Skip to main content
PMC home page
PLOS ONE logoLink to PLOS ONE
. 2013 Oct 22;8(10):e78231. doi: 10.1371/journal.pone.0078231

Nicorandil in Patients with Acute Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis

Muli Wu 1,#, Zheng Huang 1,*,#, Haojun Xie 2, Zhongjiang Zhou 1
Editor: Vincenzo Lionetti3
PMCID: PMC3805586  PMID: 24167609

Abstract

Background

Nicorandil, as an adjunctive therapy with primary percutaneous coronary intervention (PCI), had controversial benefits in cardioprotection in patients with acute myocardial infarction (AMI).

Methods and Results

We performed a systematic review of randomized controlled trials (RCTs) comparing treatment with nicorandil prior to reperfusion therapy with control (placebo or no nicorandil) in patients who suffered from AMI and performed primary PCI. PubMed, EMBASE and CENTRAL databases and other sources were searched without language and publication restriction. 14 trials involving 1680 patients were included into this meta-analysis. Nicorandil significantly reduced the incidence of thrombolysis in myocardial infarction (TIMI) flow grade ≤2 (risk ratio [RR], 0.57; 95% confidence interval [CI]: 0.42 to 0.79), the Timi frame count (TFC) (mean difference [MD], -5.19; 95% CI: -7.13 to -3.26), increased left ventricular ejection fraction (LVEF) (%) (MD, 3.08; 95% CI: 0.79 to 5.36), and reduced the incidence of ventricular arrhythmia (RR, 0.53; 95% CI: 0.37 to 0.76) and congestive heart failure (CHF) (RR, 0.41; 95% CI: 0.22 to 0.75). No difference in the pear creatine kinase (CK) value (MD, -290.19; 95% CI: -793.75 to 213.36) or cardiac death (RR, 0.39; 95% CI: 0.09 to 1.67) was observed.

Conclusions

Nicorandil prior to reperfusion is associated with improvement of coronary reflow as well as suppression of ventricular arrhythmia, and further improves left ventricular function in patients who suffered from AMI and underwent primary PCI. But the definite clinical benefits of nicorandil were not found, which may be due to the small sample size of the selected studies.

Introduction

Early reperfusion of totally occluded coronary arteries reduces infarct size, cardiac mortality rates, and in-hospital events [1,2]. However, some patients continue to have deteriorating cardiac function and bad prognoses, thought to be due to reperfusion injury. Reperfusion injury probably represents myocyte cell death due to reperfusion, no reflow, myocardial stunning and reperfusion arrhythmias [3]. Nicorandil, a hybrid of an adenosine triphosphate (ATP)-sensitive potassium channel opener and nitrates, was used as an adjunctive therapy with primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). The mechanisms for the salutary actions of nicorandil have been postulated, including anti-free radical and neutrophil modulating properties [4,5], vasodilatation of small coronary arteries [6], and mimicking of ischaemic preconditioning [7]. But relevant clinical trials showed controversial results on whether nicorandil had potential to improve coronary artery reflow and ventricular function [8-10]. In addition, rare events of clinical outcomes were reported because of many trials with limited sample size. Thus we performed a systematic review of randomized controlled trials (RCTs) to investigate the effect of nicorandil prior to reperfusion therapy on cardioprotection and clinical outcomes in patients with AMI.

Methods

Data sources and searches

We identified all published studies, including full-text and abstract, which compared the effect of nicorandil by intravenous and/or intracoronary administration with control (placebo or no nicorandil treatment) prior to reperfusion by primary PCI in AMI patients. Searches were performed using Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 12, 2012), Pubmed (1966 to December 2012), Embase.com (1974 to November 2012) and ISI meeting and proceedings (previous to November 2012) electronic databases. The search strategy was developed without language and publication restriction and used the medical subject headings and text words, such as “nicorandil”, “myocardial infarction”, and “randomized controlled trials”. We handsearched the supplements of seven international core journals on the cardiovascular field, and manually scanned the reference lists of all eligible articles and relevant meta-analyses. We also searched Google Scholar, TCTMD and www.clinicaltrial.gov websites for unpublished trials (see Table S1 ).

Studies selection

Two reviewers (M. W. and H. X.) performed study selection independently, with disagreements solved through discussion and by the opinion of a third reviewer (Z. H.) if necessary. Studies were considered potentially eligible for this systematic review if they met the following criteria: (1) RCTs about patients who suffered from AMI and performed primary PCI, (2) nicorandil was administered prior to reperfusion by intravenous and/or intracoronary and compared with control (placebo or no nicorandil treatment), and (3) the studies included at least one of the following interesting outcomes: thrombolysis in myocardial infarction (TIMI) flow grade after PCI, TIMI frame count after PCI, left ventricular ejection fraction (LVEF), peak creatine kinase (CK) value and clinical outcomes including cardiac death, ventricular tachycardia (VT) or fibrillation (VF), or congestive heart failure (CHF)

Data extraction and quality assessment

Two reviewers (M. W. and H. X.) independently undertook the data extraction and the quality assessment. The disagreements would be solved through discussion and by the opinion of a third reviewer (Z. H.) if necessary. The risk of bias was assessed according to the guidance in the Cochrane Handbook version 5.1.0 [11]. We rated the risk of selection bias by assessing randomization and allocation concealment, of performance bias by assessing blinding of participants and personnel. The risk of detection bias and attrition bias were rated by assessing blinding of outcome assessment for the outcome TIMI flow grade and LVEF, respectively and selection bias for the outcome TIMI flow grade only. We tried to contact the authors by email for obtaining information, if their articles did not report the information in detail. For studies that were reported in > 1 publications, we extracted data from the most complete publication and used other publications as supplements.

Statistical analysis

The verified data were analyzed using Review-Manager software (RevMan, version 5.1.6 for Windows). We determined pooled mean difference (MD) and corresponding 95% confidence intervals (CI) for continuous data, and pooled risk ratios (RRs) for dichotomous data. If statistically significant difference existed in the endpoints with dichotomous data, we would calculate the number needed to treat (NNT) from the pooled risk difference for each endpoint. The appropriateness of pooling data across studies was assessed with the use of the Cochran Q and the I2 test for heterogeneity. Data were pooled by use of a fixed-effects (FE) model (Mantel-Haenszel method) if I2≤50%. If I2>50%, we tried to find clinical heterogeneity across studies first and addressed it by sensitivity analyses or subgroup analyses, and if significant heterogeneity remained, a random-effects (RE) model would be used if appropriate. To avoid over-estimating a possible effect due to the exclusion of patients in studies with no events in both arms, we performed a reanalysis by adding the reciprocal of one arm size, called as “treatment arm continuity corrections”, to each cell of the opposite arm in trials with zero event [12] using standard software packages STATA version 12.0. For the outcome of TIMI flow grade ≤2, we planned to perform subgroup analyses of studies assessing intracoronary administration of nicorandil and intravenous alone before this systematic review was performed.

Results

Study selection

We identified 994 articles after duplicates removed for screening. Based on title and abstract, 889 were excluded and 107 full articles retrieved. 31 were not RCTs and another 36 were excluded for other reasons leaving 40 articles reporting 14 trials that met the inclusion criteria [8-10,13-24]. The process with reasons for exclusion was described in Figure 1 .

Figure 1. Flow Diagram for Inclusion of Studies in Meta-analysis.

Figure 1

Open in a new tab

The initial search identified 994 articles, of which, 14 trials were included in the final analysis. AMI = acute myocardial infarction; RCTs = randomized controlled trials.

Study characteristics and study quality

The 14 RCTs involved 1680 patients (range 27 to 545 patients per trial). Table 1 summarized the baseline characteristics, and Table 2 summarized the intervention characteristics of the included trials. One trial [22] was published in abstract, one [15] was a subgroup analysis, and remaining 12 trials have full-text publication. All trials included patients with ST-segment elevation myocardial infarction (STEMI) but one [20] did not report. Patients received nicorandil by intracoronary injection in seven trials, followed by oral nicorandil in four trials, and had reperfusion at mean duration from onset ranging from 3.7 to 7.0 hours in 13 trials. Overall, the quality of the randomized trials included was judged partially limited by a lack of transparency in the reporting of the generation of random sequence generation, for which 4 trials were at low risk, whereas 10 at unclear risk, and in the reporting of the allocation concealment, for which 7 trials were at low risk, whereas 7 at unclear risk. Bias risk assessment of other domains sees details in Figure 2 . In addition, we evaluated the publication bias risk using a funnel plot in Figure 3 based on the outcome TIMI flow grade ≤2.

Table 1. Baseline characteristics of included trials.

Trials Publication type Sample size (NG/CG) Age, mean (SD) Sex (M/F) STEMI or non-STEMI DM, % Occlusion of LAD, %
Akagi 2006 [20] full-text 20/10# 64.0 (11.4) 20/10 NR NR 100
Atsuchi 2007 [22] abstract 41/41 NR NR STEMI NR NR
Fujiwara 2007 [23] full-text 31/31 62.0 (10.9) 50/12 STEMI 38.7 50.0
Fukuzawa 2000 [18] full-text 31/31 61.4 (12.2) 45/17 STEMI 30.6 64.5
Han 2008 [16] full-text 37/36 58.3 (12.6) 61/12 STEMI 31.5 54.8
Ishii 2005 [8,24] full-text 185/183 63.5 (9.8) 298/70 STEMI 32.3 47.3
Ito 1999 [17] full-text 40/41 60 (9.9) 64/17 STEMI 27.2 100.0
Kawai 2009 [15] subgoup-analysis 27/37 NR NR STEMI NR NR
Kitakaze 2007 [10] full-text 276/269 62.4 (10.9) 466/79 STEMI 34.1 49.3
Miyazawa 2006 [13] full-text 35/35 62.0 (9.2) 57/13 STEMI 34.3 60.0
Nameki 2004 [19] full-text 13/14 63.0 (10.2) 22/7 STEMI 25.9 100.0
Ono 2004 [9] full-text 33/25 64.9 (12.4) 38/20 STEMI 32.6 63.8
Ota 2006 [21] full-text 63/27# 62.8 (10.5) 72/18 STEMI 30.0 46.7
Toyama 2006 [14] full-text 33/35 64.0 (12.0) 44/24 STEMI 29.4 60.3
Open in a new tab

CG = control group; DM = diabetes mellitus; LAD = Left anterior descending coronary artery; M/F = male/female; NG = nicorandil group; NR = not reported; STEMI = ST segment elevation myocardial infarction. # combining two groups into NG.

Table 2. Intervention characteristics of included trials.

Trials Intervention Subsequent oral nicorandil Combined nitrate Time to reperfusion, mean (SD), hr Rate of tenting, %
Akagi 2006 [20] NG: NIC IV drip infusion (4 mg/hr) for 48 hr, 2 mg IC, and/not 15 mg/day PO. CG: no NIC administered. Yes Yes 3.7 (1.7) NR
Atsuchi 2007 [22] NG: NIC 4 mg IV and/or 2 mg IC, IV drip infusion (6 mg/hr) for 24 hr. CG: no NIC administered. No NR NR NR
Fujiwara 2007 [23] NG: NIC 4 mg IV, IV drip infusion (8 mg/hr) for 24 hr. CG: no NIC administered. No NR 5.9 (0.6) NR
Fukuzawa 2000 [18] NG: NIC 4 mg IV, IV drip infusion (6 mg/hr) for 24 hr. CG: placebo. No Yes 4.6 (2.2) 0
Han 2008 [16] NG: NIC 2 mg IC, 2 mg IC. CG: no NIC administered. No Yes 5.9 (2.5) 87.7
Ishii 2005 [8,24] NG: NIC 12 mg IV over 20-30 min. CG: Placebo. No Yes 4.7 (2.9) 82.6
Ito 1999 [17] NG: NIC 4 mg IV, IV drip infusion (6 mg/hr) for 24 hr, 15 mg/day PO. CG: no NIC administered. Yes Yes 5.1 (2.2) NR
Kawai 2009 [15] NG: NIC 6 mg IV. CG: Placebo. No NR NR 100.0
Kitakaze 2007 [10] NG: NIC 0.067 mg/kg IV, IV drip infusion (1.67 μg/kg per min) for 24 hr. CG: placebo. Yes § ‡ Yes 3.5 (0.6) 67.9
Miyazawa 2006 [13] NG: NIC 2 mg IC, IV drip infusion (2 mg/hr) for 24 hr, 15 mg/day PO. NG: no NIC administered. Yes Yes 7.0 (5.2) 82.9
Nameki 2004 [19] NG: NIC 4 mg IV, 4 mg IC, IV drip infusion (4 mg/hr) for 24 hr. CG: no NIC administered. No Yes 6.3 (4.7) 25.9
Ono 2004 [9] NG: NIC 4 mg IV, IV drip infusion (8 mg/hr) for 24 hr. CG: no NIC administered. No Yes 5.4 (2.2) 100.0
Ota 2006 [21] NG: NIC 1-2 mg IC, and/not IV drip infusion (6 mg/hr) for 16 hr. CG: no NIC administered. No Yes 4.0 (1.5) 78.9
Toyama 2006 [14] NG: NIC 4 mg IV, 2 mg IC, IV drip infusion (4 mg/hr) for 24 hr. CG: no NIC administered. No Yes 5.0 (3.6) NR
Open in a new tab

IC = intracoronary; IV = intravenous; NIC = nicorandil; PO = per os.

§ both arms received subsequent oral nicorandil; ‡ significant difference in patients receiving nicorandil orally between two arms (P <0.05).

Figure 2. Risk of Bias Summary.

Figure 2

Open in a new tab

Figure 3. Funnel Plot for the Incidence of TIMI Flow Grade ≤ 2.

Figure 3

Open in a new tab

RR = risk ratio; SE = standard error.

TIMI flow grade

After coronary reperfusion, the events of the TIMI flow grade ≤2 occurred in 54 of 668 patients (8.1%) treated with nicorandil and in 89 of 622 patients (14.3%) without nicorandil treatment from seven trials (Figure 4 ). Use of nicorandil was associated with a significant reduction in the events of the TIMI flow grade ≤2 (RR, 0.57; 95% CI: 0.42 to 0.79; I2=43%; FE model; NNT, 16). The reanalysis including the trial [13] with no event on both arms did not change the result (p=0.002).

Figure 4. RR of the Incidence of TIMI Flow Grade ≤ 2.

Figure 4

Open in a new tab

Forest plot of RR (with 95% CI) for TIMI flow grade ≤ 2 in patients receiving nicorandil compared with those receiving no nicorandil. Significant reduction in TIMI flow grade ≤ 2 (RR: 0.57; 95% CI: 0.42 to 0.79; p=0.0006) was observed in nicorandil group. CI = confidence interval; RR = risk ratio; TIMI = thrombolysis in myocardial infarction.

TFC

The TFC was assessed in 543 patients after reperfusion therapy (Figure 5 ). Its value was significantly lower in nicorandil group (MD, -5.19; 95% CI: -7.13 to -3.26; I2=26%; FE model) than control group.

Figure 5. MD of TIMI Frame Count.

Figure 5

Open in a new tab

Forest plot of MD (with 95% CI) for TIMI frame count in patients receiving nicorandil compared with those receiving no nicorandil. Significant reduction in TIMI frame count (MD: -5.19; 95% CI: -7.13 to -3.26; p<0.00001) was observed in nicorandil group. CI = confidence interval; MD = mean difference, TIMI = thrombolysis in myocardial infarction.

LVEF

LVEF was evaluated in 964 patients after one to 12 months (Figure 6 ), and using nicorandil was associated with significant increase in LVEF (%) (MD, 3.08; 95% CI: 0.79 to 5.36; I2=53%; RF model). A sensitive analysis to exclude one trial [10] found the significant difference remained and heterogeneity reduced (MD, 4.16; 95% CI: 2.34 to 5.97; I2=0%; FE model) in the LVEF.

Figure 6. MD of LVEF.

Figure 6

Open in a new tab

Forest plot of MD (with 95% CI) for LVEF in patients receiving nicorandil compared with those receiving no nicorandil. Significant increase in LVEF (MD: 3.08; 95% CI: 0.79 to 5.36; p=0.008) was observed in nicorandil group. CI = confidence interval; LVEF = left ventricular ejection fraction; MD = mean difference.

Peak CK value

The peak CK value was evaluated in 1218 patients from eight trials. But the difference did not reach statistical significance (MD, -290.19; 95% CI: -793.75 to 213.36; I2=54%; RE model).

VT or VF

Using nicorandil was associated with a significant reduction in the events of ventricular tachycardia or fibrillation within 24 hours or immediate after reperfusion (RR, 0.53; 95% CI: 0.37 to 0.76; I2=0%; FE model; NNT, 10.4). The reanalysis including the trial [13] with no event on both arms did not change the result (p=0.001).

CHF

CHF occurred 11 of 121 patients (9.1%) treated with nicorandil and in 27 of 115 patients treated (23.5%) without nicorandil during hospital. Using nicorandil was associated with a significant reduction in CHF (RR, 0.41; 95% CI: 0.22 to 0.75; I2=0%, FE model; NNT, 7.0).

Cardiac death

Cardiac death was observed 1 of 158 patients (0.6%) in nicorandil group and in 5 of 151 patients (3.3%) in control group. Use of nicorandil was associated with a non-significant reduction in cardiac death (RR, 0.39; 95% CI: 0.09 to 1.67; I2=13%; FE model). The reanalysis including the trials with no event on both arms did not change the result (p=0.595).

Subgroup analysis

As specified, we performed a subgroup analysis separately to assess intracoronary administration of nicorandil and intravenous alone for the outcome TIMI flow grade ≤2, and found nicorandil reduced the events significantly in both subgroups (RR, 0.27; 95% CI: 0.13 to 0.59; I2=17%; FE model for the subgroup with intracoronary administration of nicorandil, and RR, 0.69; 95% CI: 0.49 to 0.99; I2=28%; FE model for the subgroup with intravenous administration alone).

Discussion

That is, to the best of our knowledge, the first systematic review and meta-analysis of RCTs that compared nicorandil with no nicorandil or placebo treatment prior to reperfusion in patients with AMI who underwent primary PCI. This systematic review, incorporating more than 1600 patients, showed nicorandil had improved coronary reflow, suppressed reperfusion ventricular arrhythmia, and further improved left ventricular function in this population.

No-reflow phenomenon, which is established at the time of reperfusion as microcirculatory damage, is one of the major causes of impaired functional recovery phase of AMI [25,26]. This analysis showed that administration of nicorandil prior to reperfusion improved the coronary TIMI flow, suppressed ventricular arrhythmia, and further improved left ventricular function. These findings may be due to the effects of nicorandil to suppress reperfusion injury. Nicorandil, as K-ATP channels opener, has potential to dilate resistance arteries with less than 100 µm in diameter [27,28], reduce reactive oxygen species production in cardiac mitochondria at reoxygenation [29], and attenuate ischemia/reperfusion induced polymorphonuclear leukocytes activation via donation of nitric oxide and potassium channel-related cascade [30].

Angiographic microvascular obstruction was defined as TIMI flow grade ≤2 or 3 with a myocardial blush grade <2 in recent studies [31]. In contrast, TIMI flow grade ≤2 and TIMI frame count were used to reflect no/slow reflow in this meta-analysis, which may underestimate the rate of no-reflow events. However, both a retrospective study and a RCT showed that nicorandil reduced the frequency of the no-reflow measured by myocardial contrast echocardiography (MCE) in patients with AMI [17,32], and MCE proves to be a better indicator for assessing microcirculation recovery [33,34].

We have to pay attention to the results of the J-WIND trial [10] which was the largest, multi-center trial among the trials included in this meta-analysis, and found nicorandil treatment could not increase LVEF. However, it was at high risk of incomplete data because of loss of 30% patients at 6 months for measurement of LVEF, and furthermore both arms received oral nicorandil subsequently at the discretion of individual investigators, and the trial showed patients who were given nicorandil orally in the chronic phase had greater increase in LVEF [10] which may be superior to nicorandil treatment prior to reperfusion in a short-term. Further, we performed a sensitive analysis to exclude the trial and found the significant difference remained and heterogeneity was reduced at the endpoint.

Patients with anterior AMI were expected to be at high risk of ventricular arrhythmia, and may have better benefit from ventricular arrhythmia after administration of nicorandil, which may drive the positive result. However, a sensitivity analysis excluding the trial [17] which only enrolled patients with anterior AMI showed significant reduction in ventricular arrhythmia remained (p=0.003).

There are limitations in the present study. Firstly, one of the major limitations is the small sample size of this meta-analysis, which may give rise to the inconclusive clinical benefit of nicorandil, as we found nicorandil has potential to improve coronary reflow and LVEF and previous studies have shown no or slow coronary reflow and LVEF are the important determinants of prognoses after AMI [35-37]. So additional large scale researches are required to confirm the impact of nicorandil prior to reperfusion on clinical outcomes. Meanwhile, the small sample size might also lower the power to conclude the benefit of these surrogate endpoints. Secondly, a majority of trials in this meta-analysis did not report whether to use random sequence or allocation concealment, thus some trials with high risk bias might be included. Thirdly, this review contained trials regardless of dose of nicorandil, administration routes, duration of follow-up and location of occlusion which may also bring some heterogeneity. Fourthly, we did not perform subgroup analyses to evaluate nicorandil in patients with angina before onset of myocardial infarction, which may mimic ischemic precondition to abolish the effect of nicorandil [38], but few related data was allowed to be pooled. Fifthly, the majority of the trials included are limited to Japan. Finally, we did not show the incidence of side effects of nicorandil since the trials included did not provide related information. Recent evidences showed that nicorandil can induce ulceration [39], but some have postulated that the risk of ulceration is dose dependent [40] , so the dose of nicorandil prior to reperfusion may be not enough to cause ulceration. In addition, a small study found that high-dose nicorandil therapy (bolus intravenous injection 0.2mg/kg followed by 0.2mg/kg/h for ≥24h) prior to reperfusion could be completed safely without any increase in hypotension, fatal arrhythmia, or nicorandil discontinuation in patients with AMI compared to standard dose nicorandil therapy (infusion at 0.2mg/kg/h for ≥24h) [41].

Conclusions

Nicorandil prior to reperfusion is associated with improvement of coronary reflow as well as suppression of reperfusion ventricular arrhythmia, and further improves left ventricular function in patients who suffered from AMI and underwent primary PCI. But the definite clinical benefits of nicorandil were not found, which may be due to the small sample size of the selected studies. Additional large scale researches are required to confirm the impact of nicorandil on clinical outcomes.

Supporting Information

Table S1

Search Strategy.

(DOC)

Click here for additional data file. (124KB, doc)
Checklist S1

PRSIMA 2009 Statement Checklist.

(DOC)

Click here for additional data file. (65.5KB, doc)

Funding Statement

The authors have no support or funding to report.

References

  • 1. ISIS 2 (Second International Study of Infarct Survival). Collaborative Group; (1988) Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 2: 349-360. [PubMed] [Google Scholar]
  • 2. The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators (1997) A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 336: 1621-1628. [DOI] [PubMed] [Google Scholar]
  • 3. Kloner RA (1993) Does reperfusion injury exist in humans? J Am Coll Cardiol 21: 537-545. doi: 10.1016/0735-1097(93)90700-B. PubMed: 8426022. [DOI] [PubMed] [Google Scholar]
  • 4. Gross G, Pieper G, Farber NE, Warltier D, Hardman H (1989) Effects of nicorandil on coronary circulation and myocardial ischemia. Am J Cardiol 63: 11-17. doi: 10.1016/0002-9149(89)90199-9. [DOI] [PubMed] [Google Scholar]
  • 5. Pieper GM, Gross GJ (1992) Anti-free-radical and neutrophil-modulating properties of the nitrovasodilator, nicorandil. Cardiovasc Drugs Ther 6: 225-232. doi: 10.1007/BF00051143. PubMed: 1322163. [DOI] [PubMed] [Google Scholar]
  • 6. Nelson MT, Quayle JM (1995) Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol 268: 799-822. PubMed: 7733230. [DOI] [PubMed] [Google Scholar]
  • 7. Imagawa J, Baxter GF, Yellon DM (1998) Myocardial protection afforded by nicorandil and ischaemic preconditioning in a rabbit infarct model in vivo. J Cardiovasc Pharmacol 31: 74-79. doi: 10.1097/00005344-199801000-00011. PubMed: 9456280. [DOI] [PubMed] [Google Scholar]
  • 8. Ishii H, Ichimiya S, Kanashiro M, Amano T, Imai K et al. (2005) Impact of a single intravenous administration of nicorandil before reperfusion in patients with ST-segment-elevation myocardial infarction. Circulation 112: 1284-1288. doi: 10.1161/CIRCULATIONAHA.104.530329. PubMed: 16116055. [DOI] [PubMed] [Google Scholar]
  • 9. Ono H, Osanai T, Ishizaka H, Hanada H, Kamada T et al. (2004) 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 148: 15-15. PubMed: 15459610. [DOI] [PubMed] [Google Scholar]
  • 10. Kitakaze M, Asakura M, Kim J, Shintani Y, Asanuma H et al. (2007) Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials. Lancet 370: 1483-1493. doi: 10.1016/S0140-6736(07)61634-1. PubMed: 17964349. [DOI] [PubMed] [Google Scholar]
  • 11. Higgins JPT, Altman DG, Sterne AC (2011) Chapter 8: Assessing risk of bias in included studies; Higgins JPT, Green S (editors) Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration 2011: 182-228
  • 12. Sweeting MJ, Sutton AJ, Lambert PC (2004) What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 23: 1351-1375. doi: 10.1002/sim.1761. PubMed: 15116347. [DOI] [PubMed] [Google Scholar]
  • 13. Miyazawa A, Ikari Y, Tanabe K, Nakajima H, Aoki J et al. (2006) Intracoronary nicorandil prior to reperfusion in acute myocardial infarction. EuroIntervention 2: 211-217. PubMed: 19755263. [PubMed] [Google Scholar]
  • 14. Toyama T, Seki R, Hoshizaki H, Kawaguchi R, Isobe N et al. (2006) Nicorandil administration shows cardioprotective effects in patients with poor TIMI and collateral flow as well as good flow after AMI. Ann Nucl Med 20: 277-285. doi: 10.1007/BF02984644. PubMed: 16856571. [DOI] [PubMed] [Google Scholar]
  • 15. Kawai Y, Hisamatsu K, Matsubara H, Dan K, Akagi S et al. (2009) Intravenous administration of nicorandil immediately before percutaneous coronary intervention can prevent slow coronary flow phenomenon. Eur Heart J 30: 765-772. PubMed: 19276198. [DOI] [PubMed] [Google Scholar]
  • 16. Han CL, Sung GA, Choi JH, Tae KL, Kim J et al. (2008) Effect of intra-coronary nicorandil administration prior to reperfusion in acute ST segment elevation myocardial infarction. Circ J 72: 1425-1429. doi: 10.1253/circj.CJ-08-0212. PubMed: 18724016. [DOI] [PubMed] [Google Scholar]
  • 17. Ito H, Taniyama Y, Iwakura K, Nishikawa N, Masuyama T et al. (1999) Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction. J Am Coll Cardiol 33: 654-660. doi: 10.1016/S0735-1097(98)00604-4. PubMed: 10080465. [DOI] [PubMed] [Google Scholar]
  • 18. Fukuzawa S, Ozawa S, Inagaki M, Shimada K, Sugioka J et al. (2000) Nicorandil affords cardioprotection in patients with acute myocardial infarction treated with primary percutaneous transluminal coronary angiosplasty: Assessment with thallium-201/iodine-123 BMIPP dual SPECT. J Nucl Cardiol 7: 447-453. doi: 10.1067/mnc.2000.107273. PubMed: 11083193. [DOI] [PubMed] [Google Scholar]
  • 19. Nameki M, Ishibashi I, Miyazaki Y, Sakai Y, Namikawa S et al. (2004) Comparison between nicorandil and magnesium as an adjunct cardioprotective agent to percutaneous coronary intervention in acute anterior myocardial infarction. Circ J 68: 192-197. doi: 10.1253/circj.68.192. PubMed: 14993771. [DOI] [PubMed] [Google Scholar]
  • 20. Akagi T, Sarazawa K, Inai Y, Kitagawa M, Takahashi N et al. (2006) Continuous administration of nicorandil decreases QT dispersion during the chronic phase of acute myocardial infarction. Int Heart J 47: 351-361. doi: 10.1536/ihj.47.351. PubMed: 16823241. [DOI] [PubMed] [Google Scholar]
  • 21. Ota S, Nishikawa H, Takeuchi M, Nakajima K, Nakamura T et al. (2006) Impact of nicorandil to prevent reperfusion injury in patients with acute myocardial infarction: Sigmart Multicenter Angioplasty Revascularization Trial (SMART). Circ J 70: 1099-1104. doi: 10.1253/circj.70.1099. PubMed: 16936418. [DOI] [PubMed] [Google Scholar]
  • 22. Atsuchi N, Yokoi H, Kamoi D, Hayashida K, Nakashima H et al. (2007) Effects of nicorandil on left-ventricular remodeling after direct percutaneous coronary interventions in patients with ST-elevation myocardial infarction. J Am Coll Cardiol 49: 215-215. [Google Scholar]
  • 23. Fujiwara T, Matsunaga T, Kameda K, Abe N, Ono H et al. (2007) Nicorandil suppresses the increases in plasma level of matrix metalloproteinase activity and attenuates left ventricular remodeling in patients with acute myocardial infarction. Heart Vessels 22: 303-309. doi: 10.1007/s00380-007-0975-z. PubMed: 17879021. [DOI] [PubMed] [Google Scholar]
  • 24. Ishii H, Amano T, Imai K, Kokubo M, Yamada T et al. (2004) Intravenous Nicorandil before percutaneous coronary intervention has pharmacological preconditioning effects in patients with acute myocardial infarction. Circulation 110: 106-106. [Google Scholar]
  • 25. Lim YJ, Nanto S, Masuyama T, Kohama A, Hori M et al. (1994) Myocardial salvage: its assessment and prediction by the analysis of serial myocardial contrast echocardiograms in patients with acute myocardial infarction. Am Heart J 128: 649-656. doi: 10.1016/0002-8703(94)90260-7. PubMed: 7942434. [DOI] [PubMed] [Google Scholar]
  • 26. Ito H, Tomooka T, Sakai N, Yu H, Higashino Y et al. (1992) Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 85: 1699-1705. doi: 10.1161/01.CIR.85.5.1699. PubMed: 1572028. [DOI] [PubMed] [Google Scholar]
  • 27. Akai K, Wang Y, Sato K, Sekiguchi N, Sugimura A et al. (1995) Vasodilatory effect of nicorandil on coronary arterial microvessels: its dependency on vessel size and the involvement of the ATP-sensitive potassium channels. J Cardiovasc Pharmacol 26: 541-547. doi: 10.1097/00005344-199510000-00006. PubMed: 8569213. [DOI] [PubMed] [Google Scholar]
  • 28. Takahashi K, Ohyanagi M, Kobayashi S, Iwasaki T, Miyamoto T (2000) Effect of angiotensin-converting enzyme inhibitors and nitroxy groups on human coronary resistance vessels in vitro. J Cardiovasc Pharmacol 36: 417-422. doi: 10.1097/00005344-200010000-00001. PubMed: 11026640. [DOI] [PubMed] [Google Scholar]
  • 29. Ozcan C, Bienengraeber M, Dzeja PP, Terzic A (2002) Potassium channel openers protect cardiac mitochondria by attenuating oxidant stress at reoxygenation. Am J Physiol Heart Circ Physiol 282: 531-539. PubMed: 11788400. [DOI] [PubMed] [Google Scholar]
  • 30. Yasu T, Ikeda N, Ishizuka N, Matsuda E, Kawakami M et al. (2002) Nicorandil and leukocyte activation. J Cardiovasc Pharmacol 40: 684-692. doi: 10.1097/00005344-200211000-00006. PubMed: 12409977. [DOI] [PubMed] [Google Scholar]
  • 31. Niccoli G, Rigattieri S, De Vita MR, Valgimigli M, Corvo P et al. (2013) Open-Label, Randomized, Placebo-Controlled Evaluation of Intracoronary Adenosine or Nitroprusside After Thrombus Aspiration During Primary Percutaneous Coronary Intervention for the Prevention of Microvascular Obstruction in Acute Myocardial Infarction: The REOPEN-AMI Study (Intracoronary Nitroprusside Versus Adenosine in Acute Myocardial Infarction). JACC Cardiovasc Intv 6: 580-589. doi: 10.1016/j.jcin.2013.02.009. [DOI] [PubMed] [Google Scholar]
  • 32. Sugimoto K, Ito H, Iwakura K, Ikushima M, Kato A et al. (2003) Intravenous nicorandil in conjunction with coronary reperfusion therapy is associated with better clinical and functional outcomes in patients with acute myocardial infarction. Circ J 67: 295-300. doi: 10.1253/circj.67.295. PubMed: 12655158. [DOI] [PubMed] [Google Scholar]
  • 33. Monassier JP (2008) Reperfusion injury in acute myocardial infarction: from bench to cath lab. Part II: Clinical issues and therapeutic options. Arch. Cardiovasc Dis 101: 565-575. doi: 10.1016/j.acvd.2008.06.013. [DOI] [PubMed] [Google Scholar]
  • 34. Hayat SA, Senior R (2008) Myocardial contrast echocardiography in ST elevation myocardial infarction: ready for prime time? Eur Heart J 29: 299-314. doi: 10.1093/eurheartj/ehm621. PubMed: 18245118. [DOI] [PubMed] [Google Scholar]
  • 35. Gibson CM, Cannon CP, Murphy SA, Marble SJ, Barron HV et al. (2002) Relationship of the TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention to long-term outcomes after thrombolytic administration in acute myocardial infarction. Circulation 105: 1909-1913. doi: 10.1161/01.CIR.0000014683.52177.B5. PubMed: 11997276. [DOI] [PubMed] [Google Scholar]
  • 36. Morishima I, Sone T, Okumura K, Tsuboi H, Kondo J et al. (2000) Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction. J Am Coll Cardiol 36: 1202-1209. doi: 10.1016/S0735-1097(00)00865-2. PubMed: 11028471. [DOI] [PubMed] [Google Scholar]
  • 37. Nicolosi GL, Latini R, Marino P, Maggioni AP, Barlera S et al. (1996) The prognostic value of predischarge quantitative two-dimensional echocardiographic measurements and the effects of early lisinopril treatment on left ventricular structure and function after acute myocardial infarction in the GISSI-3 Trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. Eur Heart J 17: 1646-1656. doi: 10.1093/oxfordjournals.eurheartj.a014747. PubMed: 8922912. [DOI] [PubMed] [Google Scholar]
  • 38. Ishii H, Ichimiya S, Kanashiro M, Amano T, Ogawa Y et al. (2007) Effect of intravenous nicorandil and preexisting angina pectoris on short- and long-term outcomes in patients with a first ST-segment elevation acute myocardial infarction. Am J Cardiol 99: 1203-1207. doi: 10.1016/j.amjcard.2006.12.034. PubMed: 17478142. [DOI] [PubMed] [Google Scholar]
  • 39. Smith VM, Lyon CC (2013) Results of an electronic survey of British Association of Dermatologists members: nicorandil ulceration. Br J Dermatol 168: 1136-1137. doi: 10.1111/bjd.12199. PubMed: 23464596. [DOI] [PubMed] [Google Scholar]
  • 40. Robinson AJ, Stevenson JH (2013) Discontinue treatment with nicorandil associated with ulceration to avoid major reconstructive surgery. BMJ 347: 4295-4295. doi: 10.1136/bmj.f4295. PubMed: 23861409. [DOI] [PubMed] [Google Scholar]
  • 41. Suematsu Y, Murasato Y, Miura SI, Horiuchi M, Yamamoto T et al. (2013) Safety and feasibility of high-dose administration of nicorandil before reperfusion therapy in acute myocardial infarction. Cardiovasc Interv Ther, 28: 2013. Apr 27 [Epub ahead of print]. PubMed: 23625617. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1

Search Strategy.

(DOC)

Click here for additional data file. (124KB, doc)
Checklist S1

PRSIMA 2009 Statement Checklist.

(DOC)

Click here for additional data file. (65.5KB, doc)

Articles from PLoS ONE are provided here courtesy of PLOS

RESOURCES