The Efficacy and Safety of Nicorandil for Periprocedural Myocardial Injury in Patients Undergoing PCI: A Meta-Analysis

Purpose To evaluate the efficacy and safety of nicorandil for periprocedural myocardial injury in patients undergoing PCI through meta-analysis of randomized controlled trials. Methods We analyzed the clinical data of patients including the incidence of periprocedural myocardial injury (PMI) and major adverse cardiovascular events (MACE) from selected articles. RCTs were retrieved from medical literature databases. RR and 95% confidence intervals (CI) were calculated to compare the endpoints. Results In total, 15 articles (16 trial comparisons) were retrieved which contained 2221 patients. In general, 1130 patients (50.9%) were randomized to the experimental group, whereas 1091 patients (49.1%) were randomized to the control group. The result showed that nicorandil significantly reduced the incidence of PMI and MACE after PCI compared to the control group. Conclusions Overall, early use of nicorandil in patients undergoing percutaneous coronary intervention (PCI) was associated with a significant reduction of PMI and MACE.


Introduction
Percutaneous coronary intervention (PCI) is a nonsurgical procedure used to treat narrowing of the coronary arteries of the heart found in coronary artery disease [1]. In patients with a restricted or blocked coronary artery, PCI may be the best option to reestablish blood flow as well as prevent angina (chest pain), myocardial infarctions (heart attacks), and death [2]. us, PCI is widely practiced in clinics.
Percutaneous coronary intervention (PCI) is associated with a small but significant incidence of serious procedural complications such as death, stroke, life-threatening bleeding, or large myocardial infarction (MI) [3]. Periprocedural myocardial injury, which can range from a lowlevel elevation of cardiac biomarkers to a large MI, is the most common complication and causes high mortality and prolonged hospital stays. e main causes of perioperative myocardial injury after PCI are distal embolization, sidebranch occlusion, coronary dissection, and disruption of collateral flow [4].
Periprocedural myocardial injury includes angiographical slow coronary flow, microvascular embolization, and elevated levels of cardiac enzyme, such as creatine kinase and troponin-T and -I. Myocardial reperfusion injury at the beginning of myocardial reperfusion, which causes tissue damage and cardiac dysfunction, may also occur in cases of acute coronary syndrome [5].
Specific biomarkers are used for quantitative diagnosis of irreversible myocardial injury, and the release of these biomarkers is associated with increased risk of death and myocardial infarction (MI) [6]. A previous report showed that serum creatine kinase MB fraction (CK-MB) is elevated above the upper limit of normal (ULN) in 10 to 38 percent of patients after an uncomplicated percutaneous coronary intervention (PCI), and elevations more than three times the ULN are considered to represent an infarction large enough to be associated with short-term complications in 7 to 18 percent of patients [7]. Another report also indicated that a 5-fold postprocedural elevation of cardiac troponin-T above normal levels is an independent predictor of a composite of death, MI, and revascularization at 1 year (hazard ratio, 2.39; 95% confidence interval, 1.09-5.26) [8].
Because PMI also occurs in a significant proportion of patients with successful surgery, and the patients with myocardial injury are associated with a wide range of myocardial infarction, the long-term prognosis is also worse than those without myocardial injury [9].
Pharmacologic interventions, such as statins and glycoprotein IIb/IIIa inhibitors, which have anti-inflammatory and antithrombotic effects, respectively, are usually used before PCI and have been shown to reduce the incidence and degree of myocardial necrosis [10]. However, articles have shown that cardiac troponin levels are still elevated in 29% of patients after PCI, and the incidence of PCI-related myocardial infarction is still as high as 15% [11].
Nitrate may have a cardioprotective effect and is an independent factor for the outcomes of patients with PMI, and nicorandil has a potential dose-dependent protective effect for cardiac ischemia [12]. Nicorandil is an antianginal medication that has the dual properties of a nitrate and ATPsensitive K + channel agonist. In humans, the nitrate action of nicorandil dilates the large coronary arteries at low plasma concentrations. At high plasma concentration, nicorandil decreased coronary resistance, which was related to the increase of (KATP) opening of ATP-sensitive potassium channel [13]. e pharmacological treatment of ATP-sensitive potassium channel openers has a cardioprotective effect similar to that of ischemic preconditioning (IPC: brief episodes of cardiac ischemia and reperfusion before a subsequent prolonged ischemia), and the effect of ischemic preconditioning helps to avoid PMI [14]. erefore, nicorandil has important therapeutic significance for myocardial injury after PCI.
However, the conclusion of whether nicorandil has myocardial protective effect is not consistent in clinic. Some studies showed that oral administration of nicorandil reduced the incidence of major cardiovascular events in patients with angina pectoris [15]. However, in other trials, intravenous nicorandil did not reduce the incidence of PMI or the slow-flow phenomenon following elective PCI, and certain studies refuted the beneficial effect of nicorandil against ischemia and reperfusion injury [8].
us, it is still uncertain whether nicorandil can effectively prevent PMI after PCI; we have carried on the systematic meta-analysis to this.

Search Strategy.
Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [16], two authors, respectively, searched the literature on evaluating the safety and efficacy of nicorandil in percutaneous coronary intervention (PCI). We comprehensively researched for RCTs in the data platforms including Embase, PubMed, and Cochrane Library without limitations on language or date of publication from inception to January 27, 2020. We used "nicorandil" and "percutaneous coronary intervention" as the key words. Additional relevant literature was obtained from other reviews and meta-analyses. e retrieved studies were double-reviewed by two authors. When there were disputes, a third author was asked to consult. In this meta-analysis, we obtained patient information from already published reports, and hence, ethical approval or patient consent was waived.

Criteria for Exclusion and Inclusion of Studies.
Inclusion criteria were as follows: (1) studies that provided sufficient data for analysis; (2) studies that evaluated the safety and efficacy of nicorandil in percutaneous coronary intervention (PCI); (3) patients treated by PCI; (4) studies where at least one group was treated with nicorandil; (5) the use of nicorandil being not limited in dose and usage; (7) studies published in English; (8) the participants being Asian; and (9) randomized controlled trials (RCTs).
Exclusion criteria were as follows: (1) animal experiments; (2) case reports, nonclinical trials, or series; (3) nonrandomized trials or semirandomized controlled trials; and (4) studies with incomplete or incorrect information, or those with information that cannot be accessed.

Endpoints.
e primary effective endpoint was perioperative myocardial injury (PMI). e safety endpoint was major adverse cardiovascular events (MACE).

Data Extraction.
e studies included were scrutinized by two investigators independently to extract data. ese investigators retrieved data regarding the primary endpoints and these data were verified by a third author. e following information was extracted: primary information: endpoints measured in each study, follow-up time, intervention, smoking, diabetes, BMI, average age, sex ratio, sample size, country of patients, year of publication, and first author's name. For missing data or the need for clarification, we contacted the first author to access such data. Any discrepancies were addressed by consensus or by involvement of a third author.

Assessment of the Risk of Bias.
e Cochrane Risk of Bias criteria [17] were used to assess the methodological quality of the articles studies which was performed by two authors working independently. e quality level of the studies was categorised as high risk, low risk, or some concerns. e bias of each trial was assessed by 5 items as follows: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome, and bias in selection of the reported result.
2.6. Data Analysis. Individual data were pooled and analyzed using the Stata (version 12.0, Stata Corp, College Station, Texas). Pooled data are presented as 95% confidence intervals (CI) with two-sided P values and risk ratios (RR). P values <0.05 were regarded as statistically significant. e I 2 test and Cochran's Q test were performed to detect heterogeneity. e heterogeneity was defined as small when I 2 < 50% and significant when I 2 < 50%. If I 2 was <50%, the fixed effect model was applied; otherwise, the random effect model was applied if I 2 was >50%. We established a funnel plot to assess publication bias and determine sources of heterogeneity if more than ten studies were included to assess this endpoint.

Assessment of Quality of the Studies.
We applied the Cochrane Risk of Bias criteria to assess the quality of the enrolled studies and this process was done by two investigators independently. All studies were randomized controlled trials. 15 studies [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] provided the process of randomization. Two studies [21,23] mentioned blinding of personnel and subjects. e quality of the literature studies is provided in Table 2 (Figure 2). us, we applied the fixed effect model.

Publication Bias and Sensitivity Analysis.
e funnel plot showed that there was low probability of publication bias among retrieved articles as shown in Figures 4 and 5.

Discussion
Percutaneous coronary intervention (PCI) has become a mature technique in the treatment of coronary artery stenosis [8]. However, severe surgical complications have also been reported and perioperative myocardial injury (PMI) is the most common. Intervention with statins and glycoprotein IIb/IIIa inhibitors prior to PCI has been shown to reduce the incidence and degree of myocardial necrosis, but the incidence is still as high as 15% [33].
Nicorandil, a combined agent with an adenosine triphosphate-sensitive K (K +-ATP) channel agonist and nitrate preparation, could improve clinical outcomes for ischemic heart disease through relieving both microcirculation dysfunction and myocardial injury [34], but it is still uncertain whether nicorandil can effectively prevent PMI after PCI, and the preventive effect of nicorandil on myocardial injury after PCI has attracted much attention in recent years. us, the purpose of the systematic meta-analysis we conducted was to evaluate the myocardial protective effect of nicorandil.
Nowadays, there are only a few meta-analyses to study the relationship between the use of nicorandil before percutaneous coronary intervention (PCI) and cardiovascular events, and the conclusions are inconsistent. Li et al. [35] conducted a meta-analysis and found that nicorandil administration reduces cardiovascular events and NRP, but the study only reflected the short-term effects of combining primary PCI with nicorandil administration. e study by Zhang et al. [36] suggested that nicorandil, as an adjuvant therapy with PCI, can reduce total mortality and cardiovascular death in patients with primary PCI (PPCI) and elective PCI (EPCI) and reduce heart failure in PPCI patients. Zhu et al. [37] said that nicorandil did not reduce the overall incidence of perioperative complications and the incidence of major adverse cardiac events (MACE) in patients with angina pectoris who underwent elective PCI. Li et al. [38] suggested that nicorandil could improve clinical outcomes in terms of perioperative myocardial infarction (MI). However, the effect of nicorandil on the major adverse cerebrovascular and cardiovascular events (MACCE) risk is not obvious. Ye et al. [39] indicated 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 population.
Our meta-analysis evaluated the efficacy of nicorandil in the prevention of myocardial infarction and major adverse cardiovascular events (MACE) in patients after PCI. e results showed that compared with the control group, nicorandil significantly reduced the incidence of myocardial infarction and major adverse cardiovascular events (MACE) after PCI (RR: 0.67, 95% CI: 0.58 to 0.79; RR: 0.71, 95% CI: 0.58 to 0.86). e potential clinical implications of this meta-analysis are as follows: (1) compared to previous studies, a total of 15 Journal of Interventional Cardiology articles (16 trial comparisons) were included, with a larger sample size of 2,221 patients. (2) In previous studies, diabetes patients accounted for a relatively high proportion, and oral sulfonylureas were considered to inhibit the effect of nicorandil and cause bias. In this study, other diseases and drug effects were excluded, and the results were more objective.
(3) Compared with previous studies, this study included literature from different regions of China, Japan, South Korea, Russia, and Egypt, and the quality of the included literature was higher. e limitations of our meta-analysis include the following aspects: (1) the included studies are mainly from Asia, and there is a lack of randomized controlled trials from North America, Europe, and so on. (2) e mode of drug administration is not uniform. Some articles adopt the method of oral administration, some articles use the method of intravenous administration, and some articles use the method of coronary artery administration, which may lead to methodological deviation. (3) Although the articles included in our meta-analysis are randomized controlled    trials, the blind methods of most studies are not clear, and there will inevitably be deviations. (4) To evaluate the myocardial protective effect of nicorandil on patients after PCI, short-term and long-term indexes need to be observed.
ere are few indicators in this article.
Our study suggests that we should pay attention to several aspects of randomized controlled trials in the future: (1) due to ethnic differences, it is necessary to conduct multiregional and multicenter randomized controlled trials. (2) Standardize the methods of drug use, including usage, dosage, and time of use, so as to reduce the occurrence of confusion bias as much as possible. (3) e methods of random grouping, single-blind or doubleblind and their implementation are described in detail to reduce the hybrid deviation. (4) Increase the short-term and long-term indicators and increase the reliability of the results.
is meta-analysis showed that compared with the control group, nicorandil significantly reduced the incidence of myocardial infarction and major adverse cardiovascular           Journal of Interventional Cardiology 9