International Journal of Cardiology 176 (2014) 661–669

Contents lists available at ScienceDirect

International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

All-cause mortality and cardiovascular events with nicorandil in patients with IHD: Systematic review and meta-analysis of the literature Bihui Luo a, Pingsheng Wu b,⁎, Tong Bu a, Zhaohua Zeng a, Dongfeng Lu a,⁎⁎ a b

Department of Cardiology, Cardiovascular Research Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China Department of Cardiovascular Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

a r t i c l e

i n f o

Article history: Received 16 November 2013 Received in revised form 12 May 2014 Accepted 5 July 2014 Available online 19 August 2014 Keywords: Nicorandil Ischemic heart disease All-cause mortality Cardiovascular events Meta-analysis

a b s t r a c t Background: Nicorandil is able to protect the cardiomyocytes from ischemic damage, but clear benefits of nicorandil in all-cause mortality and cardiovascular events were not consistently reported in patients with ischemic heart disease (IHD). Materials and results: Cochrane, PubMed, EMBASE, CBM, CNKI and Wangfang databases were searched for randomized controlled trials. Data on all-cause mortality and cardiovascular events were collected. Nicorandil groups were pooled to perform a comparison with control groups and to get the pooled odds ratios (ORs) and associated 95% confidence intervals (CIs) for all-cause mortality, relative risks (RRs), and associated 95% CIs for cardiovascular events. STATA 11.0 software was used for all-cause mortality and cardiovascular events statistics. We retrieved 17 randomized controlled studies enrolling a total of 7305 patients. The addition of nicorandil treatment significantly reduced cardiovascular events (13.83% versus 18.01%; RR, 0.77; 95% CI, 0.69 to 0.86). No differences in all-cause mortality (3.83% versus 4.70%; OR, 0.81; 95% CI, 0.64 to 1.02), and repeat revascularization rate (13.06% versus 13.54%; RR, 0.95; 95% CI, 0.70 to 1.29) were observed. There was a weak linear association between cardiovascular events and nicorandil in IHD with diabetes (P = 0.099). Conclusions: The results suggest that nicorandil as an adjunct therapy to IHD is associated with reduced cardiovascular events in patients with IHD. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Numerous studies suggest that coronary artery obstruction is a complex multifactorial pathophysiological process to induce ischemic heart disease (IHD). A more comprehensive approach seems necessary to refocus preventive and therapeutic strategies, and to decrease morbidity and mortality of IHD [1,2]. Nicorandil, a mitochondrial ATP-dependent potassium (KATP) channel opener, was recommended as an antianginal agent for relief of symptoms by the latest guideline for IHD (class IIa, level of evidence: B) [2,3]. However, in addition to relieving symptoms of ischemia, nicorandil has potential cardioprotective effects [4–6]. In a prospective, randomized control study of 5126 patients with chronic stable angina, the addition of nicorandil to standard therapy was found to produce a 17% relative risk (RR) reduction in the composite endpoint of IHD death, nonfatal MI, or unplanned hospital admission for cardiac chest pain ⁎ Correspondence to: Department of Cardiovascular Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China. Tel.: + 86 135 56174066; fax: +86 020 83062996. ⁎⁎ Correspondence to: Professor, Department of Cardiology and Cardiovascular Research Center, The First Affiliated Hospital of Guangzhou Medical College, Guangzhou, Guangdong, China, 510120. Tel.: +86 20 83062738. E-mail addresses: [email protected] (P. Wu), [email protected] (D. Lu).

http://dx.doi.org/10.1016/j.ijcard.2014.07.007 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

[4,5]. Nicorandil was therefore recommended to have both improved the symptoms of myocardial ischemia and preventedacute myocardial infarction (MI) and death, as indicated in the Guidelines for Secondary Prevention of Myocardial Infarction in Japan(class I, level of evidence: B) [6]. Nicorandil alone could protect the cardiomyocytes from ischemic damage, but the capability of nicorandil as an adjunctive treatment is still controversial. To support the development of coherent evidencebased guidance to inform future research and public health policy, we analyzed the existing randomized controlled trials relating adjunctive treatment with nicorandil to key clinical outcomes: all-cause mortality and cardiovascular events in patients with IHD. To our knowledge, this is the first meta-analysis of nicorandil treatment on the prognosis of patients with IHD. 2. Methods 2.1. Data sources and searches We searched all published studies that compared the efficacy of all-cause mortality and/or cardiovascular events in patients with IHD randomized to nicorandil groups or control group using the Cochrane Central Register of Controlled Trials, PUBMED, EMBASE, CBM, CNKI, and Wangfang electronic databases. The search strategy was developed without any language restriction by using medical subject headings and text words. The

662

B. Luo et al. / International Journal of Cardiology 176 (2014) 661–669

following medical subject heading terms were included for a MEDLINE search and adapted for other databases as needed: ( “nicorandil” OR “SG-75” OR “ikorel”) AND (“heart disease” OR “coronary disease” OR “myocardial ischemia”) AND (“death” OR “dead” OR “mortality” OR “endpoint” OR “outcome” OR “event”). In addition to searching databases, reference lists of all included studies, meta-analyses, and reviews were manually searched.

2.2. Study selection Two reviewers (Bihui Luo and Tong Bu) performed a study selection of this review independently, with disagreements solved through discussion and by the opinion of a third reviewer (Pingsheng Wu) if necessary. We defined cardiovascular events as death due to cardiovascular disease or one of the following events: myocardial infarction, acute coronary syndrome, and admission to hospital for unstable angina or coronary catheterization that resulted in angioplasty or coronary artery bypass surgery, or congestive heart failure. Studies were considered potentially eligible for this review if they met the following criteria: They were randomized controlled studies on nicorandil treatment in adult patients (≥18-year-olds) with IHD. Eligible trials have reported the outcomes of all-cause mortality and cardiovascular events. We excluded trials if nicorandil was also used in the control group.

2.3. Data extraction and quality assessment We extracted and presented data according to the Providing Innovative Service Models and Assessment (PRISMA) criteria [7,8]. Two reviewers (Bihui Luo and Tong Bu) independently extracted data on all studies (the authors of the literature, year of publication, design of the study), patient's characteristics (number of patients, mean age, sex), and the treatments (therapeutic indication, type of drug, dose, follow-up duration, etc.). Information on the following outcomes was collected in the 2 study groups: number of total all-cause mortality and cardiovascular events. If THE outcome data could not be identified or were not clear in the articles, we contacted the study authors by e-mail, with a reminder after two weeks. Two reviewers (Bihui Luo and Tong Bu) independently assessed study quality using a validated scale (according to the Jadad scoring method) based on the following criteria: methods used to generate the randomization sequence, methods of double blinding, and description of patient withdrawals and dropouts [9]. A score of 1 point was given for each criterion satisfied, and 1 additional point was given for high quality of randomization and double blinding. Studies with a score of N2 were considered high quality, and studies with a score ≤2 were considered of low quality. Although concealed treatment allocation is not part of this rating scale, it was included in our study quality assessment. We resolved disagreements about study data extraction by consensus or by discussion with a third reviewer (Pingsheng Wu).

2.4. Statistical analyses

2.4.3. Sensitivity analyses Sensitivity analyses were used to assess the robustness of our results by removing each included study at one time to obtain and evaluate the remaining overall estimates of cardiovascular events. 2.4.4. Subgroup analyses Subgroup analysis was used to investigate and identify the heterogeneity [10]. It was performed according to different sample size, country, Jadad score, duration of trials, and routes of administration.

3. Results 3.1. Study identification and selection We identified 604 potentially relevant studies: 225 from PUBMED, 297 from EMBASE, 2 from Cochrane Central Register of Controlled Trials, 16 from CBM, 32 from CNKI, 28 from Wangfang, and 4 through manual searches. All literatures were imported into reference management software Endnote. 571 studies were excluded through a review of titles and abstracts. The remaining 33 studies were retrieved in full-text for detailed evaluation. Among them, 17 studies were identified to match our inclusion criteria. A review of the reference lists of included studies did not provide any additional references. The study identification and selection progression are summarized in Fig. 1. 3.2. Study characteristics and study quality Baseline characteristics of patients included in the studies are summarized in Table 1. All of these studies were published in English (13 literatures) [4,17–28] or Chinese (4 literatures) [29–32]. They were published from 1999 to 2012 and varied in sample size. Study size was ranged from 42 patients to 5126 patients, for a total of 7305 included subjects. Duration of follow-up was ranged from 48 h to 5 years. In one study, hemodialysis patients after coronary revascularization were involved [18]. The proportion of diabetic patients with IHD was ranged from 7.8% to 59.4%. Patients who were concomitantly treated

604 potenally relevant arcles retrieved from all the databases

2.4.1. Primary analyses We determined pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for all-cause mortality. We also performed pooled relative risks (RRs) and corresponding 95% CIs for cardiovascular events in patients with IHD who received standard treatment with nicorandil or without nicorandil. It is important to consider to what extent the results of studies are consistent [10]. The Q test was used to evaluate heterogeneity between studies and we considered a threshold P value less than 0.1 as statistically significant. I2 statistic was also performed to evaluate the magnitude of the heterogeneity between studies. We considered I2 greater than 50% as substantial heterogeneity rather than sampling error [10,11]. We explored heterogeneity between studies by conducting sensitivity analyses, meta-regression and subgroup analyses [11]. A fixed-effects model (Mantel–Haenszel method) was used for analysis in the case of low or moderate heterogeneity among trials (I2 b 50%,P N 0.1) [12]. A random-effect (RE) model (DerSimonian–Laird method) was used for analysis in the case of high heterogeneity among trials (I2 ≥ 50%,P b 0.1) [13]. A value of P b 0.05 was considered statistically significant. All statistical analyses were performed using STATA 11.0 software (STATA Corp. College Station, TX, USA). For all the treatment effects that were statistically significant, we determined the absolute risk reduction (ARR) and the corresponding number needed to treat (NNT). Publication bias was estimated by the use of funnel plots and Egger's test. A value of P b 0.05 (two-sided) was considered to be statistically significant. The ‘trim and fill’ method was performed both to identify and correct for funnel plot asymmetry arising from publication bias [14].

298 arcles were excluded on the basis of the tle 184 repeated documents 34 review arcles 48 in vivo studies 23 pharmacokinecs 9 meta-analysis

306 potenal arcles retrieved for detailed assessment

187 arcles were excluded on the basis of the abstract 83 review arcles 65 non-RCT studies 4 case report 35 about gene examinaon

119 potenal arcles retrieved for detailed assessment

86 arcles were excluded due to out of scope/obviously different from study criteria 10 no nicorandil group 3 using isolated cardiac ssue from paent 25 repeated report about same studies 46 not about survival duraon and CVD events

33 potenal arcles retrieved

2 study for fetal bradycardia

for detailed assessment

2.4.2. Meta regression Univariable meta-regression was used for exploring heterogeneity when there were more than 10 trials in the meta-analysis [10,15]. Statistically significant P value was less than 0.1. We also applied Monte Carlo permutation test to calculate p-values in metaregression. All permutations were set at 10,000 shuffles and performed simultaneously across all covariates [16]. The following covariates were assessed: sample size; country; Jadad score; duration of trials; routes of administration; male proportion (%); and diabetic proportion(%). All statistical analyses were performed using STATA 11.0 software (STATA Corp. College Station, TX, USA).

22 arcles were excluded upon full-text review

17 arcles were finally included in the present meta-analysis

Fig. 1. Flow diagram of the trial selection process.

Table 1 Characteristics of included studies. Study

Year

Study design

Country

Population

Nicorandil group,n

Control group,n

Patients' characteristics Nicorandil/control Age,y

Sex, M/F, %

Stable angina, British patients Patients with AMI undergoing PCI, Japanese patients

5126

2565

2561

76.3/23.7

8.4

368

185

183

67 67 63 64

81.0/19.0

32.3

Maintenance hemodialysis patients who underwent PCI, Japanese patients Patients admitted with unstable angina, British patients Patients with AMI in Killip class I, Japanese patients

129

64

65

64.8 ± 9.7 67.2 ± 7.9

70.5/29.5

57.4

200

96

104

58.5 ± 9.6 61.3 ± 11.2

68.5/31.5

60

30

30

60 ± 9 63 ± 10

8 9 9.4 10.1

Control group

Duration of treatment

GDMT + nicorandil 20 mg bid

GDMT + identical placebo

GDMT + receive 12 mg of nicorandil intravenously just before reperfusion undergoing PCI. GDMT + oral administration of nicorandil, 15 mg/d.

GDMT + receive 100 ml of 0.9% saline intravenously just before reperfusion undergoing PCI. GDMT

1.6 y ± 0.5 Median 2.4 y ± 1.4 Median

11.5

GDMT + oral nicorandil 20 mg twice daily

GDMT + a matching placebo

2d

80.0/20.0

18.3

GDMT + nicorandil with a combination of intravenous drip infusion and intracoronary artery infusion immediately after angioplasty GDMT + injected 4 mg of nicorandil with the intracoronary injection of sonicated microbubbles followed by the infusion at 6 mg/h for 24 h and by oral nicorandil 15 mg/day GDMT + nicorandil with the intravenous injection for 48 h followed by oral nicorandil 10–15 mg/day GDMT + nicorandil 15 mg/d

GDMT + ISDN with a combination of intravenous drip infusion and intracoronary artery infusion immediately after angioplasty

3w

GDMT

25 d

GDMT + ISDN with the intravenous injection for 48 h followed by oral ISDN 80–160 mg/day

6m

GDMT + ISDN 40 mg/d

3m

GDMT + nicorandil given 2 mg intracoronary prior to CAG and an additional intracoronary dose of 2 mg nicorandil before stent implantation. GDMT + receive 12 mg of nicorandil intravenously just before reperfusion.

GDMT

30 d

GDMT + receive 100 ml of 0.9% saline intravenously just before reperfusion.

5y

GDMT + intravenous administration of 6 mg of nicorandil immediately before PCI GDMT + nicorandil injection followed by constant infusion at 8 mg/h for 24 h maintained for 24 h after PCI GDMT + nicorandil 5 mg tid

GDMT + intravenous administration of 20 ml of 0.9% saline immediately before PCI GDMT + without pretreatment with nicorandil

12 m

GDMT + ISMN 20 mg bid

2w

IONA[4]

2002

RCT

Britain

Ishii,H et al. [17]

2005

RCT

Japan

Nishimura,M et al. [18]

2009

RCT

Japan

Patel,D et al. [19]

1999

RCT

Britain

Ikeda,N et al. [20]

2004

RCT

Japan

Ito, H et al. [21]

1999

RCT

Japan

Patients with a first anterior AMI, Japanese patients

81

40

41

60 ± 10 60 ± 10

76.5/23.5

27.2

Kim, J et al. [22]

2005

RCT

South Korea

Patients with unstable angina, South Korean patients

96

42

54

60.4 ± 11.7 61.7 ± 8.2

61.5/38.5

11.5

Sekiya, M et al. [23]

2005

RCT

Japan

42

21

21

9.5

2008

RCT

South Korea

73

37

36

59 ± 7 58 ± 9 56.4 ± 13 60.2 ± 12

54.8/45.2

Lee, HC et al. [24]

Patients with ischemic heart disease, Japanese patients Patients with acute ST segment elevation MI,, South Korean patients

83.6/16.4

31.5

Ishii, H et al. [25]

2006

RCT

Japan

158

81

77

63 ± 9.3 64 ± 9.3

77.8/22.2

58.9

Kawai, Y et al. [26]

2009

RCT

Japan

364

185

179

70.5 ± 9.8 72 ± 10.55

85.2/14.8

45.1

Ono, H et al. [27]

2004

RCT

Japan

First AMI patients with stress hyperglycemia, Japanese patients Patients with AMI and unstable angina pectoris, and stable angina pectoris, Japanese patients Patients with AMI, Japanese patients

58

33

25

64 ± 13 66 ± 12

65.5/34.5

32.8

Zhu et al. [28]

2007

RCT

China

232

115

117

74.6/25.4

7.8

Liu, CH et al. [29]

2012

RCT

China

69

33

36

56.5/43.5

59.4

GDMT + nicorandil 5 mg tid

GDMT

4w

Chen, ZN et al. [30]

2011

RCT

China

57

27

30

55.1 ± 9.4 56.6 ± 8.4 75.26 ± 8.12 74.12 ± 7.32 62.4 ± 7.4 63.0 ± 6.4

52.6/47.4

22.8

GDMT + nicorandil 5 mg tid

GDMT

14 d

Chen, YX et al. [31]

2011

RCT

China

112

56

56

67.0/33.0

28.6

GDMT + nicorandil 5 mg tid

GDMT

3d

Dai, QY et al. [32]

2012

RCT

China

80

40

40

56.9 57.1 64.5 62.8

63.8/36.2

8.4

GDMT + nicorandil 5 mg tid

GDMT + ISMN 20 mg bid

4w

Patients with stable angina pectoris, Chinese patients Patients with stable angina pectoris, Chinese patients Patients with unstable angina pectoris, Chinese patients Patients with AMI, Chinaese patients Patients with stable angina pectoris, Chinaese patients

± ± ± ±

Nicorandil group Diabetes%

± ± ± ±

5.8 5.6 7.7 9.2

2.7 y ± 1.5 Median

B. Luo et al. / International Journal of Cardiology 176 (2014) 661–669

Total patients n

6m

IONA: the impact of nicorandil in angina; RCT, randomized, controlled trial; PCI: percutaneous coronary intervention; GDMT: Guideline-Directed Medical Therapy; ISDN: isosorbide dinitrate; ISMN: isosorbide mononitrate. 663

664

B. Luo et al. / International Journal of Cardiology 176 (2014) 661–669

with a sulfonylurea were excluded from the IONA study [4,5]. The proportion of males ranged from 52.6% to 85.2%. Fourteen studies reported all-cause mortality by using counting as the outcome [4,17–21,23,24,26,28–32]. Eleven studies evaluated cardiovascular events by using counting as the outcome. Overall, 1077 cardiovascular events were reported and the overall incidence of cardiovascular events in the included population (6765 participants) was 15.92% during follow-up period [4,17–19,21,22,24–27,31]. We assessed the quality of each included trial using the Jadad score. Quality assessment items are summarized in Table 2. According to the Jadad scoring method, 7 studies (41%) were classified as low quality [21,22,24,29–32] and 10 studies (59%) as high quality [4,17–20,23, 25–28]. All trials were randomized, but the method to generate the randomization sequence was adequately reported in 8 studies [4,17–19, 25–27,31]. Eight studies were double blind [4,17,19,20,23,25,26,28]. Thirteen studies provided a description of patient withdrawals [4,17–23,25–28,32], and 7 reported concealed treatment allocation [4,17–19,22,25,26]. 3.3. Outcomes The outcomes of included randomized trials are summarized in Table 3.

3.4. Primary analysis 3.4.1. All-cause mortality Fourteen studies reported all-cause mortality [4,17–21,23,24,26, 28–32]. Death occurred in 135 of 3527 patients (3.83%) treated with nicorandil and in 166 of 3529 patients (4.70%) without nicorandil treatment (Fig. 2a). Nicorandi treatment did not show a significant reduction in all-cause mortality in patients with IHD (OR, 0.81; 95% confidence interval 0.64 to 1.02; I2 = 0.0%). 3.4.2. Cardiovascular events Eleven studies reported cardiovascular events. Cardiovascular events occurred in 468 of 3384 patients (13.83%) treated with nicorandil and in 609 of 3381 patients (18.01%) treated without nicorandil (Fig. 2b). Nicorandil treatment was associated with a significant reduction in cardiovascular events (RR, 0.77; 95% confidence interval 0.69 to 0.86; I2 = 29.7%, P = 0.163; ARR, 4.18%; NNT, 24). Given the heterogeneity (I2 = 29.7%, P = 0.163), we performed sensitivity analyses, meta-regression and subgroup analyses.

3.4.3. Repeat revascularization We defined repeat revascularization as coronary catheterization that resulted in angioplasty or coronary artery bypass surgery due to admission to hospital for unstable angina again. Five studies reported on repeat revascularization (PCI or CABG) because of unacceptable angina despite guideline-directed medical therapy (GDMT) with or without nicorandil. Repeat revascularization occurred in 67 of 513 patients (13.0%) treated with nicorandil and in 70 of 517 patients (13.5%) treated without nicorandil (Fig. 2c). The repeat revascularization rate was not significantly reduced by the nicorandil treatment (RR, 0.987; 95% confidence interval 0.613 to 1.588; I2 = 31.2%). 3.4.4. Sensitivity analysis and major sources of heterogeneity The analysis result for cardiovascular events showed that IONA study appeared to be different from the rest of the studies (Fig. 3). 3.4.5. Subgroup analysis We divided up the 11 studies for cardiovascular events by sample size, country, Jadad score, duration of trials, and routes of administration (Fig. 1a, b, c, d, e in the Supplemental data). 3.4.6. Meta regression Meta-regression is an extension to subgroup analyses [15,33]. As a result, the identified major sources of heterogeneity were sample size (coefficient = − 0.306; P = 0.031; adjusted R2 = 100%; Fig. 4a), diabetic proportion (%) (coefficient = − 0.008; P = 0.099; adjusted R2 = 81.48%; Fig. 4b), and duration of trials (coefficient = − 0.191; P = 0.084; adjusted R2 = 77.45%; Fig. 4c) for cardiovascular events. We ran 10,000 iterations in the permutation test in order to reduce the chance of a false positive of P values for covariable sample size (adjusted P = 0.095), diabetic proportion (%) (adjusted P = 0.239), and duration of trials (adjusted P = 0.192). 3.4.7. Publication bias The funnel plot for cardiovascular events was asymmetrical with the absence of studies on the upper side of the plot (Egger's test P = 0.039, 95%CI −2.05 to −0.07). There appears to be no change in the pooled RR for cardiovascular events of all 11 studies after using the fill and trim methodology (Fig. 2a, b in the Supplemental data). 4. Discussion Despite optimal therapy, such as antiplatelet therapy, β-blocker therapy, and renin–angiotensin–aldosterone therapy which is recommended in the latest guideline [34], patients with IHD still suffer

Table 2 Quality of included studies. Study

Year

Sum of Jadad Concealed treatment Country Trial described Adequate description of Trials described Adequate description Description of allocation as double blind of method of double withdrawal and score as randomized method of generate dropouts blinding randomization sequence

IONA [4] Ishii, H et al. [17] Nishimura,M et al. [18] Patel, D et al. [19] Ikeda, N et al. [20] Ito, H et al. [21] Kim, J et al. [22] Sekiya, M et al. [23] Lee, HC et al. [24] Ishii, H et al. [25] Kawai, Y et al. [26] Ono, H et al. [27] Zhu et al. [28] Liu, CH et al. [29] Chen, ZN et al. [30] Chen, YX et al. [31] Dai, QY et al. [32]

2002 2005 2009 1999 2004 1999 2005 2005 2008 2006 2009 2004 2007 2012 2011 2011 2012

UK JPN JPN UK JPN JPN KOR JPN KOR JPN JPN JPN CHN CHN CHN CHN CHN

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Yes Yes Yes Yes No No No No No Yes Yes Yes No No No Yes No

Yes Yes No Yes Yes No No Yes No Yes Yes No Yes No No No No

Yes Yes No Yes No No No No No Yes Yes No No No No No No

Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes No No No Yes

5 5 3 5 3 2 2 3 1 5 5 3 3 1 1 2 2

Adequately concealed Adequately concealed Adequately concealed Adequately concealed Unclearly concealed Unclearly concealed Adequately concealed Unclearly concealed Unclearly concealed Adequately concealed Adequately concealed Unclearly concealed Unclearly concealed Unclearly concealed Unclearly concealed Unclearly concealed Unclearly concealed

B. Luo et al. / International Journal of Cardiology 176 (2014) 661–669

665

Table 3 Outcomes of included studies. Study

IONA [4] Ishii, H et al. [17] Nishimura, M et al. [18] Patel, D et al. [19] Ikeda, N et al. [20] Ito, H et al. [21] Kim, J et al. [22] Sekiya, M et al. [23] Lee, HC et al. [24] Ishii, H et al. [25] Kawai, Y et al. [26] Ono, H et al. [27] Zhu et al. [28] Liu, CH et al. [29] Chen, ZN et al. [30] Chen, YX et al. [31] Dai, QY et al. [32]

Repeat revascularization

Cardiovascular events

Outcomes of all-cause mortality

Nicorandil group n

Control group n

Nicorandil group n

Control group n

Death of nicorandil group n

Total of nicorandil group n

Death of control group n

Total of control group n

NA 35 6 NA NA NA 4 NA 1 NA 21 NA NA NA NA NA NA

NA 37 2 NA NA NA 1 NA 2 NA 28 NA NA NA NA NA NA

337 41 13 22 NA 7 5 NA 2 5 25 5 NA NA NA 6 NA

398 57 21 40 NA 20 3 NA 4 11 35 10 NA NA NA 10 NA

111 7 5 12 0 0 0 0 0 0 0 0 0 0 NA NA NA

2565 185 64 96 30 40 42 21 37 81 185 33 115 33 27 56 40

129 12 7 12 4 2 0 0 0 0 0 0 0 0 NA NA NA

2561 183 65 104 30 41 54 21 36 77 179 25 117 36 30 56 40

significant morbidity and mortality [2,35]. In addition, PCI cannot always improve long-term outcomes in patients with stable angina and current optimal medical treatment as described in some recent studies [36,37]. The importance of novel drug treatment is therefore being reconsidered.

Nicorandil is a hybrid drug that functions as a K-ATP channel opener and nitric oxide releaser [4,5]. The drug has been demonstrated to be able to protect the myocardium against ischemic injury under both experimental and clinical conditions [38].

A All-cause mortality Study ID

OR (95% CI)

Events,

Events,

%

Treatment

Control

Weight

IONA (2002)

0.85 (0.66, 1.11)

111/2565 129/2561

77.94

Ishii,H et al (2005)

0.56 (0.22, 1.46)

7/185

12/183

7.33

Nishimura,M et al (2009)

0.70 (0.21, 2.34)

5/64

7/65

4.04

Patel,D et al (1999)

1.10 (0.47, 2.57) 12/96

12/104

6.36

Ikeda,N et al (2004)

0.10 (0.00, 1.88) 0/30

4/30

2.79

Ito,H et al (1999)

0.20 (0.01, 4.19) 0/40

2/41

1.54

Kim,J et al (2005)

(Excluded)

0/42

0/54

0.00

Sekiya,M et al (2005)

(Excluded)

0/21

0/21

0.00

Lee HC et al (2008)

(Excluded)

0/37

0/36

0.00

Ishii H et al (2006)

(Excluded)

0/81

0/77

0.00

Kawai Y et al (2009)

(Excluded)

0/185

0/179

0.00

Ono H et al (2004)

(Excluded)

0/33

0/25

0.00

ZHU et al (2007)

(Excluded)

0/115

0/117

0.00

Liu CH et al (2012)

(Excluded)

0/33

0/36

Overall (I-squared = 0.0%, p = 0.541)

0.81 (0.64, 1.02) 135/3527 166/3529

.00496

1

0.00 100.00

201

Fig. 2. (A) Meta-analysis of all-cause mortality in people with IHD. Weights are from fixed effects analysis, test of OR = 1: z = 1.78 P = 0.075; IONA, impact of nicorandil in angina; CI, confidence interval. (B) Meta-analysis of cardiovascular events in people with IHD. Weights are from fixed effects analysis.Test of RR = 1: z = 4.72 P = 0.000 b 0.001;IONA indicates impact of nicorandil in angina; CI, confidence interval. (C) Meta-analysis of repeat revascularization in people with IHD. Weights are from fixed effects analysis;test of RR = 1: z = 0.33 P = 0.741; CI, confidence interval.

666

B. Luo et al. / International Journal of Cardiology 176 (2014) 661–669

B cardiovascular events Study ID

RR (95% CI)

Events,

Events,

%

Treatment

Control

Weight

IONA (2002)

0.85 (0.74, 0.97) 337/2565 398/2561 65.35

Ishii,H et al (2005)

0.71 (0.50, 1.01)

Nishimura,M et al (2009)

57/183

9.40

0.63 (0.35, 1.14) 13/64

21/65

3.42

Patel,D et al (1999)

0.60 (0.38, 0.93) 22/96

40/104

6.30

Ito,H et al (1999)

0.36 (0.17, 0.75) 7/40

20/41

3.24

Kim,J et al (2005)

2.14 (0.54, 8.46) 5/42

3/54

0.43

Lee HC et al (2008)

0.49 (0.09, 2.49) 2/37

4/36

0.67

Ishii H et al (2006)

0.43 (0.16, 1.19) 5/81

11/77

1.85

Kawai Y et al (2009)

0.69 (0.43, 1.11) 25/185

35/179

5.84

Ono H et al (2004)

0.38 (0.15, 0.97) 5/33

10/25

1.87

Chen YX et al (2011)

0.60 (0.23, 1.54) 6/56

10/56

1.64

Overall (I-squared = 29.7%, p = 0.163)

0.77 (0.69, 0.86) 468/3384

.0949

1

41/185

609/3381 100.00

10.5

C Repeat Revascularization Study

Events,

Events,

Treatment

Control Weight

ID

RR (95% CI)

Ishii,H et al (2005)

0.94 (0.62, 1.42) 35/185 37/183 52.73

Nishimura,M et al (2009)

3.05 (0.64, 14.54) 6/64

2/65

2.81

Kim,J et al (2005)

5.14 (0.60, 44.32) 4/42

1/54

1.24

Lee HC et al (2008)

0.49 (0.05, 5.13)

2/36

2.87

Kawai Y et al (2009)

0.73 (0.43, 1.23) 21/185 28/179 40.34

Overall (I-squared = 31.2%, p = 0.213)

0.95 (0.70, 1.29) 67/513 70/517 100.00

.0226

1

44.3

Fig. 2 (continued).

1/37

%

B. Luo et al. / International Journal of Cardiology 176 (2014) 661–669

667

Meta-analysis estimates, given named study is omitted Lower CI Limit Estimate Upper CI Limit IONA (2002) Ishii,H et al (2005) Nishimura,M et al (2009) Patel,D et al (1999) Ito,H et al (1999) Kim,J et al (2005) Lee HC et al (2008) Ishii H et al (2006) Kawai Y et al (2009) Ono H et al (2004) Chen YX et al (2011) 0.51

0.69

0.77

0.860.87

Fig. 3. Results of sensitivity analyses for cardiovascular events. CI, confidence interval.

Four large-scale clinical studies on nicorandil for all-cause mortality and cardiovascular events in patients with IHD have been reported: IONA (Impact of Nicorandil in Angina study, reported in 2002) [4,5], J-WIND-KATP (Japan Working Groups of Acute Myocardial Infarction for the Reduction of Necrotic Damage by a K-ATP channel opener, reported in 2004) [39], JCAD (JapaneseCoronaryArteryDiseasestudy, reported in 2010) [40], and OACIS (Osaka Acute Coronary Insufficiency Study, reported in 2012) [41]. J-WIND-KATP trial is a prospective, randomized, multicenter study. But in this trial, oral administration of nicorandil was given to some of the participants in both the nicorandil group and control group during the follow-up. JCAD and OACIS studies were multicenter collaborative prospective observational studies, not randomized control trials. Thus J-WIND-KATP, JCAD study, and OACIS were excluded in our analyses. With the increasing studies on nicorandil in patients with IHD, meta-analysis is needed to evaluate its potential clinical benefits in all-cause mortality and cardiovascular events. To the best of our knowledge, the current study is the first systematic review and meta-analysis of randomized control studies on nicorandil for all-cause mortality and cardiovascular events in patients with IHD. Population characteristics were different, which were involved in a wide spectrum of IHD, such as stable angina, unstable angina, AMI, ACS, and with or without undergoing PCI. Based on the data of 7056 patients, we did not find any difference between nicorandil and placebo group in all-cause mortality (3.83% vs. 4.70%, respectively; OR 0.81, P = 0.075). IONA study included 5126 patients with chronic stable angina, the addition of nicorandil to standard therapy had no benefit on death or nonfatal MI (4.3% vs. 5.0%, respectively; HR 0.85, P = 0.222) during follow-up period of 1.6 years (SD 0.5) [4]. The negative effect of nicorandil on death of IHD may not be related to the time of the follow-up, as ISHii et al. also did not find difference in all-cause mortality between nicorandil and control groups during a 5-year follow-up in a randomized, double-blinded research including 368 patients with first ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) (HR,0.72; 95% CI, 0.49 to 1.04; P = 0.08) [17]. In another randomized trial, however, it was reported that oral administration of nicorandil may reduce cardiac death and improve the survival of hemodialysis patients after coronary revascularization (HR 0.42, 95%CI 0.21–0.82, P = 0.01) [18]. This trial enrolled a total of 129 hemodialysis individuals with an average duration of a

2.7 ± 1.5-year follow-up. The potential reasons of the different benefits of nicorandil in IHD patients with and without hemodialysis are not clear. It is well known that the ischemic injuries of the heart in hemodialysis patients with IHD might be induced not only by obstructive arteries but also by the increased inflammation [42,43], microvascular dysfunction [44,45], endothelial dysfunction [46–49], platelet dysfunction, thrombosis, and vasomotor dysfunction [50,51]. The biological functions of nicorandil of nitric oxide release and its antiinflammatory effects might partially explain its benefit effect in hemodialysis individuals. The benefit effects of nicorandil were also observed in diabetes mellitus patients with IHD. Although a permutation test of P value was not statistically significant for diabetes (%), our meta-regression analysis seems to reveal a trend that diabetes mellitus patients with IHD could obtain more benefits of reduced cardiovascular events from the adjunct use of nicorandil compared to the standard therapy alone. Other studies came to the similar conclusion about the beneficial effects of nicorandil on diabetic patients [52,53]. In this study, we identified in a total of 6765 patients that nicorandil treatment was associated with a significant reduction in cardiovascular events. The data of repeat revascularization events extracted from cardiovascular events in our analysis were further analyzed. We defined the repeat revascularization as coronary catheterization that resulted in angioplasty or coronary artery bypass surgery due to admission to hospital for unstable angina again, which was previously included in our cardiovascular event analysis. A pooled RR result of 5 trials suggests that there was no significant difference between the nicorandil and control groups. Analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses. The funnel plot for cardiovascular events in this analysis was asymmetrical with a lack of studies on the upper part of the plot, suggesting that unpublished studies were likely to demonstrate an increased risk of cardiovascular events that were not included in our analysis. After using the method of trim and fill, however, there appears to be no change in the pooled RR for cardiovascular events. The results suggest that our meta-analysis does not suffer from publication bias. The current study has several limitations. First, meta-analysis itself is the “file-drawer” effect, in which studies with negative results might remain unpublished thus biasing the literature towards positive findings. Second, confounder is the small sample size, with its high chance of false positive results. When data from IONA was excluded (being the main

668

B. Luo et al. / International Journal of Cardiology 176 (2014) 661–669

1

5. Conclusion

0

Conflict of interest -.5

logrr

.5

In this study, we have identified that administration of nicorandil, compared with standard treatment, reduced cardiovascular events when it is used as an adjunctive therapy in patient with IHD. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2014.07.007.

The authors report no relationships that could be construed as a conflict of interest.

-1

Acknowledgments 1

2

1

a) sample size of trials

We wish to thank Dr. Chunxiang Zhang, an Endowed Professor and Chairman, at Rush University at Chicago for the manuscript revision and editorial assistant. We also wish to thank Drs. Jianghua Zhong and Yufeng Zhuo for the literature assistance.

0 -1

-.5

logrr

.5

References

10

20

30

40

50

60

0 -1

-.5

logrr

.5

1

b) diabetic proportion (%)

1

1.5

2

2.5

3

c) duration of trials Fig. 4. Random effect meta-regression for cardiovascular events (logrr) with the following covariates: (a)sample size. “1” indicated more than 1000 patients; “2” indicated less than 1000 patients.(b)Diabetic proportion (%);(c)duration of trials. “1” indicated follow-up duration of more than 1 year; “2” indicated follow-up duration of 6 months; and “3” indicated follow-up duration of less than 1 month.

source of heterogeneity for cardiovascular events) from the analysis, there was unequivocal and strong evidence of reduced cardiovascular events with nicorandil use, without any heterogeneity in small studies. In addition, we only assessed the risk of all-cause mortality, rather than death from specific diseases such as AMI or specific event such as cardiovascular death. Further large randomized clinical investigations are thus needed to reflect more accurate benefit effects of nicorandil treatment in patients with IHD.

[1] Marzilli M, Merz CN, Boden WE, et al. Obstructive coronary atherosclerosis and ischemic heart disease: an elusive link! J Am Coll Cardiol 2012;60:951–6. [2] Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/ PCNA/ SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/ American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2012 Dec 18;126(25):e354–471. [3] Task Force M, Montalescot G, Sechtem U, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the Management of Stable Coronary Artery Disease of the European Society of Cardiology. Eur Heart J 2013;34: 2949–3003. [4] IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the impact of nicorandil in angina (IONA) randomised trial. Lancet 2002; 359:1269–75. [5] Group IS. Trial to show the impact of nicorandil in angina (IONA): design, methodology, and management. Heart 2001;85:E9. [6] JCS Joint Working Group. Guidelines for secondary prevention of myocardial infarction (JCS 2011). Circ J 2013;77(1):231–48. [7] Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009;151:W65–94. [8] Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535. [9] Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12. [10] Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated March 2011]. Available at http://handbook.cochrane.org/ whnjs.htm; 2011. [11] Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60. [12] Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719–48. [13] DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7: 177–88. [14] Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000;56:455–63. [15] Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted? Stat Med 2002;21(11):1559–73. [16] Harbord Roger M, Higgins Julian PT. Meta-regression in STATA. Stata J 2008;8(4): 493–519. [17] Ishii H, Ichimiya S, Kanashiro M, et al. Impact of a single intravenous administration of nicorandil before reperfusion in patients with st-segment-elevation myocardial infarction. Circulation 2005;112:1284–8. [18] Nishimura M, Tokoro T, Nishida M, et al. Oral nicorandil to reduce cardiac death after coronary revascularization in hemodialysis patients: a randomized trial. Am J Kidney Dis 2009;54:307–17. [19] Patel DJ, Purcell HJ, Fox KM. Cardioprotection by opening of the k(atp) channel in unstable angina. Is this a clinical manifestation of myocardial preconditioning? Results of a randomized study with nicorandil. Cesar 2 investigation. Clinical European studies in angina and revascularization. Eur Heart J 1999;20:51–7. [20] Ikeda N, Yasu T, Kubo N, et al. Nicorandil versus isosorbide dinitrate as adjunctive treatment to direct balloon angioplasty in acute myocardial infarction. Heart 2004; 90:181–5. [21] Ito H, Taniyama Y, Iwakura K, et al. 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.

B. Luo et al. / International Journal of Cardiology 176 (2014) 661–669 [22] Kim JH, Jeong MH, Yun KH, et al. Myocardial protective effects of nicorandil during percutaneous coronary intervention in patients with unstable angina. Circ J 2005; 69:306–10. [23] Sekiya M, Sato M, Funada J, et al. Effects of the long-term administration of nicorandil on vascular endothelial function and the progression of arteriosclerosis. J Cardiovasc Pharmacol 2005;46:63–7. [24] Lee HC, An SG, Choi JH, et al. Effect of intra-coronary nicorandil administration prior to reperfusion in acute st segment elevation myocardial infarction. Circ J 2008;72: 1425–9. [25] Ishii H, Ichimiya S, Kanashiro M, et al. Effects of intravenous nicorandil before reperfusion for acute myocardial infarction in patients with stress hyperglycemia. Diabetes Care 2006;29(2):202–6. [26] Kawai Y, Hisamatsu K, Matsubara H, et al. Intravenous administration of nicorandil immediately before percutaneous coronary intervention can prevent slow coronary flow phenomenon. Eur Heart J 2009;30(7):765–72. [27] Ono H, Osanai T, Ishizaka H, et al. Nicorandil improves cardiac function and clinical outcome in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention:role of inhibitory effect on reactive oxygen species formation. Am Heart J 2004;148(4):E15. [28] Zhu WL, Shan YD, Guo JX, et al. Double-blind, multicenter, active-controlled, randomized clinical trial to assess the safety and efficacy of orally administered nicorandil in patients with stable angina pectoris in China. Circ J 2007;71:826–33. [29] Liu Chang-hong, Li Guang-ping. Effect of nicorandil for patients with angina pectoris after undergoing incomplete revascularization. J Tianjin Med Univ 2012;18(2):214–6. [30] Chen Zong-ning, Lu Jing-qian, Li Yi, et al. The effect of nicorandil on angina after percutaneous coronary intervention therapy. Chin Gen Pract 2011;14(8):870–1. [31] Chen Ya-xiang, Chen Shan, Jin-fu Wang. The short-term efficacy on thrombolytic therapy combined with cardiac ischemic preconditioning of Nicorandil in acute myocardial infarction. Chin J Postgrad Med 2011;34(13):58–9. [32] Dai Qing-yuan. A comparison of nicorandil with isosorbide mononitrate in patients with stable coronary heart disease. Natl Med Front Chin 2012;07(2):25 [17]. [33] Gagnier JJ, Moher D, Boon H, et al. An empirical study using permutation-based resampling in meta-regression. Syst Rev 2012;1:18. [34] Mitka M. Guideline stresses medical therapy for treating stable ischemic heart disease. JAMA 2013;309:221–2. [35] Lim SY, Hausenloy DJ. Remote ischemic conditioning: from bench to bedside. Front Physiol 2012;3:27. [36] Horinaka S. Use of nicorandil in cardiovascular disease and its optimization. Drugs 2011;71(9):1105–19. [37] Bangalore S, Pursnani S, Kumar S, et al. Percutaneous coronary intervention versus optimal medical therapy for prevention of spontaneous myocardial infarction in subjects with stable ischemic heart disease. Circulation 2013;127:769–81. [38] Wang A, Chen F, Xie Y, et al. Protective mechanism of nicorandil on rat myocardial ischemia–reperfusion. J Cardiovasc Med (Hagerstown) 2012;13(8):511–5. [39] Kitakaze M, Asakura M, Kim J, et al. Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials. Lancet 2007;370:1483–93.

669

[40] Horinaka S, Yabe A, Yagi H, et al. Effects of nicorandil on cardiovascular events in patients with coronary artery disease in the Japanese coronary artery disease (JCAD) study. Circ J 2010;74:503–9. [41] Sakata Y, Nakatani D, Shimizu M, et al. Oral treatment with nicorandil at discharge is associated with reduced mortality after acute myocardial infarction. J Cardiol 2012; 59(1):14–21. [42] Huttunen K, Siponen T, Salonen I, et al. Low-level exposure to ambient particulate matter is associated with systemic inflammation in ischemic heart disease patients. Environ Res 2012;116:44–51. [43] Karpov Iu A, Buza VV. Prognostic value of markers of inflammation in patients with stable ischemic heart disease after implantation of stents with drug covering at the background of long-term therapy with statins (inhospital period). Kardiologiia 2012;52:4–9. [44] Vecoli C, Caselli C, Caruso R, et al. Coronary microvascular disease: from experimental models to clinical practice. Recenti Prog Med 2012;103:288–96. [45] Lombardo A, Niccoli G, Natale L, et al. Impact of microvascular obstruction and infarct size on left ventricular remodeling in reperfused myocardial infarction: a contrast-enhanced cardiac magnetic resonance imaging study. Int J Cardiovasc Imaging 2012;28:835–42. [46] Minami Y, Kaneda H, Inoue M, et al. Endothelial dysfunction following drug-eluting stent implantation: a systematic review of the literature. Int J Cardiol 2013;165(2): 222–8. [47] Dominguez-Rodriguez A, Abreu-Gonzalez P. C-reactive protein and endothelial dysfunction: the clinicians should have in mind diurnal variations. Int J Cardiol 2012; 154:353. [48] Hong SJ, Chang HJ, Park S, et al. Impact of atorvastatin treatment in first-degree relatives of patients with premature coronary artery disease with endothelial dysfunction: a double-blind, randomized, placebo-controlled crossover trial. Clin Cardiol 2013;36(8):480–5. [49] Gargiulo P, Marciano C, Savarese G, et al. Endothelial dysfunction in type 2 diabetic patients with normal coronary arteries: a digital reactive hyperemia study. Int J Cardiol 2013;165:67–71. [50] Rajan L, Moliterno DJ. New anticoagulants in ischemic heart disease. Curr Cardiol Rep 2012;14:450–6. [51] Sanidas EA, Mintz GS, Maehara A, et al. Adverse cardiovascular events arising from atherosclerotic lesions with and without angiographic disease progression. JACC Cardiovasc Imaging 2012;5(3 Suppl):S95–S105. [52] Serizawa K, Yogo K, Aizawa K, et al. Nicorandil prevents endothelial dysfunction due to antioxidative effects via normalisation of NADPH oxidase and nitric oxide synthase in streptozotocin diabetic rats. Cardiovasc Diabetol 2011;10:105. [53] Tanabe K, Lanaspa MA, Kitagawa W, et al. Nicorandil as a novel therapy for advanced diabetic nephropathy in the eNOS-deficient mouse. Am J Physiol Renal Physiol 2012; 302(9):F1151–60.