http://orcid.org/0000-0002-9039-3439
Figures
Abstract
Background
Our previous study examined an effect of remote ischemic preconditioning (RIPC) or intravenous nicorandil on reduction of periprocedural myocardial injury (pMI) following percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD). We further investigated the effect of RIPC or nicorandil on pMI in older patients.
Methods
Patients with stable CAD who planned to undergo PCI were assigned to a 1:1:1 ratio to control, intravenous nicorandil, or upper-limb RIPC groups. This substudy analyzed patients aged >65 years (n = 282) from the principal cohort. The primary outcome was the incidence of pMI following PCI. We defined pMI as an elevated level of high-sensitive cardiac troponin T or creatine kinase myocardial band 12 or 24 hours after PCI.
Results
We found that pMI following PCI was significantly reduced in the nicorandil group compared with the control group (37.2% vs. 53.7%, multiplicity-adjusted p = 0.046), but not in the RIPC group compared with the control group (43.0% vs. 53.7%, multiplicity-adjusted p = 0.245). The adjusted odds ratios (95% confidence interval) for pMI in the RIPC and nicorandil groups versus the control group were 0.63 (0.34 to 1.16) and 0.51 (0.27 to 0.96), respectively.
Citation: Kawakita N, Ejiri K, Miyoshi T, Kohno K, Nakahama M, Doi M, et al. (2018) Protective effect of nicorandil on myocardial injury following percutaneous coronary intervention in older patients with stable coronary artery disease: Secondary analysis of a randomized, controlled trial (RINC). PLoS ONE 13(4): e0194623. https://doi.org/10.1371/journal.pone.0194623
Editor: Yoshihiro Fukumoto, Kurume University School of Medicine, JAPAN
Received: September 2, 2017; Accepted: February 27, 2018; Published: April 16, 2018
Copyright: © 2018 Kawakita et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This study was funded by the Okayama Medical Foundation, http://omf.umin.ac.jp. TM received honorarium from Chugai Pharmaceutical Co. HI received a research grant and honorarium from Chugai Pharmaceutical Co. The funder provided support in the form of salaries for authors [TM and HI], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
Competing interests: TM received honorarium from Chugai Pharmaceutical Co. HI received a research grant and honorarium from Chugai Pharmaceutical Co. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Introduction
Periprocedural myocardial injury (pMI) is a complication of elective percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) and affects long-term prognosis [1,2]. The potential contributing mechanisms for pMI following elective PCI in patients with stable angina include downstream embolization of atheromatous material and coronary side-branch occlusion [3,4]. However, pMI is associated with various factors, including procedure-related, lesion-related, and patient-related factors [5]. Patient-related factors are involved in multivessel disease, diabetes mellitus, chronic kidney disease and older age, which increase the risk of postprocedural creatine kinase myocardial band (CK-MB) release by 1.3- to 1.8-fold. [6,7,8,9,10]
Several approaches, including remote ischemic preconditioning (RIPC) and nicorandil, have been evaluated to increase cardiac tolerance to ischemic injury following PCI [11,12,13,14,15,16,17,18,19]. RIPC is defined as when transient nonfatal ischemia and reperfusion applied to one organ or tissue protects another organ or tissue from a subsequent episode of fatal ischemia and reperfusion [20]. Nicorandil activates adenosine triphosphate-sensitive potassium channels in mitochondria, and this plays a role in imitating ischemic preconditioning [21,22,23].
We recently reported a multicenter, randomized trial that examined whether pre-procedural RIPC or intravenous nicorandil reduces pMI in patients who undergo elective PCI for stable CAD. This study showed that RIPC or intravenous nicorandil moderately reduced biomarker release and pMI in patients with stable CAD, but these results were not significant [24]. Therefore, an exploratory analysis to identify a population in whom RIPC or intravenous nicorandil is effective was planned. We hypothesized that age influences the effect of RIPC or intravenous nicorandil on pMI. This hypothesis was based on the finding that age was a predictor of pMI [5] and related to short-term and long-term critical events, such as death, in patients who had PCI for acute coronary syndrome [25,26]
This study aimed to investigate the efficacy of RIPC or intravenous nicorandil on pMI in older patients with stable CAD undergoing elective PCI. This was a substudy of our previous multicenter, randomized study.
Materials and methods
The protocol for this trial, supporting CONSORT checklist, and full data set are available as supporting information (see S1 CONSORT Checklist, S1 Protocol and S1 Data Set).
Ethics statement
The study was approved by the ethics committees of all hospitals. All participants provided written informed consent before enrolling. This study was conducted according to the principles expressed in the Declaration of Helsinki. The study is registered at the UMIN Clinical Trials Registry (UMIN000005607) at https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000006626. A list of investigators is provided in the Acknowledgments.
Study design
The principal study (Cardiac Preconditioning Effect of Remote Ischemia and Nicorandil in Patients Undergoing Elective Percutaneous Coronary Intervention: RINC) was a prospective, open-label, multicenter, randomized, controlled trial, which was conducted between February 2011 and January 2013 [24]. This was a post-hoc analysis of the RINC study. Fig 1 shows a flow diagram of the study. Eligible patients were adults (>20 years old) who were diagnosed with stable CAD, including silent myocardial ischemia and stable angina, and planned to have elective PCI. All of the patients underwent coronary angiography before enrollment in this study. Indication of PCI was evaluated according to the guideline for elective percutaneous coronary intervention in patients with stable coronary artery disease from the Japanese Society of Cardiology [27]. Patients were excluded for the following reasons: they had acute coronary syndrome, there was contraindication of intravenous nicorandil administration, they planned elective PCI for chronic total occlusion lesion or PCI with a rotablator, use of sulfonylurea, an arterio-venous shunt was present in the arms, and prognosis was regarded as less than 12 months. In the principal study, we enrolled 405 patients at 18 coronary intervention centers in Japan. Among them, 396 patients underwent randomization. Using post-hoc analysis, we aimed to identify any myocardial protective effect of RIPC during elective PCI in older patients. Therefore, patients aged 65 years or younger were excluded. Finally, 282 patients were included in this post-hoc analysis (control: n = 95, nicorandil: n = 94, RIPC: n = 93).
PCI, percutaneous coronary intervention; RIPC, remote ischemic preconditioning.
The intervention protocol and PCI procedure have been described previously [24]. In patients who were assigned to the nicorandil group, 4 mg of nicorandil was intravenously administered for 5 minutes for at least 1 hour before PCI, followed by continuous infusion of nicorandil (6 mg/h) for at least 8 hours. In patients who were assigned to the RIPC group, 5-minute inflation of a blood pressure cuff to 200 mmHg around the upper arm was performed. This was followed by 5-minute deflation of the cuff to 0 mmHg. This process was performed three times at least 1 hour before PCI. This procedure was automatically performed by a newly developed automated continuous blood pressure device (FB-270; Fukuda Denshi, Tokyo, Japan) [28]. Stopping the infusion was dependent on the practice of each hospital. Patients in the control group did not receive any additional pretreatment before PCI. PCI was performed in a conventional manner.
The primary outcome in the current study was the incidence of pMI following PCI. The definition of pMI was as follows: an elevation in high-sensitive cardiac troponin T (cTnT) levels >0.07 ng/ml (5×99th percentile upper reference limit); or CK-MB levels >10 ng/ml and CK-MB/creatinine kinase levels >5%, at 12 or 24 hours after PCI. If patients were discharged before regular assessment, these cardiac biomarkers were assessed at discharge.
The secondary outcomes in the current study were ischemic events during PCI, including chest pain during PCI, ST segment change on an electrocardiogram (>0.1 mV) during PCI, ventricular arrhythmia required for cardioversion during PCI, and final thrombolysis in myocardial infarction (TIMI) grade. We also studied adverse clinical events at 8 months after PCI as a secondary outcome. Adverse clinical events included cardiovascular or non-cardiovascular death, admission for acute coronary syndrome, any revascularization, and admission for heart failure.
Statistical analysis
Continuous variables are presented as mean±standard deviation (SD) or as median with the interquartile range. Categorical variables are presented as frequencies and proportions (%). Continuous variables were compared using analysis of variance or the Kruskal–Wallis test for non-normally distributed parameters. Categorical variables were compared using Pearson’s chi-square test.
Fisher’s exact test was applied to compare proportions of pMI following PCI between the nicorandil and control or the RIPC and control groups. The p values were adjusted using the bootstrap method (1,000,000 iterations) to account for multiplicity [29]. The odds ratios (ORs) between groups and their 95% exact confidence intervals (CIs) were calculated. Additionally, a logistic regression model was used to calculate ORs between study groups with adjustment for sex, and with or without chronic kidney disease (estimated glomerular filtration rate [eGFR] at baseline <60 or ≥60 ml/min/1.73 m2). The adjusted ORs between groups and their 95% exact CIs were calculated. The p values were adjusted using the Dunnett–Hsu method to account for multiplicity. The Hosmer–Lemeshow lack-of-fit test was also applied. The same models of the primary outcome were applied to ischemic events during PCI. For analysis of the primary outcome, we also used a mixed-effect logistic regression model in which the center ID was included as a random-intercept term to assess the robustness of the primary analysis. Sandwich estimators of the covariance matrix of regression coefficients were used for the analysis.
For adverse clinical events at 8 months after PCI, the Kaplan–Meier estimate was used by treatment group and compared using the log-rank test. The p values were adjusted using the Dunnett–Hsu method to account for multiplicity. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and their 95% profile likelihood CIs between treatment groups. The statistical test of Lin, Wei, and Ying (1993) for checking the adequacy of proportional hazard assumption was also applied [30].
All analyses were performed with IBM SPSS Statistics 24.0 and SAS system 9.4. Two-tailed values of p<0.05 were considered statistically significant.
Results
Baseline characteristics
Table 1 shows the baseline characteristics of the patients. In patients aged >65 years, 50.0% of patients were diagnosed with diabetes previously. A total of 59.9% of patients were current or past smokers. Procedural characteristics were not significantly different among the groups. A total of 51.1% of patients had complex coronary lesions, such as AHA-ACC characteristics of types B2 (31.9%) and C (19.1%). Target vessels and AHA-ACC characteristics of types of lesions, and the diameter and length of stents were not significantly different among the groups. Baseline characteristics in patients aged ≤65 years (n = 109) are shown in S1 Table.
Primary outcome
The incidence of pMI following PCI in the nicorandil group (35/94, 37.2%) was significantly lower than that in the control group (51/95, 53.7%) (Fig 2). However, the incidence of pMI was not significantly different between the RIPC and control groups (40/93, 43.0%). In adjusted analysis, the risk reduction remained significant between the control and nicorandil groups (adjusted OR: 0.51; 95% CI: 0.27 to 0.96; multiplicity-adjusted p = 0.045) (Table 2). However, the incidence of pMI was not significantly different between the control and RIPC groups (adjusted OR: 0.63; 95% CI: 0.34 to 1.16; multiplicity-adjusted p = 0.196). In mixed-effect logistic regression analysis, the incidence of pMI was also significantly different between the control and nicorandil groups (OR: 0.50; 95% CI: 0.31 to 0.82; multiplicity-adjusted p = 0.010). However, the incidence of pMI was not significantly different between the control and RIPC groups (OR: 0.65; 95% CI: 0.41 to 1.03; multiplicity-adjusted p = 0.119). The p values in Hosmer–Lemeshow lack-of-fit tests were non-significant. In patients aged ≤65 years, the incidence of pMI in the nicorandil group (17/35, 48.6%) and in the RIPC group (11/36, 30.6%) was not significantly different compared with that in the control group (14/38, 36.8%) (multiplicity-adjusted p = 0.511 and multiplicity-adjusted p = 0.745, respectively) (S1 Fig).
pMI, periprocedural myocardial injury; RIPC, remote ischemic preconditioning.
Secondary outcomes
During PCI, few ischemic events occurred in each group. The incidence of each event (chest pain during PCI, ST segment change on an electrocardiogram [>0.1 mV] during PCI, ventricular arrhythmia required for cardioversion during PCI, and final TIMI grade) was not significantly different among the control, nicorandil, and RIPC groups (Table 2).
As shown in Fig 3, Kaplan–Meier estimates by the log-rank test for adverse clinical events at 8 months after PCI were not significantly different between the control and nicorandil groups (11/94 [12.5%]; multiplicity-adjusted p = 0.685), or between the control and RIPC groups (8/95 [10.4%] vs. 7/92 [8.1%]; multiplicity-adjusted p = 0.955). Furthermore, in Cox regression analysis in the older cohorts, the incidence of adverse clinical events at 8 months after PCI was not significantly different between the control and nicorandil groups (HR: 1.38; 95% CI: 0.56 to 3.57), or between the control and RIPC groups (HR: 0.87; 95% CI: 0.31 to 2.42) (Table 2).
MACCE included cardiovascular or non-cardiovascular death, admission for acute coronary syndrome, any revascularization, and admission for heart failure. MACCE, major adverse cardiac or cerebrovascular events; RIPC, remote ischemic preconditioning.
Discussion
In this post-hoc analysis of a multicenter, randomized controlled trial, we demonstrated that intravenous nicorandil significantly reduced the incidence of pMI following PCI in older patients with stable CAD compared with the control group. However, RIPC failed to show a significant reduction in pMI. Nicorandil or RIPC did not reduce ischemic complications during elective PCI and clinical adverse events within 8 months after PCI, similar to the principal study [24].
This sub-analysis showed a significant effect of intravenous nicorandil on pMI in older patients with stable CAD. However, in sub-analysis of patients aged ≤65 years, the incidence of pMI was not significantly different between the nicorandil and control groups. In patients with advanced age, microvascular function is considered to be impaired [31]. Nicorandil is a unique hybrid pharmacological agent of an adenosine triphosphate-sensitive potassium channel opener and nicotinamide nitrate. Therefore, an explanation for the beneficial effect of nicorandil is that nicorandil might compensate for a decline in cardiac mitochondrial function and ability of nitric oxide production in older patients. Notably, the route of nicorandil administration was different among previous studies. Single-center studies showed that intravenous nicorandil reduced pMI or the slow flow phenomenon following PCI in patients who had elective and emergent PCI [15,16,32,33]. However, the effect of intracoronary nicorandil is controversial [17,18,19]. In our study, intravenous nicorandil administration before and after PCI might have increased tissue concentrations of nicorandil before PCI, and this could have contributed to the protective effect against pMI.
This sub-analysis also showed that pre-procedural upper limb RIPC moderately, but not significantly, reduced pMI in older patients with stable CAD. There are several possible reasons for this lack of significance. One reason is the small sample size of this sub-analysis. This sub-analysis might not have been sufficiently powered for differences that we expected, similar to our previous study. Another reason for this lack of significance could be an influence of age on the effect of RIPC. A meta-analysis showed that age was negatively correlated with a reduction in acute kidney injury by RIPC [34]. Therefore, various comorbidities and/or confounders could influence the effect of RIPC on target organs. However, further study to identify the populations who benefit from RIPC is warranted because RIPC is easily delivered, safe, and has a low cost.
The present study also showed that the overall incidence of pMI was 43.3% as determined with cardiac troponin T and 30.1% as determined with CK-MB. In line with our results, previous studies have shown that the incidence of pMI following elective PCI determined with cardiac troponin is higher than that determined with CK-MB when using the cut-off established by the Third Universal Definition of Myocardial Infarction [35]. For example, Li et al. [36] reported that the incidence of elevated biomarkers after elective PCI in patients with stable angina pectoris using the defined cut-off (>5× the upper reference limit) was 32.9% using cardiac troponin T and 14.5% using CK-MB. The present study demonstrated that the incidence of pMI in the control group was 53.7% based on the Third Universal Definition of Myocardial Infarction [35], which was relatively higher that that in other studies (15%–63%) [13,25,26,29,30,37,38,39,40,41]. Several factors in our study may explain the high incidence of pMI. First, the present study included patients aged >65 years. Older age is an important patient-related risk factor for pMI [5]. Second, the higher prevalence of diabetes mellitus (53.5%) in our study than previous studies may have been associated with the higher presence of lipid-rich plaques at target lesions. This could lead to distal embolization of atheromatous material or occlusion of small side branches despite angiographic success. In fact, the highest reported incidence of pMI was 63% in patients with diabetes mellitus [41]. This difference in risk factors in the populations of different studies could have resulted in the greater incidence of pMI in our study.
This study has several limitations. First, this study was a post-hoc analysis of a randomized, controlled trial. Although the RINC study was a large randomized, controlled trial of RIPC in patients with elective PCI, the study sample size was relatively small because of subgroup analysis. A small sample size might have resulted in low statistical power in analysis of intravenous RIPC in this study. Second, this sub-analysis attempted to compare the nicorandil and RIPC groups separately with the control group. However, two treatment comparisons (i.e., nicorandil vs. control and RIPC vs. control) were not independent because of the same control group. Therefore, we should not consider the study results as separate independent comparisons of the two forms of treatment (nicorandil and RIPC). Third, data regarding side branch occlusion, which is one of the causes of pMI during PCI, were not available in the current study. Although final TIMI grades did not differ among treatment groups, side branch occlusion may have affected the result of this sub-analysis.
Conclusions
In conclusion, in this secondary analysis of the RINC study, periprocedural intravenous nicorandil significantly reduced the incidence of pMI in older patients with stable CAD. Our study suggests that intravenous nicorandil is effective in myocardial protection for stable PCI in these patients. Further investigation using a multicenter, prospective study is required to evaluate the effect of nicorandil on pMI following PCI in older patients.
Supporting information
S1 Table. Baseline characteristics of patients aged ≤65 years.
https://doi.org/10.1371/journal.pone.0194623.s004
(DOCX)
S1 Fig. Incidence of periprocedural myocardial injury in patients aged ≤65 years.
https://doi.org/10.1371/journal.pone.0194623.s005
(TIF)
Acknowledgments
We thank the RINC collaborators, in addition to the authors, Yusuke Kawai (Department of Cardiology, Okayama City General Medical Center, Okayama, Japan), Tetsuya Sato (Department of Cardiology, Japanese Red Cross Okayama Hospital, Okayama, Japan), Katsumasa Sato (Department of Cardiology, Fukuyama Cardiovascular Hospital, Hiroshima, Japan), Takefumi Oka (Department of Cardiology, Tsuyama chuo Hospital, Okayama, Japan), Natsuki Takahashi (Department of Cardiology, Matsuyama Shimin Hospital, Ehime, Japan), Satoru Sakuragi (Department of Cardiology, Iwakuni Medical Center, Yamaguchi, Japan), Atsushi Mima (Department of Cardiology, Saiseikai Imabari Hospital, Ehime, Japan), Kenki Enko (Department of Cardiology, Onomichi Municipal Hospital, Hiroshima, Japan), Shingo Hosogi (Department of Cardiology, Kochi Medical Center, Kochi, Japan), Seiji Nanba (Department of Cardiology, Okayama Rosai Hospital, Okayama, Japan), and Ryoichi Hirami (Department of Cardiology, Japanese Red Cross Himeji Hospital, Hyogo, Japan). Hiroshi Ito (itomd@md.okayama-u.ac.jp) is a lead author for the RINC investigators.
We thank Miyuki Fujiwara and Masayo Ohmori for their technical assistance. We thank Ellen Knapp, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
References
- 1. Kizer J (2003) Role of cardiac troponin T in the long-term risk stratification of patients undergoing percutaneous coronary intervention. European Heart Journal 24: 1314–1322. pmid:12871688
- 2. Feldman DN, Kim L, Rene AG, Minutello RM, Bergman G, Wong SC (2011) Prognostic value of cardiac troponin-I or troponin-T elevation following nonemergent percutaneous coronary intervention: a meta-analysis. Catheter Cardiovasc Interv 77: 1020–1030. pmid:21574239
- 3. Heusch G, Kleinbongard P, Bose D, Levkau B, Haude M, Schulz R, et al. (2009) Coronary microembolization: from bedside to bench and back to bedside. Circulation 120: 1822–1836. pmid:19884481
- 4. Selvanayagam JB, Porto I, Channon K, Petersen SE, Francis JM, Neubauer S, et al. (2005) Troponin elevation after percutaneous coronary intervention directly represents the extent of irreversible myocardial injury: insights from cardiovascular magnetic resonance imaging. Circulation 111: 1027–1032. pmid:15723982
- 5. Lansky AJ, Stone GW (2010) Periprocedural myocardial infarction: prevalence, prognosis, and prevention. Circ Cardiovasc Interv 3: 602–610. pmid:21156928
- 6. Fuchs S, Kornowski R, Mehran R, Satler LF, Pichard AD, Kent KM, et al. (1999) Cardiac troponin I levels and clinical outcomes in patients with acute coronary syndromes: the potential role of early percutaneous revascularization. Journal of the American College of Cardiology 34: 1704–1710. pmid:10577560
- 7. Thygesen K, Alpert JS, White HD, Jaffe AS, Apple FS, Galvani M, et al. (2007) Universal definition of myocardial infarction. Circulation 116: 2634–2653. pmid:17951284
- 8. Wu AH, Smith A, Christenson RH, Murakami MM, Apple FS (2004) Evaluation of a point-of-care assay for cardiac markers for patients suspected of acute myocardial infarction. Clinica chimica acta; international journal of clinical chemistry 346: 211–219. pmid:15256323
- 9. Piran U, Kohn DW, Uretsky LS, Bernier D, Barlow EH, Niswander CA, et al. (1987) Immunochemiluminometric assay of creatine kinase MB with a monoclonal antibody to the MB isoenzyme. Clinical chemistry 33: 1517–1520. pmid:3304711
- 10. Roe MT, Mahaffey KW, Kilaru R, Alexander JH, Akkerhuis KM, Simoons ML, et al. (2004) Creatine kinase-MB elevation after percutaneous coronary intervention predicts adverse outcomes in patients with acute coronary syndromes. European heart journal 25: 313–321. pmid:14984920
- 11. Zografos TA, Katritsis GD, Tsiafoutis I, Bourboulis N, Katsivas A, Katritsis DG (2014) Effect of one-cycle remote ischemic preconditioning to reduce myocardial injury during percutaneous coronary intervention. Am J Cardiol 113: 2013–2017. pmid:24793669
- 12. Ahmed RM, Mohamed el HA, Ashraf M, Maithili S, Nabil F, Rami R, et al. (2013) Effect of remote ischemic preconditioning on serum troponin T level following elective percutaneous coronary intervention. Catheter Cardiovasc Interv 82: E647–653. pmid:23404916
- 13. Hoole SP, Heck PM, Sharples L, Khan SN, Duehmke R, Densem CG, et al. (2009) Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) Study: a prospective, randomized control trial. Circulation 119: 820–827. pmid:19188504
- 14. Davies WR, Brown AJ, Watson W, McCormick LM, West NE, Dutka DP, et al. (2013) Remote ischemic preconditioning improves outcome at 6 years after elective percutaneous coronary intervention: the CRISP stent trial long-term follow-up. Circ Cardiovasc Interv 6: 246–251. pmid:23696599
- 15. Isono T, Kamihata H, Sutani Y, Motohiro M, Yamamoto S, Kyoui S, et al. (2008) Nicorandil suppressed myocardial injury after percutaneous coronary intervention. Int J Cardiol 123: 123–128. pmid:17346816
- 16. Hirohata A, Yamamoto K, Hirose E, Kobayashi Y, Takafuji H, Sano F, et al. (2014) Nicorandil prevents microvascular dysfunction resulting from PCI in patients with stable angina pectoris: a randomised study. EuroIntervention 9: 1050–1056. pmid:24457276
- 17. Matsuo H, Watanabe S, Watanabe T, Warita S, Kojima T, Hirose T, et al. (2007) Prevention of no-reflow/slow-flow phenomenon during rotational atherectomy—a prospective randomized study comparing intracoronary continuous infusion of verapamil and nicorandil. Am Heart J 154: 994 e991-996. pmid:17967610
- 18. Hwang J, Lee HC, Kim BW, Yang MJ, Park JS, Park JH, et al. (2013) Effect on periprocedural myocardial infarction of intra-coronary nicorandil prior to percutaneous coronary intervention in stable and unstable angina. J Cardiol 62: 77–81. pmid:23731922
- 19. Kim SJ, Kim W, Woo JS, Ha SJ, Kang WY, Hwang SH, et al. (2012) Effect of myocardial protection of intracoronary adenosine and nicorandil injection in patients undergoing non-urgent percutaneous coronary intervention: a randomized controlled trial. Int J Cardiol 158: 88–92. pmid:21256606
- 20. Heusch G, Botker HE, Przyklenk K, Redington A, Yellon D (2015) Remote ischemic conditioning. J Am Coll Cardiol 65: 177–195. pmid:25593060
- 21. Ito N, Nanto S, Doi Y, Kurozumi Y, Natsukawa T, Shibata H, et al. (2013) Beneficial effects of intracoronary nicorandil on microvascular dysfunction after primary percutaneous coronary intervention: demonstration of its superiority to nitroglycerin in a cross-over study. Cardiovasc Drugs Ther 27: 279–287. pmid:23722418
- 22. Garg V, Hu K (2007) Protein kinase C isoform-dependent modulation of ATP-sensitive K+ channels in mitochondrial inner membrane. Am J Physiol Heart Circ Physiol 293: H322–332. pmid:17351068
- 23. O'Rourke B (2000) Myocardial K(ATP) channels in preconditioning. Circ Res 87: 845–855. pmid:11073879
- 24. Miyoshi T, Ejiri K, Kohno K, Nakahama M, Doi M, Munemasa M, et al. (2017) Effect of remote ischemia or nicorandil on myocardial injury following percutaneous coronary intervention in patients with stable coronary artery disease: A randomized controlled trial. Int J Cardiol 236: 36–42. pmid:28214082
- 25. Higuchi Y, Hiro T, Takayama T, Kanai T, Kawano T, Fukamachi D, et al. (2014) Impact of coronary plaque burden and composition on periprocedural myocardial infarction and coronary flow reserve after percutaneous coronary intervention. International heart journal 55: 391–396. pmid:25070121
- 26. Cavallini C, Savonitto S, Violini R, Arraiz G, Plebani M, Olivari Z, et al. (2005) Impact of the elevation of biochemical markers of myocardial damage on long-term mortality after percutaneous coronary intervention: results of the CK-MB and PCI study. European heart journal 26: 1494–1498. pmid:15741227
- 27. Group JCSJW (2013) Guidelines for Elective Percutaneous Coronary Intervention in Patients With Stable Coronary Artery Disease (JCS 2011) Published in 2012. Circulation Journal 77: 1590–1607. pmid:23657129
- 28. Yamanaka T, Kawai Y, Miyoshi T, Mima T, Takagaki K, Tsukuda S, et al. (2015) Remote ischemic preconditioning reduces contrast-induced acute kidney injury in patients with ST-elevation myocardial infarction: a randomized controlled trial. Int J Cardiol 178: 136–141. pmid:25464237
- 29. Prasad A, Gossl M, Hoyt J, Lennon RJ, Polk L, Simari R, et al. (2013) Remote ischemic preconditioning immediately before percutaneous coronary intervention does not impact myocardial necrosis, inflammatory response, and circulating endothelial progenitor cell counts: a single center randomized sham controlled trial. Catheterization and cardiovascular interventions: official journal of the Society for Cardiac Angiography & Interventions 81: 930–936.
- 30. Testa L, Latini RA, Agostoni P, Banning AP, Bedogni F (2009) Prognostic significance of small troponin I rise after a successful elective percutaneous coronary intervention of a native artery. The American journal of cardiology 103: 1622–1623.
- 31. Lee JM, Layland J, Jung JH, Lee HJ, Echavarria-Pinto M, Watkins S, et al. (2015) Integrated physiologic assessment of ischemic heart disease in real-world practice using index of microcirculatory resistance and fractional flow reserve: insights from the International Index of Microcirculatory Resistance Registry. Circ Cardiovasc Interv 8: e002857. pmid:26499500
- 32. Murakami M, Iwasaki K, Kusachi S, Hina K, Hirota M, Hirohata S, et al. (2006) Nicorandil reduces the incidence of minor cardiac marker elevation after coronary stenting. Int J Cardiol 107: 48–53. pmid:16337497
- 33. Kawai Y, Hisamatsu K, Matsubara H, Dan K, Akagi S, Miyaji K, et al. (2009) Intravenous administration of nicorandil immediately before percutaneous coronary intervention can prevent slow coronary flow phenomenon. Eur Heart J 30: 765–772. pmid:19276198
- 34. Zhou C, Bulluck H, Fang N, Li L, Hausenloy DJ (2017) Age and Surgical Complexity impact on Renoprotection by Remote Ischemic Preconditioning during Adult Cardiac Surgery: A Meta analysis. Sci Rep 7: 215. pmid:28303021
- 35. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD (2012) Third universal definition of myocardial infarction. Global heart 7: 275–295. pmid:25689940
- 36. Li J, Xu JP, Zhao XZ, Sun XJ, Xu ZW, Song SJ (2014) Protective effect of metformin on myocardial injury in metabolic syndrome patients following percutaneous coronary intervention. Cardiology 127: 133–139. pmid:24335026
- 37. Zografos TA, Katritsis GD, Tsiafoutis I, Bourboulis N, Katsivas A, Katritsis DG (2014) Effect of one-cycle remote ischemic preconditioning to reduce myocardial injury during percutaneous coronary intervention. The American journal of cardiology 113: 2013–2017. pmid:24793669
- 38. Luo SJ, Zhou YJ, Shi DM, Ge HL, Wang JL, Liu RF (2013) Remote ischemic preconditioning reduces myocardial injury in patients undergoing coronary stent implantation. The Canadian journal of cardiology 29: 1084–1089. pmid:23414904
- 39. Lavi S, D'Alfonso S, Diamantouros P, Camuglia A, Garg P, Teefy P, et al. (2014) Remote ischemic postconditioning during percutaneous coronary interventions: remote ischemic postconditioning-percutaneous coronary intervention randomized trial. Circulation Cardiovascular interventions 7: 225–232. pmid:24692535
- 40. Zeitouni M, Silvain J, Guedeney P, Kerneis M, Yan Y, Overtchouk P, et al. (2018) Periprocedural myocardial infarction and injury in elective coronary stenting. European heart journal.
- 41. Xu X, Zhou Y, Luo S, Zhang W, Zhao Y, Yu M, et al. (2014) Effect of remote ischemic preconditioning in the elderly patients with coronary artery disease with diabetes mellitus undergoing elective drug-eluting stent implantation. Angiology 65: 660–666. pmid:24163121