endothelial function [13,23], especially protecting mitochondrial function [4] and energy-modulating function [6,24,25]. Cumulative evidences suggest that nicorandil has several beneficial effects on the myocardium and is promising for therapy of heart failure. Therefore, we hypothesized that nicorandil offers myocardial protection and is able to improve cardiac function and be used for therapy of heart failure. However, there is still no large-scale, multicenter RCT on the effects of nicorandil in patients with heart failure, so this systematic review and meta-analysis were performed to estimate the effects of nicorandil treatment on patients with heart failure.
Results Study Selection and Characteristics The flow of selecting studies for this systematic review and metaanalysis is shown in Figure 1. Briefly, of the initial 2907 hits, 113 articles were retrieved for detailed evaluation, and 20 articles
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Figure 1 Search flow diagram for studies included in the systematic review and meta-analysis.
including a total of 21 trials (D€ oring G. et al. study [26] included two different trials) were finally included in our systematic review, encompassing 1222 patients. In Akihiro Shirakabe [27] and Takahisa Yamada [28] studies, some patients were included in both the controlled and uncontrolled study analyses, but they were only included once in any given analysis, and so, there was no overlap in patients included in our meta-analyses. Some studies [27–34] either they were designed with an inappropriate control or only data about the nicorandil group could be extracted, although they were RCT, we still treated them as observational studies without a control group. Table 1 summarizes the design and methods of the included studies. There were five randomized controlled trials [27,28,35–37] (n = 271), three observational study with a control group [38–40] (n = 587) (i.e., controlled studies), and 12 observational studies without a control group [26,29–34,41–45] (n = 391) (i.e., uncontrolled studies). Table 2 summarizes the baseline characteristics of the included study subjects. The risk of bias was low in the majority of studies, with a detailed assessment available in Table 3 and 4.
All-Cause Mortality and Hospitalization for Cardiac Causes In controlled studies, treatment with nicorandil was associated with a statistically significant 65% reduction in all-cause mortality and hospitalization for cardiac causes (HR: 0.35, 95% CI: 0.16– 0.54, P < 0.001; Figure 2) (three trials, 663 patients included, with a mean follow-up of 1.6 years). The degree of heterogeneity in the treatment effect across all trials was low (I2: 47.2%) and nonsignificant (P = 0.128).
Cardiac Structure and Function n controlled studies, the results indicated that nicorandil therapy was superior to control therapy in terms of cardiac pump function
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improvement (SMD: 0.31, P = 0.02; Figure 3A.a). Additionally, nicorandil therapy tended to decrease pulmonary capillary wedge pressure (PCWP) (WMD: 3.23 mm Hg, 95% CI: 8.18 to 1.72 mm Hg, P = 0.20; Figure 3A.b),left ventricular diastolic diameter (LVDd) (WMD: 3.67 mm, P = 0.12; Figure 3A.c), end diastolic volume (EDV) (WMD: 6.33 mL, P = 0.54; Figure 3A.d), and end systolic volume (ESV) (WMD: 9.28 mL, P = 0.32; Figure 3A.e). Furthermore, echocardiography results indicated that nicorandil therapy significantly decreased the ratio of early transmitral diastolic velocity to early diastolic mitral annular tissue Doppler (E/Ea) (WMD: 4.64, 95% CI: 8.24 to 1.04, P = 0.01; Figure 3A.f), increased deceleration time of early transmitral diastolic velocity (DcT) (WMD: 19.95 ms, 95% CI: 3.51– 36.39 ms, P = 0.02; Figure 3A.g), and tended to reduce early transmitral diastolic velocity (E) (WMD: 6.17 cm/s, P = 0.16; Figure 3A.h) and increase early diastolic mitral annular measured by tissue Doppler (Ea) (WMD: 0.32 cm/s, P = 0.27; Figure 3A.i). This meant nicorandil therapy can improve left ventricular diastolic function. In uncontrolled studies, the results also indicated that nicorandil therapy was superior to control therapy in terms of cardiac pump function improvement (SMD: 0.75, P < 0.001; Figure 3B.a) and reducing PCWP (WMD: 6.86 mm Hg, 95% CI: 8.10 to 5.61 mm Hg, P < 0.001; Figure 3B.b). Furthermore, nicorandil therapy was similarly found to reduce right atrial pressure (RAP) (WMD: 1.27 mm Hg, 95% CI: 2.38 to 0.16 mm Hg, P = 0.03; Figure 3B.c).
Functional Capacity In uncontrolled studies, nicorandil treatment significantly improved NYHA functional class (WMD: 1.33, 95% CI: 1.83 to 0.83, P < 0.001; Figure 3C). The degree of heterogeneity in the treatment effect across all trials was modest (I2: 59.0%) but nonsignificant (P = 0.12).
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Retrospective Cohort Prospective Cohort
1990
2012
2011
2012
2014
1987
2009
, et al. [35] Galie
Masahito, et al. [36]
Masahito, et al. [37]
Observational control studies Ishihara, et al. [38.] Kasama, et al. [39]
Yokota, et al. [40]
Observational studies Minami, et al. [41] Tanaka, et al. [42]
1992
1994
1995
1997
2013
NR 2005
Tsutamoto, et al. [29]
Tsutamoto, et al. [30]
Larsen, et al. [31]
Hattori, et al. [32]
Choi, et al. [33] Kasama, et al. [34]
1992
1992
Giles, et al. [45]
€ring, et al. [26] Do Study 2
€ring, et al. [26] Do Study 1
RCT
2009
2010
RCT
2010
Randomized control trials Shirakabea, et al. [27] Yamadaa, et al. [28]
Prospective Cohort Prospective Cohort
Prospective Cohort
Prospective Cohort
Prospective Cohort
Before-and-after Comparison Prospective Cohort
Prospective Cohort
Before-and-after Comparison Before-and-after comparison Prospective Cohort
Prospective Cohort
RCT
RCT
RCT
Type of study
Year
Study/First author (Ref. #)
Table 1 Characteristics of all included studies
Academic Report Article
Article
Article
Article
Article
Article
Article
Article
Article
Article
Article
Article
Conference Abstract Conference Abstract Article
Conference Abstract Article
Article
Publication type
Nicorandil 21 Nicorandil 18
Nicorandil 19
Nicorandil 20
Nicorandil 7
Nicorandil 14
Nicorandil 12
Nicorandil 56
Nicorandil 54
Nicorandil 99
Nicorandil 14
Nicorandil + BT 85 Nicorandil 9
Nicorandil + ST 43 Nicorandil + ST 59 Nicorandil + BT 78
Nicorandil 9
Nicorandil 11
Nicorandil 16
Experiment group/Patients (n)
BT 85 Placebo 6 No N/A No N/A Isosorbide Mononitrate N/A Isosorbide Dinitrate N/A No N/A GTN N/A GTN N/A GTN N/A Carperitide N/A Placebo N/A Isosorbide Mononitrate N/A
Placebo 11 Placebo 9 ST 48 ST 59 BT 324
NR 15
Control group/ Patients (n)
AHF
I.V 0.1–0.2 mg/kgb + 0.1 mg/kg/h
AHF
I.V 0.2 mg/kgb + 0.05 mg/kg/h or 0.10 mg/kg/h or 0.20 mg/kg/h Oral 40 mg/day
I.V the average dose of 0.161 mg/kg/h. I.V 0.2 mg/kgb + 0.20 mg/kg/h Oral 15 mg/day
I.V0.158 mg/kg or 0.630 mg/kg bolus administration I.V the average dose of 0.144 mg/kg/h I.V the average dose of 0.192 mg/kg/h I.V doses were not fixed
Oral 30 mg/day or 60 mg/day
AHF
I.V 0.2 mg/kgb + 0.20 mg/kg/h
AHF CHF
AHF
CHF
CHF
CHF
CHF
CHF
CHF
CHF
Oral 15 mg/day
CHF
AHF
I.V 0.2 mg/kgb + 0.2 mg/kg/h
Oral 15 mg/day
AHF
CHF
I.V 0.2 mg/kgb + 0.2 mg/kg/h
Oral 40 mg/day or 60 mg/day
CHF
AHF
I.V 0.1 mg/kgb + 0.06–0.1 mg/kg/h
Oral 30 mg/day
Type of HF
Nicorandil (dose and administration route)
48 h, 1 month 6 months
48 h
24 h
24 h
24 h
6h
8 weeks
10 weeks
6h
48 h
6 months, 0.78–7.48 year Unclear
3 h, 1 day, 7 day, 180 day
1, 24 h
1 h, 24 h, 60 day
1, 3 day
3 years
1, 3, 7 day
Length of follow-up
0.00 0.00
0.00
0.00
0.00
0.00
0.00
3.57
1.85
0.00
0.00
0.00
0.00
0.00
0.00
3.30
0.00
0.00
9.68
Nonresponder rate, %
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AHF I.V only 0.2 mg/kg bolus administration Abstract 2012 Fukushima, et al. [44]
Before-and-after Comparison
2011 Kunishige, et al. [43]
Values are mean SD or %; asome data in this study were used in the observational studies’ meta-analysis; group; NR, not reported; bintravenous bolus injection; ST, standard therapy; BT, basic therapy; AHF, acute heart failure; CHF, chronic heart failure; N/A, not available; GTN, nitroglycerine.
NR
0.00
2 day, 14 days and 6 months 30 min, 2 days AHF I.V dose not reported
GTN N/A No N/A Nicorandil 10 Nicorandil 20 Abstract Prospective Cohort
Type of HF Nicorandil (dose and administration route) Control group/ Patients (n) Experiment group/Patients (n) Publication type Type of study Year Study/First author (Ref. #)
Table 1 (Continued)
Length of follow-up
Nonresponder rate, %
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Blood Pressure and Heart Rate In controlled studies, nicorandil treatment resulted in significant changes in systolic blood pressure (SBP) (WMD: 5.87 mm Hg, 95% CI: 10.04 to 1.70 mm Hg; P = 0.006; Figure 3D.a), diastolic blood pressure (DBP) (WMD: 6.61 mm Hg, 95% CI: 11.38 to 1.84 mm Hg; P = 0.007; Figure 3D.b), and mean blood pressure (MBP) (WMD: 7.46 mm Hg, 95% CI: 11.78 to 3.14; P < 0.001; Figure 3D.c), whereas no significant differences were observed in heart rate (WMD: 0.74 beats/min, P = 0.77; Figure 3D.d). In uncontrolled studies, nicorandil treatment also resulted in significant changes in SBP (WMD: 7.96 mm Hg, 95% CI: 10.99 to 4.94 mm Hg; P < 0.001; Figure 3E.a), DBP (WMD: 2.36 mm Hg, 95% CI: 2.89 to 1.84 mm Hg; P < 0.001; Figure 3E.b), and MBP (WMD: 7.92 mm Hg, 95% CI: 11.89 to 3.95; P < 0.001; Figure 3E.c), whereas no significant differences were observed in heart rate (WMD: 1.29 beats/min, P = 0.18; Figure 3E.d). Additional, nicorandil therapy also reduced pulmonary arterial pressure (SMD: 0.84, P < 0.001; Figure 3E.e) and peripheral resistance (SMD: 0.64, P = 0.006; Figure 3E.f).
Serum Biomarkers In controlled studies, nicorandil treatment tended to reduce serum biomarker for heart failure, B-type natriuretic peptide (BNP) (WMD: 111.46 pg/mL; P = 0.43; Figure 3F.a). In uncontrolled studies, BNP level was downregulated by nicorandil treatment (SMD: 1.09, P < 0.001; Figure 3F.b). Matrix metalloproteinases (MMPs) (including MMP-2 and MMP-9) level was also downregulated by nicorandil treatment (SMD: 1.18, P = 0.04; Figure 3F.c).
Myocardial Microvascular Circulation The total defect score (TDS), evaluated by 123I-MIBG (Kasama S et al.) or by 99 m Tc-MIBI (Fukushima Y et al.), is known to represent a microvascular dysfunction. Nicorandil therapy significantly improved TDS (WMD: 6.81, 95% CI: 12.67 to 0.94, P = 0.02; Figure 3G).
Sensitivity Analyses Sensitivity analyses were performed on all the variables included, but no significant results were found.
Discussion We have conducted the first systematic review and meta-analysis to evaluate the therapeutic effect of nicorandil on patients with HF. We found that use of nicorandil in HF patients may exert markedly beneficial effects, not only in improving cardiac pump function, NYHA functional class, left ventricular diastolic function, myocardial microvascular circulation, but in reducing allcause mortality and hospitalization for cardiac causes, pulmonary capillary wedge pressure, right atrial pressure, and systolic blood pressure, diastolic blood pressure, mean blood pressure, pulmonary arterial pressure, peripheral resistance, and reducing serum
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68.69 60.32 68.75 90.91 NR NR 80.00 74.00 NR 72.22 NR 68.42
8.00 10.00
11.00 8.54 6.93 4.10 16.84 18.52 10.40 16.00
60.00 100.00 71.43
68.00 11.00 47.00 12.68 73.90 11.80 67.10 62.90 60.50 63.00 61.50 62.00 63.00 69.00 NR 62.00 74.00 67.00
NR 44.00 49.00 52.54 39.70
4.00 11.60 11.80 9.80
NR 52.20 75.80 75.20 79.60
71.00
Male (%)
70.10 13.00
Age (years)
2.90 NR NR NR 3.70 3.40 3.00 4.00 3.26 2.67 NR NR 0.87 0.49
0.75 0.53
1.00
2.82 0.66 2.20 0.41 4.00 NR NR NR NR NR 30.00 26.00 35.00 NR 33.00 NR NR 6.00
7.94 7.00 15.00
42.00 9.00 NR 35.00 16.00
36.40 8.90 30.10 2.80 NR NR 46.50 16.2
0.50 0.50 0.53 0.58 0.16
2.10 2.67 3.75 3.73 3.03
38.50 13.30
EF (%)
3.84 0.37
NYHA Functional class
15.15 NR NR NR NR NR NR 63.00 NR NR NR NR
53.50 NR 78.57
NR NR 74.80 73.75 75.6
22.58
HBP (%)
Basic disease
18.18 NR NR NR NR NR 20.00 NR NR NR NR NR
NR NR NR
NR NR NR NR NR
12.90
Dilated cardiomyopathy (%)
Values are mean SD or %; NYHA, New York Heart Association; EF, ejection fraction; HBP, hypertension; DM, diabetes mellitus; NR, not reported.
Randomized control trials Shirakabe*, et al. [27] Yamada*, et al. [28] Gali e, et al. [35] Masahito, et al. [36] Masahito, et al. [37] Observational control studies Ishihara, et al. [38.] Kasama, et al. [39] Yokota, et al. [40] Observational studies Minami, et al. [41.] Tanaka, et al. [42] €ring, et al. [26] Study 1 Do €ring, et al. [26] Study 2 Do Giles, et al. [45] Tsutamoto, et al. [29] Tsutamoto, et al. [30] Larsen, et al. [31] Hattori, et al. [32] Choi, et al. [33] Kasama, et al. [34] Kunishige, et al. [43] Fukushima, et al. [44]
Study/First author (Reference)
Table 2 Baseline characteristics of the included study subjects
NR NR NR NR NR NR NR 42.00 NR NR NR NR
35.50 NR 42.86
NR NR 41.80 39.85 42.4
NR
DM (%)
40.40 100.00 100.00 NR NR NR 80.00 53.00 NR 100.00 NR 100.00
43.50 100.00 64.29
73.00 NR 20.00 18.65 44.9
45.00
Ischemic heart disease (%)
NR NR NR NR NR NR NR NR NR NR NR NR
38.00 NR NR
NR NR 28.55 26.25 NR
NR
Dyslipidemia (%)
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Table 3 Risk of bias analysis for randomized control studies
Bias
Authors’ judgment
Shirakabe, et al. 2010 [27] Random sequence generation (selection bias)
Unclear risk
Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias Gali e, et al. 1990 [35] Random sequence generation (selection bias)
Unclear risk Unclear risk Low Risk Low Risk Low Risk Low Risk
Unclear risk
Allocation concealment (selection bias)
Unclear risk
Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias)
Low Risk
Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias
Low Risk Low Risk Low Risk
Yamada, et al. 2009 [28] Random sequence generation (selection bias)
Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias Masahito, et al. 2012, [36] Random sequence generation (selection bias)
Low Risk
Unclear risk
Unclear risk Low Risk Unclear risk Low Risk Low Risk Low Risk Unclear risk
Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias)
Unclear risk Unclear risk
Selective reporting (reporting bias) Other bias
Low Risk Low Risk
288
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Unclear risk Low Risk
Support for judgment
Quote: The AHF patients were reciprocally randomized into either the nicorandil (n = 16) or the control group (n = 15). Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Comment: No information provided. Comment: No information provided. Comment: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding. Follow-up rate >90%. Report on all primary and secondary outcomes. No other sources of bias identified.
Quote: The sequence of administration of the 3 preparations was randomized and double blind. Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Quote: The sequence of administration of the 3 preparations was randomized and double blind. Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Quote: The sequence of administration of the 3 preparations was randomized and double blind. Quote: This double-blind, randomized, placebo-controlled trial. . . Comment: Blinding of outcome assessment was not described in detail, but the review authors judge that the outcome is not likely to be influenced by this. No patients lost to follow-up Report on all primary and secondary outcomes No other sources of bias identified
Patients were randomly assigned to receive nicorandil or placebo in a one-to-one ratio. Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Double blind with patient and clinician For the initial 6 months in a double-blinded fashion. Thereafter, this study was opened and patients were prospectively followed up for three years. No patients lost to follow-up Report on all primary and secondary outcomes No other sources of bias identified Patients were randomly assigned to receive standard therapy or nicorandil in addition to standard therapy group. Comment: No explanation of the generation of the randomization No description of whether allocation was adequately concealed Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Only 3 (3/91) patients did not attend the 60 days follow-up appointment either for withdrawing consent or missing a visit Report on all primary and secondary outcomes No other sources of bias identified
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Table 3 (Continued)
Bias
Authors’ judgment
Masahito, et al. 2011 [37] Random sequence generation (selection bias)
Unclear risk
Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias
Support for judgment
Unclear risk Unclear risk
Patients were randomly assigned to receive standard therapy or nicorandil in addition to standard therapy group in a one-to-one ratio. Comment: No description of the generation of the randomization No description of whether allocation was adequately concealed Comment: Insufficient information to permit judgment of “Low risk” or “High risk”.
Unclear risk Low Risk Low Risk Low Risk
Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. No patients lost to follow-up Report on all primary and secondary outcomes No other sources of bias identified
Table 4 Bias assessment of cohort and uncontrolled studies Study, year, (Reference)
Selection
Minami et al., 2009, [41] Tanaka et al., 2010, [42] €ring, et al., 1992, [26] Do Giles, et al., 1992, [45] Shirakabe et al., 2010, [27] Yamada, et al., 2009, [28] Tsutamoto, et al., 1994, [29] Tsutamoto, et al., 1995, [30] Larsen, et al., 1997, [31] Hattori, et al., 2013, [32] Choi’ study, [33] Kasama, et al., 2005, [34] Ishihara, et al., 2012, [38] Kasama, et al., 2014, [39] Yokota, et al., 1987, [40] Kunishige, et al., 2011, [43] Fukushima, et al., 2012, [44]
☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆☆ ☆☆☆☆ ☆☆☆ ☆☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆☆ ☆☆☆☆ ☆☆☆
Comparability
☆☆ ☆☆
☆☆ ☆☆ ☆☆ ☆☆ ☆☆ ☆
Outcome ☆☆☆ ☆☆☆ ☆☆☆ ☆☆ ☆☆ ☆☆☆ ☆☆ ☆☆ ☆☆ ☆☆☆ ☆☆ ☆☆☆ ☆☆ ☆☆ ☆☆ ☆☆ ☆☆
level of BNP and matrix metalloproteinases, which are biomarker for heart failure, indicating that it may be an additional therapeutic agent for HF. Besides, as reported by Fukushima [44], intravenous injection of nicorandil improves myocardial perfusion not only in the myocardial segments with coronary stenosis, but also in the myocardial segments without coronary stenosis. These results suggest that nicorandil might improve the myocardial microcirculation in both ischemic and nonischemic heart failure. The reduction of preload and afterload was the effect of nicorandil as a vasodilator through nitrate-like and ATP-sensitive potassium-channel activating properties. In addition, it is noteworthy that nicorandil also exerts cardioprotective effects and energymodulating function by reducing oxidative damage [3,4], preserving ATP production [4], and protecting mitochondrial function [4]. It seems plausible that the amelioration effects may finally translate into mechanical efficiency and contribute to the improvement of cardiac function, ameliorating clinical symptoms and long-term prognosis of patients with heart failure. Further-
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more, it seems reasonable that the BNP level could be downregulated by nicorandil treatment. Considering that the BNP level is negatively related to the alteration of cardiac structure and function [46], it seems reasonable to presume that nicorandil may play beneficial roles, not only in improvement of hemodynamics but also in cardiac remodeling. Furthermore, compared with nitroglycerin, nicorandil is associated with less hemodynamic tolerance and is safer [29–31]. In addition, Further, recent studies found that nicorandil not only improves the cardiac function but also preserves kidney function and decreases mortality in acute heart failure patients with preexisting renal dysfunction [36,47,48]. This may provide a unique niche to nicorandil in heart failure therapy.
Study Limitations First, most of the included studies were observational in nature and thus may be affected by confounding by indication and/or selection bias. Second, there were differences in patients’ type of heart failure, differences in time to treatment success evaluation within the different studies, differences in nicorandil administration (dose and route), and differences in patients’ characteristics among included studies, and all these factors might influenced the overall results of this systematic review and meta-analysis. However, with the use of published aggregate data, we were unable to examine the effect of nicorandil in patient subgroups or do metaregression analyses to evaluate these factors. Third, inclusion was restricted to published studies and may therefore be affected by publication bias. Fourth, twenty-seven years of clinical experience and medical therapy progress have been included into this analysis [34,40]; therefore, significant changes in treatment strategy might have influenced the overall results of this meta-analysis. Finally, but importantly, lack of large-scale and long-term RCTs for evaluating the impact of nicorandil treatment on patients with heart failure might be a fetal flaw of this meta-analysis. In conclusion, the use of nicorandil in HF patients can exert beneficial effects, not only in ameliorating clinical symptoms, hemodynamic effects, myocardial microvascular circulation, and cardiac structure and function, but in reducing all-cause mortality and hospitalization for cardiac causes, indicating that it may be an additional therapeutic agent for HF. Additional well-designed and
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Figure 2 All-cause mortality and hospitalization for cardiac causes. In controlled studies, treatment with nicorandil was associated with a statistically significant 65% reduction in all-cause mortality and hospitalization for cardiac causes (HR: 0.35, 95% CI: 0.16 0.54, P < 0.001).
long-term follow-up studies that include more diverse patient populations to further support the protective effects of nicorandil on cardiac function in patients with heart failure, especially in chronic heart failure, are needed.
Methods Data Sources and Search Strategy We performed a systematic review and meta-analysis in accordance with the standards set forth by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement [49,50]. We searched PubMed, EMBASE, the Cochrane Collaboration database, Wiley online library, and ISI Web of Science using the terms “nicorandil”, “KATP channel openers”, “sigmart”, “SG-75″, “heart failure”, “cardiac dysfunction”, “cardiac insufficiency”, “cardiac inadequacy”, “cardiomyopathy”, “cardiovascular disease”, “clinical trials”, and “patient analysis”. The search was not restricted to any language. In addition, we hand-searched references of retrieved articles and used PubMed’s related articles feature to identify studies not captured by our primary search strategy. We also try to get some articles or original data by author contact. The final search was run on January 25, 2014.
Study Selection We included randomized controlled trials (RCTs), observational controlled studies, and observational uncontrolled studies. Inclusion criteria were as follows: (1) all the patients included were clearly diagnosed as having heart failure and (2) follow-up rate of >85%. Reviews, animal studies, case reports, editorials, and letters were excluded. Once full articles or abstracts were
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retrieved, studies that met the following criteria were further excluded: (1) irrelevant study design; (2) no access to either the full-text or abstracts for quality assessment and data extraction; (3) indeterminate title/abstract; and (4) there was an overlap in patients with another study within the same analysis (in which case, the larger sample size of the 2 studies was selected). Thus, whereas some patients could possibly have been included in both the controlled and uncontrolled study analyses, they were only included once in any given analysis. Consequently, there was no overlap in patients included in our meta-analyses.
Data Extraction and Quality Assessment Data were extracted in duplicate by two independent reviewers (Drs. Zhao and Chaugai). Disagreements were resolved by consensus. For controlled studies, mean value and standard deviation of the outcome measurements in each intervention group (nicorandil group and control group), and number of participants on whom the outcome was measured in each intervention group were extracted. For uncontrolled studies, mean value and standard deviation, and number of participants for a given measure before and after nicorandil treatment were extracted. If the outcome measurements or baseline measurements were not reported, they were calculated from the differences in changes from baseline under the guidance of Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0. To determine the quality of the included studies, we used the Cochrane Collaboration Risk of Bias Tool (Table 3 and 4) for the five randomized control trials and the Newcastle–Ottawa scale for the observational studies. We set a followup rate of >85% as a limit to determine high risks of bias at follow-up for studies evaluated with the Newcastle–Ottawa scale in the outcome section of this scale (Table 1).
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A a
b
c
d
e
f
g
h
i
Figure 3 Beneficial effects of nicorandil on ameliorating clinical symptoms, improving left ventricular function and hemodynamics. (A) Beneficial effects of nicorandil on improvement in cardiac structure and function in controlled studies. A.a, cardiac pump function; A.b, pulmonary capillary wedge pressure (PCWP); A.c, left ventricular diastolic diameter (LVDd); A.d, end diastolic volume (EDV); A.e, end systolic volume (ESV); A.f, the ratio of early transmitral diastolic velocity to early diastolic mitral annular tissue Doppler (E/Ea); A.g, deceleration time of early transmitral diastolic velocity (DcT); h, early transmitral diastolic velocity (E); i, early diastolic mitral annular tissue Doppler (Ea). (B) Beneficial effects of nicorandil on improvement in cardiac structure and function in uncontrolled studies. B.a, cardiac pump function; B.b, pulmonary capillary wedge pressure (PCWP); B.c, right atrial pressure (RAP). (C). Beneficial effects of nicorandil on improvement in NYHA functional class in uncontrolled studies. (D) Beneficial effects of nicorandil on blood pressure and heart rate in controlled studies. D.a, systolic blood pressure (SBP); D.b, diastolic blood pressure (DBP); D.c, MBP; D.d, heart rate. (E) Beneficial effects of nicorandil on blood pressure and heart rate in uncontrolled studies. E.a, systolic blood pressure (SBP); E.b, diastolic blood pressure (DBP); E.c, mean blood pressure (MBP); E.d, heart rate; E.e, pulmonary arterial pressure; E.f, peripheral resistance. (F) Beneficial effects of nicorandil on serum markers. F.a, change in B-type natriuretic peptide (BNP) in controlled studies. F.b, change in BNP in uncontrolled studies; F.c, change in matrix metalloproteinases (MMPs) in uncontrolled studies. (G) Beneficial effects of nicorandil on improving myocardial microvascular circulation in uncontrolled studies.
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Figure 3 Continued.
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Figure 3 Continued.
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Figure 3 Continued.
Data Synthesis and Statistical Analysis For both controlled studies and uncontrolled studies, the measurement data were pooled across studies and analyzed using random-effects meta-analysis models with inverse variance weighting. In case some variables were too few to do meta-analysis, we combined some variables together and used as one new variable. For example, we defined a new variable cardiac pump function meaning ejection fraction (EF) or cardiac index (CI) or cardiac output (CO). Similarly, variable pulmonary arterial pressure was used as a representation of mean pulmonary arterial pressure or pulmonary arterial systolic pressure (PASP), and a new variable peripheral resistance to represent total peripheral resistance (TPR) or systemic vascular resistance (SVR) or systemic vascular resistance index (SVRI). All these new variables were analyzed using standardized mean differences (SMD). We chose to pool the results of the studies based on the study design. Hence, the randomized controlled trials were pooled with the controlled cohort studies, and the uncontrolled observational studies were pooled together. Observational studies tend to overestimate treatment effects by confounding by indication. The magnitude of heterogeneity present was estimated using the I2statistic, an estimate of the proportion of the total observed variance, that is, attributed to between-study variance. To compare the effect of nicorandil based on pretreatment systolic blood pressure (SBP), we constructed a separate meta-analysis stratified by systolic blood pressure using a random-effects generic inverse
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variance-weighting model to compare heterogeneity using the I2statistic. In the study by Minami et al. [41], the only measure of variability reported was interquartile range. By including this study in the meta-analysis models, we are assuming a normal distribution of change in B-type natriuretic peptide (BNP). Besides, Tanaka et al. study [42], D€ oring G. et al. study 2 [26], and Thomas D. Giles. et al. study [45]were designed as parallel study, although they were used more than once in one meta-analysis, they were based on different population. That is to say, there was no overlap in patients included in our meta-analyses. Sensitivity analyses (exclusion of 1 study at a time) were performed to determine the stability of the overall treatment effects. All p values were 2-tailed, and the statistical significance was set at 0.05. Throughout, values are presented as mean SD unless otherwise stated. All statistical analyses were performed using RevMan 5.0 (The Cochrane Collaboration, Copenhagen, Denmark) and STATA software 12.0 (Stata Corp, College Station, TX, USA).
Study Highlights What is the Current Knowledge on the Topic? With the progress of various treatment methods, heart failure is still a major potential threat to human health. Nicorandil, a recently developed vasodilator and metabolic therapeutic drug, has been
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Nicorandil and Therapy of Heart Failure
used as a novel antianginal agent. But its cardioprotective effect on heart failure patients has not been well evaluated.
How this Might Change Clinical Pharmacology and Therapeutics?
What Question this Study Addressed?
Nicorandil may be an additional therapeutic agent for HF patients.
We performed a systematic review and meta-analysis of published studies to evaluate the effect of nicorandil on HF patients.
Acknowledgments
What this Study Adds to Our Knowledge?
This work was supported by National Basic Research Programs (No. 2012CB518004 and 2014CB541601). The authors thank Drs. Chaugai and Chen for data extraction and statistical analysis. Many thanks to all those who helped us.
The use of nicorandil in HF patients exerts beneficial effects, including ameliorating clinical symptoms, improving left ventricular function, and reducing all-cause mortality and hospitalization for cardiac causes, indicating that it may be an additional therapeutic agent for HF.
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Conflict of Interest The authors declared no conflict of interest.
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Effect of Nicorandil in Patients with Heart Failure: A Systematic Review and Meta-Analysis Fujie Zhao, Sandip Chaugai, Peng Chen, Yan Wang & Dao Wen Wang Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Keywords Hypertension; Ischemic heart disease; Molecular cardio-biology; Vascular biology. Correspondence Dao Wen Wang, M.D., Ph.D., Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China Tel.: (86-27)8366-2826 Fax: (86-27)8366-2826 E-mail: [email protected]
doi: 10.1111/1755-5922.12097
SUMMARY Background and purpose: It is unclear whether nicorandil, a metabolic therapeutic drug, can be applied clinically to therapy of heart failure (HF). This meta-analysis evaluated therapeutic effects of nicorandil on HF patients. Experimental approach: We performed a systematic review and meta-analysis of published studies evaluating effect of nicorandil on HF patients. Studies were stratified according to controlled versus uncontrolled designs and analyzed using random-effects meta-analysis models. Key results: We identified a total of 20 studies with a total of 1222 patients. In five randomized controlled studies, nicorandil treatment resulted in reduction in all-cause mortality and hospitalization for cardiac causes (HR: 0.35, P < 0.001) and improved cardiac pump function (SMD: 0.31, P = 0.02). In 15 observational studies, nicorandil therapy increases cardiac pump function (SMD: 0.75, P < 0.001), improves NYHA functional class (WMD: 1.33, P < 0.001), decreases PCWP (WMD: 6.86 mm Hg, P < 0.001), and pulmonary arterial pressure (SMD: 0.84, P < 0.001). Conclusions and implications: The use of nicorandil in HF patients exerts substantial beneficial effects, suggesting that it may be an additional therapeutic agent for HF.
Introduction Heart Failure (HF) represents a raising health care concern in developed and developing countries, reaching epidemic proportions [1]. About 1–2% of adult population in developed countries suffers HF, with ≥10% prevalence among elderly (>70 years) [2]. Heart failure is generally a chronic condition but can present acutely with pulmonary edema, cardiogenic shock, or decompensation of CHF requiring emergency care. Vasodilators remain the conventional treatment for urgent care of patients with heart failure. Nicorandil, a nicotinamide derivative, is a recently developed vasodilator with potent coronary and peripheral vascular activity and has been used as a novel antianginal agent. It has a nitrate component and it is also a sarcolemmal ATP-sensitive potassium channels (K-ATP) opener. Nicorandil thus has a dual mechanism of vasodilation, which increases coronary blood flow and reduces preload and afterload, and has been shown to have antianginal efficacy similar to other traditional drugs. Besides, experimental studies have shown that nicorandil exerted cardioprotective effects through opening mitochondrial ATP-dependent potassium channels by reducing oxidative damage [3,4], preserving ATP production [4], preventing cytochrome c release [4], modulating neutrophil properties [5], enhancing the production of prostacyclin (PGI2) [6], accelerating Na+ recovery [7], and attenuating the mitochondrial Ca2+ overload with accompanying depolarization of the mitochondrial membrane [8]. On the other hand, opening of
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sarcolemmal ATP-dependent potassium channels may also show cardioprotective effects by abbreviating excitability such that calcium overload and energy consumption would be attenuated [9]. In addition, many other effects of nicorandil on cardiovascular system have been investigated, such as anti-inflammatory and antiproliferative effects [10], antiapoptosis [4,11–14], antiischemic and antiinfract [15–17], antiarrhythmic [18–20], improving microvascular circulation [21,22], protecting endothelial function [13,23], especially protecting mitochondrial function [4] and energy-modulating function [6,24,25]. Cumulative evidences suggest that nicorandil has several beneficial effects on the myocardium and is promising for therapy of heart failure. Therefore, we hypothesized that nicorandil offers myocardial protection and is able to improve cardiac function and be used for therapy of heart failure. However, there is still no large-scale, multicenter RCT on the effects of nicorandil in patients with heart failure, so this systematic review and meta-analysis were performed to estimate the effects of nicorandil treatment on patients with heart failure.
Results Study Selection and Characteristics The flow of selecting studies for this systematic review and metaanalysis is shown in Figure 1. Briefly, of the initial 2907 hits, 113 articles were retrieved for detailed evaluation, and 20 articles
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Figure 1 Search flow diagram for studies included in the systematic review and meta-analysis.
including a total of 21 trials (D€ oring G. et al. study [26] included two different trials) were finally included in our systematic review, encompassing 1222 patients. In Akihiro Shirakabe [27] and Takahisa Yamada [28] studies, some patients were included in both the controlled and uncontrolled study analyses, but they were only included once in any given analysis, and so, there was no overlap in patients included in our meta-analyses. Some studies [27–34] either they were designed with an inappropriate control or only data about the nicorandil group could be extracted, although they were RCT, we still treated them as observational studies without a control group. Table 1 summarizes the design and methods of the included studies. There were five randomized controlled trials [27,28,35–37] (n = 271), three observational study with a control group [38–40] (n = 587) (i.e., controlled studies), and 12 observational studies without a control group [26,29–34,41–45] (n = 391) (i.e., uncontrolled studies). Table 2 summarizes the baseline characteristics of the included study subjects. The risk of bias was low in the majority of studies, with a detailed assessment available in Table 3 and 4.
All-Cause Mortality and Hospitalization for Cardiac Causes In controlled studies, treatment with nicorandil was associated with a statistically significant 65% reduction in all-cause mortality and hospitalization for cardiac causes (HR: 0.35, 95% CI: 0.16– 0.54, P < 0.001; Figure 2) (three trials, 663 patients included, with a mean follow-up of 1.6 years). The degree of heterogeneity in the treatment effect across all trials was low (I2: 47.2%) and nonsignificant (P = 0.128).
Cardiac Structure and Function n controlled studies, the results indicated that nicorandil therapy was superior to control therapy in terms of cardiac pump function
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improvement (SMD: 0.31, P = 0.02; Figure 3A.a). Additionally, nicorandil therapy tended to decrease pulmonary capillary wedge pressure (PCWP) (WMD: 3.23 mm Hg, 95% CI: 8.18 to 1.72 mm Hg, P = 0.20; Figure 3A.b),left ventricular diastolic diameter (LVDd) (WMD: 3.67 mm, P = 0.12; Figure 3A.c), end diastolic volume (EDV) (WMD: 6.33 mL, P = 0.54; Figure 3A.d), and end systolic volume (ESV) (WMD: 9.28 mL, P = 0.32; Figure 3A.e). Furthermore, echocardiography results indicated that nicorandil therapy significantly decreased the ratio of early transmitral diastolic velocity to early diastolic mitral annular tissue Doppler (E/Ea) (WMD: 4.64, 95% CI: 8.24 to 1.04, P = 0.01; Figure 3A.f), increased deceleration time of early transmitral diastolic velocity (DcT) (WMD: 19.95 ms, 95% CI: 3.51– 36.39 ms, P = 0.02; Figure 3A.g), and tended to reduce early transmitral diastolic velocity (E) (WMD: 6.17 cm/s, P = 0.16; Figure 3A.h) and increase early diastolic mitral annular measured by tissue Doppler (Ea) (WMD: 0.32 cm/s, P = 0.27; Figure 3A.i). This meant nicorandil therapy can improve left ventricular diastolic function. In uncontrolled studies, the results also indicated that nicorandil therapy was superior to control therapy in terms of cardiac pump function improvement (SMD: 0.75, P < 0.001; Figure 3B.a) and reducing PCWP (WMD: 6.86 mm Hg, 95% CI: 8.10 to 5.61 mm Hg, P < 0.001; Figure 3B.b). Furthermore, nicorandil therapy was similarly found to reduce right atrial pressure (RAP) (WMD: 1.27 mm Hg, 95% CI: 2.38 to 0.16 mm Hg, P = 0.03; Figure 3B.c).
Functional Capacity In uncontrolled studies, nicorandil treatment significantly improved NYHA functional class (WMD: 1.33, 95% CI: 1.83 to 0.83, P < 0.001; Figure 3C). The degree of heterogeneity in the treatment effect across all trials was modest (I2: 59.0%) but nonsignificant (P = 0.12).
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Retrospective Cohort Prospective Cohort
1990
2012
2011
2012
2014
1987
2009
, et al. [35] Galie
Masahito, et al. [36]
Masahito, et al. [37]
Observational control studies Ishihara, et al. [38.] Kasama, et al. [39]
Yokota, et al. [40]
Observational studies Minami, et al. [41] Tanaka, et al. [42]
1992
1994
1995
1997
2013
NR 2005
Tsutamoto, et al. [29]
Tsutamoto, et al. [30]
Larsen, et al. [31]
Hattori, et al. [32]
Choi, et al. [33] Kasama, et al. [34]
1992
1992
Giles, et al. [45]
€ring, et al. [26] Do Study 2
€ring, et al. [26] Do Study 1
RCT
2009
2010
RCT
2010
Randomized control trials Shirakabea, et al. [27] Yamadaa, et al. [28]
Prospective Cohort Prospective Cohort
Prospective Cohort
Prospective Cohort
Prospective Cohort
Before-and-after Comparison Prospective Cohort
Prospective Cohort
Before-and-after Comparison Before-and-after comparison Prospective Cohort
Prospective Cohort
RCT
RCT
RCT
Type of study
Year
Study/First author (Ref. #)
Table 1 Characteristics of all included studies
Academic Report Article
Article
Article
Article
Article
Article
Article
Article
Article
Article
Article
Article
Conference Abstract Conference Abstract Article
Conference Abstract Article
Article
Publication type
Nicorandil 21 Nicorandil 18
Nicorandil 19
Nicorandil 20
Nicorandil 7
Nicorandil 14
Nicorandil 12
Nicorandil 56
Nicorandil 54
Nicorandil 99
Nicorandil 14
Nicorandil + BT 85 Nicorandil 9
Nicorandil + ST 43 Nicorandil + ST 59 Nicorandil + BT 78
Nicorandil 9
Nicorandil 11
Nicorandil 16
Experiment group/Patients (n)
BT 85 Placebo 6 No N/A No N/A Isosorbide Mononitrate N/A Isosorbide Dinitrate N/A No N/A GTN N/A GTN N/A GTN N/A Carperitide N/A Placebo N/A Isosorbide Mononitrate N/A
Placebo 11 Placebo 9 ST 48 ST 59 BT 324
NR 15
Control group/ Patients (n)
AHF
I.V 0.1–0.2 mg/kgb + 0.1 mg/kg/h
AHF
I.V 0.2 mg/kgb + 0.05 mg/kg/h or 0.10 mg/kg/h or 0.20 mg/kg/h Oral 40 mg/day
I.V the average dose of 0.161 mg/kg/h. I.V 0.2 mg/kgb + 0.20 mg/kg/h Oral 15 mg/day
I.V0.158 mg/kg or 0.630 mg/kg bolus administration I.V the average dose of 0.144 mg/kg/h I.V the average dose of 0.192 mg/kg/h I.V doses were not fixed
Oral 30 mg/day or 60 mg/day
AHF
I.V 0.2 mg/kgb + 0.20 mg/kg/h
AHF CHF
AHF
CHF
CHF
CHF
CHF
CHF
CHF
CHF
Oral 15 mg/day
CHF
AHF
I.V 0.2 mg/kgb + 0.2 mg/kg/h
Oral 15 mg/day
AHF
CHF
I.V 0.2 mg/kgb + 0.2 mg/kg/h
Oral 40 mg/day or 60 mg/day
CHF
AHF
I.V 0.1 mg/kgb + 0.06–0.1 mg/kg/h
Oral 30 mg/day
Type of HF
Nicorandil (dose and administration route)
48 h, 1 month 6 months
48 h
24 h
24 h
24 h
6h
8 weeks
10 weeks
6h
48 h
6 months, 0.78–7.48 year Unclear
3 h, 1 day, 7 day, 180 day
1, 24 h
1 h, 24 h, 60 day
1, 3 day
3 years
1, 3, 7 day
Length of follow-up
0.00 0.00
0.00
0.00
0.00
0.00
0.00
3.57
1.85
0.00
0.00
0.00
0.00
0.00
0.00
3.30
0.00
0.00
9.68
Nonresponder rate, %
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AHF I.V only 0.2 mg/kg bolus administration Abstract 2012 Fukushima, et al. [44]
Before-and-after Comparison
2011 Kunishige, et al. [43]
Values are mean SD or %; asome data in this study were used in the observational studies’ meta-analysis; group; NR, not reported; bintravenous bolus injection; ST, standard therapy; BT, basic therapy; AHF, acute heart failure; CHF, chronic heart failure; N/A, not available; GTN, nitroglycerine.
NR
0.00
2 day, 14 days and 6 months 30 min, 2 days AHF I.V dose not reported
GTN N/A No N/A Nicorandil 10 Nicorandil 20 Abstract Prospective Cohort
Type of HF Nicorandil (dose and administration route) Control group/ Patients (n) Experiment group/Patients (n) Publication type Type of study Year Study/First author (Ref. #)
Table 1 (Continued)
Length of follow-up
Nonresponder rate, %
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Blood Pressure and Heart Rate In controlled studies, nicorandil treatment resulted in significant changes in systolic blood pressure (SBP) (WMD: 5.87 mm Hg, 95% CI: 10.04 to 1.70 mm Hg; P = 0.006; Figure 3D.a), diastolic blood pressure (DBP) (WMD: 6.61 mm Hg, 95% CI: 11.38 to 1.84 mm Hg; P = 0.007; Figure 3D.b), and mean blood pressure (MBP) (WMD: 7.46 mm Hg, 95% CI: 11.78 to 3.14; P < 0.001; Figure 3D.c), whereas no significant differences were observed in heart rate (WMD: 0.74 beats/min, P = 0.77; Figure 3D.d). In uncontrolled studies, nicorandil treatment also resulted in significant changes in SBP (WMD: 7.96 mm Hg, 95% CI: 10.99 to 4.94 mm Hg; P < 0.001; Figure 3E.a), DBP (WMD: 2.36 mm Hg, 95% CI: 2.89 to 1.84 mm Hg; P < 0.001; Figure 3E.b), and MBP (WMD: 7.92 mm Hg, 95% CI: 11.89 to 3.95; P < 0.001; Figure 3E.c), whereas no significant differences were observed in heart rate (WMD: 1.29 beats/min, P = 0.18; Figure 3E.d). Additional, nicorandil therapy also reduced pulmonary arterial pressure (SMD: 0.84, P < 0.001; Figure 3E.e) and peripheral resistance (SMD: 0.64, P = 0.006; Figure 3E.f).
Serum Biomarkers In controlled studies, nicorandil treatment tended to reduce serum biomarker for heart failure, B-type natriuretic peptide (BNP) (WMD: 111.46 pg/mL; P = 0.43; Figure 3F.a). In uncontrolled studies, BNP level was downregulated by nicorandil treatment (SMD: 1.09, P < 0.001; Figure 3F.b). Matrix metalloproteinases (MMPs) (including MMP-2 and MMP-9) level was also downregulated by nicorandil treatment (SMD: 1.18, P = 0.04; Figure 3F.c).
Myocardial Microvascular Circulation The total defect score (TDS), evaluated by 123I-MIBG (Kasama S et al.) or by 99 m Tc-MIBI (Fukushima Y et al.), is known to represent a microvascular dysfunction. Nicorandil therapy significantly improved TDS (WMD: 6.81, 95% CI: 12.67 to 0.94, P = 0.02; Figure 3G).
Sensitivity Analyses Sensitivity analyses were performed on all the variables included, but no significant results were found.
Discussion We have conducted the first systematic review and meta-analysis to evaluate the therapeutic effect of nicorandil on patients with HF. We found that use of nicorandil in HF patients may exert markedly beneficial effects, not only in improving cardiac pump function, NYHA functional class, left ventricular diastolic function, myocardial microvascular circulation, but in reducing allcause mortality and hospitalization for cardiac causes, pulmonary capillary wedge pressure, right atrial pressure, and systolic blood pressure, diastolic blood pressure, mean blood pressure, pulmonary arterial pressure, peripheral resistance, and reducing serum
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68.69 60.32 68.75 90.91 NR NR 80.00 74.00 NR 72.22 NR 68.42
8.00 10.00
11.00 8.54 6.93 4.10 16.84 18.52 10.40 16.00
60.00 100.00 71.43
68.00 11.00 47.00 12.68 73.90 11.80 67.10 62.90 60.50 63.00 61.50 62.00 63.00 69.00 NR 62.00 74.00 67.00
NR 44.00 49.00 52.54 39.70
4.00 11.60 11.80 9.80
NR 52.20 75.80 75.20 79.60
71.00
Male (%)
70.10 13.00
Age (years)
2.90 NR NR NR 3.70 3.40 3.00 4.00 3.26 2.67 NR NR 0.87 0.49
0.75 0.53
1.00
2.82 0.66 2.20 0.41 4.00 NR NR NR NR NR 30.00 26.00 35.00 NR 33.00 NR NR 6.00
7.94 7.00 15.00
42.00 9.00 NR 35.00 16.00
36.40 8.90 30.10 2.80 NR NR 46.50 16.2
0.50 0.50 0.53 0.58 0.16
2.10 2.67 3.75 3.73 3.03
38.50 13.30
EF (%)
3.84 0.37
NYHA Functional class
15.15 NR NR NR NR NR NR 63.00 NR NR NR NR
53.50 NR 78.57
NR NR 74.80 73.75 75.6
22.58
HBP (%)
Basic disease
18.18 NR NR NR NR NR 20.00 NR NR NR NR NR
NR NR NR
NR NR NR NR NR
12.90
Dilated cardiomyopathy (%)
Values are mean SD or %; NYHA, New York Heart Association; EF, ejection fraction; HBP, hypertension; DM, diabetes mellitus; NR, not reported.
Randomized control trials Shirakabe*, et al. [27] Yamada*, et al. [28] Gali e, et al. [35] Masahito, et al. [36] Masahito, et al. [37] Observational control studies Ishihara, et al. [38.] Kasama, et al. [39] Yokota, et al. [40] Observational studies Minami, et al. [41.] Tanaka, et al. [42] €ring, et al. [26] Study 1 Do €ring, et al. [26] Study 2 Do Giles, et al. [45] Tsutamoto, et al. [29] Tsutamoto, et al. [30] Larsen, et al. [31] Hattori, et al. [32] Choi, et al. [33] Kasama, et al. [34] Kunishige, et al. [43] Fukushima, et al. [44]
Study/First author (Reference)
Table 2 Baseline characteristics of the included study subjects
NR NR NR NR NR NR NR 42.00 NR NR NR NR
35.50 NR 42.86
NR NR 41.80 39.85 42.4
NR
DM (%)
40.40 100.00 100.00 NR NR NR 80.00 53.00 NR 100.00 NR 100.00
43.50 100.00 64.29
73.00 NR 20.00 18.65 44.9
45.00
Ischemic heart disease (%)
NR NR NR NR NR NR NR NR NR NR NR NR
38.00 NR NR
NR NR 28.55 26.25 NR
NR
Dyslipidemia (%)
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Table 3 Risk of bias analysis for randomized control studies
Bias
Authors’ judgment
Shirakabe, et al. 2010 [27] Random sequence generation (selection bias)
Unclear risk
Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias Gali e, et al. 1990 [35] Random sequence generation (selection bias)
Unclear risk Unclear risk Low Risk Low Risk Low Risk Low Risk
Unclear risk
Allocation concealment (selection bias)
Unclear risk
Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias)
Low Risk
Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias
Low Risk Low Risk Low Risk
Yamada, et al. 2009 [28] Random sequence generation (selection bias)
Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias Masahito, et al. 2012, [36] Random sequence generation (selection bias)
Low Risk
Unclear risk
Unclear risk Low Risk Unclear risk Low Risk Low Risk Low Risk Unclear risk
Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias)
Unclear risk Unclear risk
Selective reporting (reporting bias) Other bias
Low Risk Low Risk
288
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Unclear risk Low Risk
Support for judgment
Quote: The AHF patients were reciprocally randomized into either the nicorandil (n = 16) or the control group (n = 15). Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Comment: No information provided. Comment: No information provided. Comment: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding. Follow-up rate >90%. Report on all primary and secondary outcomes. No other sources of bias identified.
Quote: The sequence of administration of the 3 preparations was randomized and double blind. Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Quote: The sequence of administration of the 3 preparations was randomized and double blind. Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Quote: The sequence of administration of the 3 preparations was randomized and double blind. Quote: This double-blind, randomized, placebo-controlled trial. . . Comment: Blinding of outcome assessment was not described in detail, but the review authors judge that the outcome is not likely to be influenced by this. No patients lost to follow-up Report on all primary and secondary outcomes No other sources of bias identified
Patients were randomly assigned to receive nicorandil or placebo in a one-to-one ratio. Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Double blind with patient and clinician For the initial 6 months in a double-blinded fashion. Thereafter, this study was opened and patients were prospectively followed up for three years. No patients lost to follow-up Report on all primary and secondary outcomes No other sources of bias identified Patients were randomly assigned to receive standard therapy or nicorandil in addition to standard therapy group. Comment: No explanation of the generation of the randomization No description of whether allocation was adequately concealed Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. Only 3 (3/91) patients did not attend the 60 days follow-up appointment either for withdrawing consent or missing a visit Report on all primary and secondary outcomes No other sources of bias identified
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Table 3 (Continued)
Bias
Authors’ judgment
Masahito, et al. 2011 [37] Random sequence generation (selection bias)
Unclear risk
Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias
Support for judgment
Unclear risk Unclear risk
Patients were randomly assigned to receive standard therapy or nicorandil in addition to standard therapy group in a one-to-one ratio. Comment: No description of the generation of the randomization No description of whether allocation was adequately concealed Comment: Insufficient information to permit judgment of “Low risk” or “High risk”.
Unclear risk Low Risk Low Risk Low Risk
Comment: Insufficient information to permit judgment of “Low risk” or “High risk”. No patients lost to follow-up Report on all primary and secondary outcomes No other sources of bias identified
Table 4 Bias assessment of cohort and uncontrolled studies Study, year, (Reference)
Selection
Minami et al., 2009, [41] Tanaka et al., 2010, [42] €ring, et al., 1992, [26] Do Giles, et al., 1992, [45] Shirakabe et al., 2010, [27] Yamada, et al., 2009, [28] Tsutamoto, et al., 1994, [29] Tsutamoto, et al., 1995, [30] Larsen, et al., 1997, [31] Hattori, et al., 2013, [32] Choi’ study, [33] Kasama, et al., 2005, [34] Ishihara, et al., 2012, [38] Kasama, et al., 2014, [39] Yokota, et al., 1987, [40] Kunishige, et al., 2011, [43] Fukushima, et al., 2012, [44]
☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆☆ ☆☆☆☆ ☆☆☆ ☆☆☆☆ ☆☆☆ ☆☆☆ ☆☆☆☆ ☆☆☆☆ ☆☆☆
Comparability
☆☆ ☆☆
☆☆ ☆☆ ☆☆ ☆☆ ☆☆ ☆
Outcome ☆☆☆ ☆☆☆ ☆☆☆ ☆☆ ☆☆ ☆☆☆ ☆☆ ☆☆ ☆☆ ☆☆☆ ☆☆ ☆☆☆ ☆☆ ☆☆ ☆☆ ☆☆ ☆☆
level of BNP and matrix metalloproteinases, which are biomarker for heart failure, indicating that it may be an additional therapeutic agent for HF. Besides, as reported by Fukushima [44], intravenous injection of nicorandil improves myocardial perfusion not only in the myocardial segments with coronary stenosis, but also in the myocardial segments without coronary stenosis. These results suggest that nicorandil might improve the myocardial microcirculation in both ischemic and nonischemic heart failure. The reduction of preload and afterload was the effect of nicorandil as a vasodilator through nitrate-like and ATP-sensitive potassium-channel activating properties. In addition, it is noteworthy that nicorandil also exerts cardioprotective effects and energymodulating function by reducing oxidative damage [3,4], preserving ATP production [4], and protecting mitochondrial function [4]. It seems plausible that the amelioration effects may finally translate into mechanical efficiency and contribute to the improvement of cardiac function, ameliorating clinical symptoms and long-term prognosis of patients with heart failure. Further-
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more, it seems reasonable that the BNP level could be downregulated by nicorandil treatment. Considering that the BNP level is negatively related to the alteration of cardiac structure and function [46], it seems reasonable to presume that nicorandil may play beneficial roles, not only in improvement of hemodynamics but also in cardiac remodeling. Furthermore, compared with nitroglycerin, nicorandil is associated with less hemodynamic tolerance and is safer [29–31]. In addition, Further, recent studies found that nicorandil not only improves the cardiac function but also preserves kidney function and decreases mortality in acute heart failure patients with preexisting renal dysfunction [36,47,48]. This may provide a unique niche to nicorandil in heart failure therapy.
Study Limitations First, most of the included studies were observational in nature and thus may be affected by confounding by indication and/or selection bias. Second, there were differences in patients’ type of heart failure, differences in time to treatment success evaluation within the different studies, differences in nicorandil administration (dose and route), and differences in patients’ characteristics among included studies, and all these factors might influenced the overall results of this systematic review and meta-analysis. However, with the use of published aggregate data, we were unable to examine the effect of nicorandil in patient subgroups or do metaregression analyses to evaluate these factors. Third, inclusion was restricted to published studies and may therefore be affected by publication bias. Fourth, twenty-seven years of clinical experience and medical therapy progress have been included into this analysis [34,40]; therefore, significant changes in treatment strategy might have influenced the overall results of this meta-analysis. Finally, but importantly, lack of large-scale and long-term RCTs for evaluating the impact of nicorandil treatment on patients with heart failure might be a fetal flaw of this meta-analysis. In conclusion, the use of nicorandil in HF patients can exert beneficial effects, not only in ameliorating clinical symptoms, hemodynamic effects, myocardial microvascular circulation, and cardiac structure and function, but in reducing all-cause mortality and hospitalization for cardiac causes, indicating that it may be an additional therapeutic agent for HF. Additional well-designed and
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Figure 2 All-cause mortality and hospitalization for cardiac causes. In controlled studies, treatment with nicorandil was associated with a statistically significant 65% reduction in all-cause mortality and hospitalization for cardiac causes (HR: 0.35, 95% CI: 0.16 0.54, P < 0.001).
long-term follow-up studies that include more diverse patient populations to further support the protective effects of nicorandil on cardiac function in patients with heart failure, especially in chronic heart failure, are needed.
Methods Data Sources and Search Strategy We performed a systematic review and meta-analysis in accordance with the standards set forth by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement [49,50]. We searched PubMed, EMBASE, the Cochrane Collaboration database, Wiley online library, and ISI Web of Science using the terms “nicorandil”, “KATP channel openers”, “sigmart”, “SG-75″, “heart failure”, “cardiac dysfunction”, “cardiac insufficiency”, “cardiac inadequacy”, “cardiomyopathy”, “cardiovascular disease”, “clinical trials”, and “patient analysis”. The search was not restricted to any language. In addition, we hand-searched references of retrieved articles and used PubMed’s related articles feature to identify studies not captured by our primary search strategy. We also try to get some articles or original data by author contact. The final search was run on January 25, 2014.
Study Selection We included randomized controlled trials (RCTs), observational controlled studies, and observational uncontrolled studies. Inclusion criteria were as follows: (1) all the patients included were clearly diagnosed as having heart failure and (2) follow-up rate of >85%. Reviews, animal studies, case reports, editorials, and letters were excluded. Once full articles or abstracts were
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retrieved, studies that met the following criteria were further excluded: (1) irrelevant study design; (2) no access to either the full-text or abstracts for quality assessment and data extraction; (3) indeterminate title/abstract; and (4) there was an overlap in patients with another study within the same analysis (in which case, the larger sample size of the 2 studies was selected). Thus, whereas some patients could possibly have been included in both the controlled and uncontrolled study analyses, they were only included once in any given analysis. Consequently, there was no overlap in patients included in our meta-analyses.
Data Extraction and Quality Assessment Data were extracted in duplicate by two independent reviewers (Drs. Zhao and Chaugai). Disagreements were resolved by consensus. For controlled studies, mean value and standard deviation of the outcome measurements in each intervention group (nicorandil group and control group), and number of participants on whom the outcome was measured in each intervention group were extracted. For uncontrolled studies, mean value and standard deviation, and number of participants for a given measure before and after nicorandil treatment were extracted. If the outcome measurements or baseline measurements were not reported, they were calculated from the differences in changes from baseline under the guidance of Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0. To determine the quality of the included studies, we used the Cochrane Collaboration Risk of Bias Tool (Table 3 and 4) for the five randomized control trials and the Newcastle–Ottawa scale for the observational studies. We set a followup rate of >85% as a limit to determine high risks of bias at follow-up for studies evaluated with the Newcastle–Ottawa scale in the outcome section of this scale (Table 1).
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A a
b
c
d
e
f
g
h
i
Figure 3 Beneficial effects of nicorandil on ameliorating clinical symptoms, improving left ventricular function and hemodynamics. (A) Beneficial effects of nicorandil on improvement in cardiac structure and function in controlled studies. A.a, cardiac pump function; A.b, pulmonary capillary wedge pressure (PCWP); A.c, left ventricular diastolic diameter (LVDd); A.d, end diastolic volume (EDV); A.e, end systolic volume (ESV); A.f, the ratio of early transmitral diastolic velocity to early diastolic mitral annular tissue Doppler (E/Ea); A.g, deceleration time of early transmitral diastolic velocity (DcT); h, early transmitral diastolic velocity (E); i, early diastolic mitral annular tissue Doppler (Ea). (B) Beneficial effects of nicorandil on improvement in cardiac structure and function in uncontrolled studies. B.a, cardiac pump function; B.b, pulmonary capillary wedge pressure (PCWP); B.c, right atrial pressure (RAP). (C). Beneficial effects of nicorandil on improvement in NYHA functional class in uncontrolled studies. (D) Beneficial effects of nicorandil on blood pressure and heart rate in controlled studies. D.a, systolic blood pressure (SBP); D.b, diastolic blood pressure (DBP); D.c, MBP; D.d, heart rate. (E) Beneficial effects of nicorandil on blood pressure and heart rate in uncontrolled studies. E.a, systolic blood pressure (SBP); E.b, diastolic blood pressure (DBP); E.c, mean blood pressure (MBP); E.d, heart rate; E.e, pulmonary arterial pressure; E.f, peripheral resistance. (F) Beneficial effects of nicorandil on serum markers. F.a, change in B-type natriuretic peptide (BNP) in controlled studies. F.b, change in BNP in uncontrolled studies; F.c, change in matrix metalloproteinases (MMPs) in uncontrolled studies. (G) Beneficial effects of nicorandil on improving myocardial microvascular circulation in uncontrolled studies.
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Figure 3 Continued.
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E
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(a)
(b)
(c)
(d)
(e)
(f)
Figure 3 Continued.
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F
(a)
(b)
(c)
G
Figure 3 Continued.
Data Synthesis and Statistical Analysis For both controlled studies and uncontrolled studies, the measurement data were pooled across studies and analyzed using random-effects meta-analysis models with inverse variance weighting. In case some variables were too few to do meta-analysis, we combined some variables together and used as one new variable. For example, we defined a new variable cardiac pump function meaning ejection fraction (EF) or cardiac index (CI) or cardiac output (CO). Similarly, variable pulmonary arterial pressure was used as a representation of mean pulmonary arterial pressure or pulmonary arterial systolic pressure (PASP), and a new variable peripheral resistance to represent total peripheral resistance (TPR) or systemic vascular resistance (SVR) or systemic vascular resistance index (SVRI). All these new variables were analyzed using standardized mean differences (SMD). We chose to pool the results of the studies based on the study design. Hence, the randomized controlled trials were pooled with the controlled cohort studies, and the uncontrolled observational studies were pooled together. Observational studies tend to overestimate treatment effects by confounding by indication. The magnitude of heterogeneity present was estimated using the I2statistic, an estimate of the proportion of the total observed variance, that is, attributed to between-study variance. To compare the effect of nicorandil based on pretreatment systolic blood pressure (SBP), we constructed a separate meta-analysis stratified by systolic blood pressure using a random-effects generic inverse
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variance-weighting model to compare heterogeneity using the I2statistic. In the study by Minami et al. [41], the only measure of variability reported was interquartile range. By including this study in the meta-analysis models, we are assuming a normal distribution of change in B-type natriuretic peptide (BNP). Besides, Tanaka et al. study [42], D€ oring G. et al. study 2 [26], and Thomas D. Giles. et al. study [45]were designed as parallel study, although they were used more than once in one meta-analysis, they were based on different population. That is to say, there was no overlap in patients included in our meta-analyses. Sensitivity analyses (exclusion of 1 study at a time) were performed to determine the stability of the overall treatment effects. All p values were 2-tailed, and the statistical significance was set at 0.05. Throughout, values are presented as mean SD unless otherwise stated. All statistical analyses were performed using RevMan 5.0 (The Cochrane Collaboration, Copenhagen, Denmark) and STATA software 12.0 (Stata Corp, College Station, TX, USA).
Study Highlights What is the Current Knowledge on the Topic? With the progress of various treatment methods, heart failure is still a major potential threat to human health. Nicorandil, a recently developed vasodilator and metabolic therapeutic drug, has been
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used as a novel antianginal agent. But its cardioprotective effect on heart failure patients has not been well evaluated.
How this Might Change Clinical Pharmacology and Therapeutics?
What Question this Study Addressed?
Nicorandil may be an additional therapeutic agent for HF patients.
We performed a systematic review and meta-analysis of published studies to evaluate the effect of nicorandil on HF patients.
Acknowledgments
What this Study Adds to Our Knowledge?
This work was supported by National Basic Research Programs (No. 2012CB518004 and 2014CB541601). The authors thank Drs. Chaugai and Chen for data extraction and statistical analysis. Many thanks to all those who helped us.
The use of nicorandil in HF patients exerts beneficial effects, including ameliorating clinical symptoms, improving left ventricular function, and reducing all-cause mortality and hospitalization for cardiac causes, indicating that it may be an additional therapeutic agent for HF.
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Conflict of Interest The authors declared no conflict of interest.
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