The clinical effect of nicorandil on perioperative myocardial protection in patients undergoing elective PCI: A Systematic Review and Meta-Analysis

Many scholars have studied the effect of nicorandil on perioperative myocardial protection in patients undergoing elective percutaneous coronary intervention (PCI), but results are inconsistent. Therefore, we performed this meta-analysis. Finally, 16 articles, including 1616 patients, were included into this meta-analysis. Meta-analysis results showed that: (1) Nicorandil can reduce the level of CK-MB after PCI, including at 6 hours, 12 hours, 18 hours and 24 hours. (2) Nicorandil can reduce the level of TnT after PCI, including at 6 hours, 12 hours, 18 hours and 24 hours. (3) Nicorandil can reduce the incidence of adverse reactions after PCI. (4) Nicorandil cannot reduce the level of MVP after PCI, including at 12 hours and 24 hours. (5) Subgroup analysis showed that nicorandil can reduce CK-MB and TnT level at 24 hours after PCI for Chinese’s population (P < 0.05), but can not reduce CK-MB and TnT level at 24 hours after PCI for non Chinese’s population (P > 0.05). Our meta-analysis indicate that nicorandil can reduce myocardial injury and reduce the incidence of adverse reaction caused by PCI for Chinese’s population, but is not obvious for non Chinese’s population. However, this conclusion still needs to be confirmed in the future.


Results
Study Selection and Characteristics. Finally, 543 articles were retrieval by searching the electronic databases and references of relevant articles. After excluding duplicate articles, 425 articles were left. By screening titles and abstracts of remaining articles, 382 apparently irrelevant articles were excluded. Then, the full texts of 43 articles were downloaded to evaluate in detail. Eventually, data from 16 articles [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] include 1616 patients were listed into this meta-analysis. Among these patients, 804 patients in the nicorandil group and 812 patients in the control group. The flow diagram of study selection is shown in Fig. 1. The basic information of each included literature is shown in Table 1.
MPV after PCI. Nicorandil cannot significantly reduce the level of MVP in patients after PCI, including at 12 hours (P = 0.078) and 24 hours (P = 0.445). As showed in Fig. 7.
Publication bias. Egger regression analysis was used to evaluate the publication bias. There was no publication bias of CK-MB at 24 hours after PCI (Egger's test: P = 0.214) (Fig. 8A). There was also no publication bias of TnT at 24 hours after PCI (Egger's test: P = 0.978) (Fig. 8B).

Discussion
Percutaneous coronary intervention (PCI) is one of the most effective methods for the treatment of myocardial infarction (MI) or unstable angina [42][43][44] . Compared with traditional drug therapy, PCI can more effectively restore the blood supply to the myocardium and improve the prognosis of patients. However, a lot of studies have shown that there are still approximately 3% of patients failing to benefit from the treatment of PCI. On the contrary, the phenomenon of myocardial injury was appeared in a patient after PCI, which seriously affects the patient's heart function and prognosis. Therefore, how to improve the blood flow perfusion of the ischemic myocardium after PCI and reduce the occurrence of myocardial injury is of particular importance. Research has shown that the K+ -ATP channel opener (such as nicorandil) can significantly reduce arrhythmia, chest pain and slow reflow phenomenon caused by PCI 45,46 . However, the conclusion, whether nicorandil has a myocardial protective effect is inconsistent. Thus, we conduct this meta-analysis.
In 2012, Kim S 28 enrolled 213 consecutive patients with stable or unstable angina, which were expected in non-urgent PCI for de-novo coronary lesions. 54 patients in the nicorandil group and 55 patients in the control group. The purpose of the study is to assess whether nicorandil has a myocardial protective effect or not. Finally,   they found that there were no significant differences in the incidence of post-procedural myocardial necrosis among the two groups (10.9% vs 14.8%, respectively, p = 0.9) and there were no significant differences in the incidence of post-procedural MI among two groups (p = 0.6). Meanwhile, in 2013, Hwang J 26 conducted a clinical experiment includes 41 patients in the nicorandil group (n = 41) and 40 patients in the control group (n = 40). In the nicorandil group before PCI, four mg of intracoronary nicorandil was infused prior, and the results showed that the post-PCI peak CK-MB and troponin I levels were not significantly different between the two groups. However, Isono T 41 conducted an experiment, including 29 patients undergoing elective PCI. And they found that nicorandil can suppress elevations of cardiac enzymes after elective PCI, suggesting that nicorandil enhances the myocardial protective effect of PCI against angioplasty-related myocardial injury. Kim S 28 and Shehata M 29 have also carried out a trial, and they results showed that nicorandil can protect the myocardium, which was different from Hwang J and Kim J. Therefore, it is necessary to make a systematic evaluation of this conclusion. In our meta-analysis, a total of 16 randomized controlled trials (RCTs) were included, and 1616 patients entered our study. Our results showed that nicorandil can reduce the levels of CK-MB and TnT after elective PCI and the     (Fig. 8A). There was also no publication biasof TnT at 24 hours after PCI (Egger's test: P = 0.978) (Fig. 8B).
Scientific RepoRts | 7:45117 | DOI: 10.1038/srep45117 incidence of adverse reaction caused by PCI for Chinese's population, but the clinical benefit of nicorandil is not obvious for non Chinese's population. Through this meta-analysis, we speculated that nicorandil has a cardioprotective effect for Chinese's population, but may not be appropriate for non Chinese's population.
Nicorandil is an ATP sensitive potassium channel (KATP) open agent with the effect of nitrate 47,48 . At the present, research on the myocardial protective effect of nicorandil after PCI is intravenous administration. Results have shown that intravenous nicorandil before PCI can significantly reduce the incidence of coronary slow flow after postoperative 49,50 . The mechanism may be related with the decrease of infiltration of neutrophils into the ischemic area, which leading to the decrease of neutrophil mediated microcirculation. Our meta analysis results showed that when compared with the control group, the myocardial enzyme levels were significantly decreased in the nicorandil group after PCI, and the myocardial enzyme level of some time point was lower than that of the control group (P < 0.05). Acting as a KATP agent, nicorandil can shorten the action potential duration, inhibit calcium overload. Furthermore, nicorandil can antagonize ADP induced platelet aggregation, improve microcirculation in ischemia area, decrease no reflow phenomenon. In addition, nicorandil can inhibit the formation of active oxygen, which is one of the mechanisms implicated in the protective effect on the myocardium 51 .
The limitations of our meta-analysis include the following aspects: ① The included studies are mainly coming from China, Japan and Korea, lacking of randomized controlled trials from North America and Europe. ② The method of drug delivery is uniform. Some articles adopted the method of oral administration, and some articles adopted the method of intravenous administration, even some articles using the method of coronary administration, which may lead to a certain bias in implementation. In addition, there is no unity for the dosage and using time for Nicorandil. The possibility of implementation bias is further increased. ③ Although the articles included in our meta-analysis were RCT, but most of the studies were single-blind RCT, bias will be inevitable appear. ④ Short-term and long-term index need to be observed to evaluate the myocardial protective effects of nicorandil in patients after PCI. Because CK-MB, TnT, MPV and adverse reactions all belongs to short-term index, lacking the long-term index (For example, heart failure, myocardial infarction and arrhythmia, etc.) to estimate the effect of nicorandil, the representation is poor.
Our study also suggests that some aspects should be paid attention to in the future when carrying out RCT: ① Due to the difference of nation and race, it needs to conduct RCT of multi-regional and multi-center, in order to evaluate the clinical efficacy of a drug. ② To regulate the use method of drugs, including usage, dosage and use of time, as far as possible to reduce the occurrence of confounding bias. ③ Describe the method of random grouping, single-blind or double-blind and the implementation of the method in detail, so as to reduce confounding bias. ④ Long-term indicators should be increased to estimate the clinical effect after PCI, and then increase the reliability of results.

Conclusion
Our systematic review and meta-analysis indicate that nicorandil can reduce myocardial injury and reduce the incidence of adverse reaction caused by PCI for Chinese's population, but the clinical benefit of Nicorandil is not obvious for Non Chinese's population. However, due to the limitations of the quality and quantity of the articles, this conclusion still needs to be confirmed by multi-center, double-blind, randomized controlled trials.

Methods
Literature search. According to the statement of the preferred reporting items for Systematic Reviews and Meta-Analyses, two researchers independently searched published randomized controlled trial(RCT) that investigated the clinical effect of nicorandil on prevention of perioperative myocardial injury in patients undergoing elective PCI. The retrieved database includes PubMed, Embase, the Cochrane Library, Web of Science, CBM, CNKI, VIP database and Wang Fang database, the retrieval time was limited from inception to October 7, 2016. Relevant keywords related to nicorandil in combination as MeSH terms and text words ("Nicorandil" or "2-Nicotinamidoethyl Nitrate" or "2 Nicotinamidoethyl Nitrate" or "Nitrate, 2-Nicotinamidoethyl" or "2-Nicotinamidethyl Nitrate" or "2 Nicotinamidethyl Nitrate" or "Nitrate, 2-Nicotinamidethyl" or "SG-75" or "SG 75" or "SG75" or "Ikorel" or "Aventis Pharma Brand of Nicorandil" or "Rhône-Poulenc Rorer Brand of Nicorandil" or "Rhône Poulenc Rorer Brand of Nicorandil" or "Aventis Brand of Nicorandil" or "Nicorandil Aventis Brand" or "Adancor") were used in combination with words related to percutaneous coronary intervention and myocardial reperfusion injury("Coronary Intervention, Percutaneous" or "Coronary Interventions, Percutaneous" or "Intervention, Percutaneous Coronary" or "Interventions, Percutaneous Coronary" or "Percutaneous Coronary Interventions" or "Percutaneous Coronary Revascularization" or "Injuries, Myocardial Reperfusion" or "Myocardial Reperfusion Injuries" or "Reperfusion Injuries, Myocardial" or "Myocardial Ischemic Reperfusion Injury" or "Reperfusion Injury, Myocardial" or "Injury, Myocardial Reperfusion"). The retrieval language was limited to Chinese and English. In addition, reference articles of the extracted articles were also retrieved. When multiple reports of the same study were present, we used the most recent publication and supplemented it. All analyses were based on previously published studies, and thus no ethical approval or patient consent was required.

Study selection.
We identified studies that prospectively evaluated the clinical effect of nicorandil on prevention of perioperative myocardial injury in patients undergoing elective PCI. Inclusion criteria:① The study was limited to randomized controlled trials (randomized controlled trials, RCTs), and the purpose of the study was to evaluate the effect of nicorandil on prevention of perioperative myocardial injury in patients undergoing elective PCI; ② At least one of the observation group was applied nicorandil in the experiment; ③ The does and usage of nicorandil is not limited; ④ The article should provide sufficient data for analysis; ⑤ The study subjects were patients undergoing elective PCI, and coronary angiography was performed; ⑥ The retrieval language is limited to Chinese and English.
Scientific RepoRts | 7:45117 | DOI: 10.1038/srep45117 Exclusion criteria: ① Retrospective, non-randomized trial; ② Semi randomized controlled trial, in which the grouping method of the participants in the experiment was not strictly random; ③ Patients with acute myocardial infarction (AMI) or with AMI within the last 6 months; ④ Articles with incomplete or erroneous data. Data extraction. The contents of the retrieved articles were reviewed by two researchers (ZY and QS) in accordance with the prior search methods. Data to be extracted including basic data of subjects (First author, publication year, country, sample number, average age, use method of nicorandil (dose), preoperative method of control group and outcome measures). If there was a lack of necessary data or some content to be clarified in the articles, an effort was made to try to make contact with the study authors, and if the necessary data to analyze was still unavailable, this article was excluded.
Statistical analyses. We used the Stata software, version 11.0 (Stata Corp, College Station, Tex) to pool and analyze results from the individual studies. Pooled results were reported as relative risks (RRs) and standardized mean difference (SMD), and presented with 95% confidence interval (CI) with two-sided P-values. P < 0.05 indicates that the difference was statistically significant. Heterogeneity of the inclusion study was assessed by I 2 test, which assessed the appropriateness of pooling the individual study results. When I 2 < 50%, the heterogeneity of the study was considered small; When I 2 > 50%, the heterogeneity of the study was considered substantial, and then subgroup analysis and sensitivity analysis were performed to investigate the sources of heterogeneity. If necessary, meta-regression analysis was performed to explore heterogeneity.