后适应在接受直接PCI治疗的急性ST段抬高性心肌梗死患者中的临床疗效：基于随机对照试验的meta分析

Clinical effect of postconditioning in ST-elevation myocardial infarction patients treated with primary percutaneous coronary intervention: a meta-analysis of randomized controlled trials 后适应在接受直接PCI治疗的急性ST段抬高性心肌梗死患者中的临床疗效：基于随机对照试验的meta分析 1 first-author 1 1 2 1 1 1 1 1 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:fushenwen@medmail.com.cn †E-mail:fushenwen@medmail.com.cn fushenwen@medmail.com.cn Department of Cardiovascular Medicine, Jinhua Municipal Central Hospital, Jinhua 321000, China Department of Cardiovascular Medicine, Jinhua Municipal Central Hospital, Jinhua 321000, China Department of Critical Care Medicine, Jinhua Municipal Central Hospital, Jinhua 321000, China Department of Critical Care Medicine, Jinhua Municipal Central Hospital, Jinhua 321000, China Objective: 2 To evaluate the clinical effect of postconditioning on patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). Methods: 2 Randomized controlled trials were identified by searching relevant databases published up to April 2nd, 2014. A meta-analysis of eligible studies was performed by Stata 12.0 and Review Manager 5.2 with a fixed-effect model. Results: 2 Ten studies providing adverse cardiac events in a total of 1346 STEMI patients treated with primary PCI were identified. The occurrence of heart failure was significantly reduced in patients treated with postconditioning compared with usual care (risk ratio (RR) 0.533; 95% confidence intervals (CI) 0.368–0.770), whereas non-fatal reinfarction slightly increased in the postconditioning group (RR 2.746; 95% CI 1.007–7.488). No significant difference in total major adverse cardiac events (MACEs) was observed between the two groups (RR 0.876; 95% CI 0.671–1.144). Conclusions: 2 Postconditioning in STEMI patients undergoing primary PCI significantly reduces the risk of heart failure, but fails to decrease the incidence of total MACEs and the risk of non-fatal reinfarction. 目的 2 探讨后适应对接受直接经皮冠状动脉介入（PCI）治疗的急性ST段抬高性心肌梗死（STEMI）患者心血管不良事件的影响。 创新点 2 进一步明确后适应处理对STEMI患者临床预后的影响。 方法 2 对符合入选标准的随机对照临床试验进行meta分析。 结论 2 缺血后适应显著降低ST段抬高性心肌梗死患者心衰风险。 Myocardial infarction Postconditioning Coronary intervention 后适应 心肌梗死 冠状动脉介入治疗 Introduction 1 Although the acute treatment and follow-up strategy of patients with acute ST-segment elevation myocardial infarction (STEMI) has improved, the incidence of death or heart failure after STEMI is still high. Reperfusion of the infarct-related artery (IRA), preferably by primary percutaneous coronary intervention (PCI), is the most effective method to limit infarct size, preserve the left ventricular (LV) function, and prevent the development of heart failure (Steg et al., 2012 2012 ). However, effective restoration of blood flow in the IRA may paradoxically result in further damage to the heart muscle (i.e. reperfusion injury). This phenomenon, occurring within the first minute following reperfusion and responsible for 50% of the final infarct volume as indicated by animal studies (Yellon and Hausenloy, 2007 2007 ), can exert an adverse effect on the efficacy of primary PCI. Therefore, it is necessary to explore a clinically feasible, applicable, and effective therapeutic strategy to decrease the reperfusion injury and increase the benefit of primary PCI. Ischemic preconditioning, referring to repetitive cycles of occlusion-reperfusion conducted just before the longer coronary artery occlusion, was first introduced as an effective method to mitigate reperfusion injury (Murry et al., 1986 1986 ). However, its clinical application has been limited as the occlusion is often established at the admission of a patient for acute myocardial infarction (AMI). Zhao et al. ( 2003 2003 ) first described postconditioning in which a sequence of repetitive interruption of the coronary blood flow applied immediately after reopening of the occluded vessel remarkably decreased myocardial infarct size in a canine model. Unlike preconditioning, postconditioning can be directly translated into clinical practice, especially in patients undergoing primary PCI. Staat et al. ( 2005 2005 ) first identified reduction of infarct size measured by creatine kinase using a postconditioning procedure in the human heart. Subsequently, postconditioning has been extensively investigated, and some beneficial effect has been reported, such as improvement of distal myocardial perfusion (Laskey, 2005 2005 ), enhancement of coronary endothelial function and cardiomyocyte salvage (Ma et al., 2006 2006 ), reduction in myocardial infarct size determined by single-photon emission computed tomography (Yang et al., 2007 2007 ; Thibault et al., 2008 2008 ) or cardiac magnetic resonance (Lønborg et al., 2010a 2010a ), and amelioration of the left ventricular ejection fraction (LVEF) (Thibault et al., 2008 2008 ). Patients treated with postconditioning were suggested to have improved on the New York Heart Association classification (Lønborg et al., 2010b 2010b ). However, recent studies suggested that postconditioning could neither decrease infarct size (Sörensson et al., 2010 2010 ; Freixa et al., 2012 2012 ; Elżbieciak et al., 2013 2013 ) nor increase LVEF in short- or long-term follow-up (Freixa et al., 2012 2012 ; Elżbieciak et al., 2013 2013 ). A multicenter, prospective, and randomized trial observed no improvement of myocardial reperfusion or short-term clinical outcomes in the postconditioning arm (Hahn et al., 2013 2013 ). To date, the clinical role of postconditioning still remains elusive because of such factors as small-sample size, using surrogate end points such as infarct size, coronary flow, or LV function rather than clinical events to evaluate the effect of postconditioning. Therefore, we undertook a meta-analysis focusing on adverse cardiac events to assess postconditioning’s clinical effect in STEMI patients treated with primary PCI. Materials and methods 1 Literature search 2 Literature searches were performed to identify all relevant and published randomized, controlled, prospective studies comparing postconditioning with usual care in patients with STEMI through the PubMed, EMBASE, Cochrane Central Register of Controlled Trials database, and the ClinicalTrials.gov database up to April 2nd, 2014. References of all the retrieved articles were also screened and reviewed. No language limitation constraint was applied. The following search terms were used: myocardial infarction, postconditioning, and coronary intervention. We contacted authors of original studies for detailed data if needed. Criteria for inclusion were as follows: (1) completed randomized, controlled, and prospective trial comparing postconditioning with usual care in STEMI patients treated with primary PCI; (2) study published in peer-reviewed journals with full text available; (3) study reporting one or more kinds of adverse cardiac events including deaths, heart failure, target vessel revascularization (TVR), stent thrombosis, non-fatal reinfarction, and angina. All the three criteria had to be satisfied for inclusion. Data extraction and quality assessment 2 Two investigators (Biao TANG and Jian CHENG) independently performed the literature search, study selection, and data evaluation. Disagreements were resolved by discussion or referred to a third investigator (Shen-wen FU) if necessary. The main information was extracted, including name of the first author, year of publication, article title, study characteristics, and clinical events such as death, heart failure, TVR, stent thrombosis, non-fatal reinfarction, and angina. Major adverse cardiac event (MACE) was defined as a composite of death, heart failure, TVR, stent thrombosis, and non-fatal reinfarction. The bias of each study was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1 (Higgins and Green, 2011 2011 ). Statistical analysis 2 For discrete variables (events of death, heart failure, TVR, stent thrombosis, reinfarction, angina, and MACE), we calculated the risk ratio (RR) with 95% confidence interval (CI) comparing the postconditioning group with the control group. The Cochrane Chi-square test was used to examine heterogeneity across studies. The I 2 statistic was calculated as an estimation of the proportion of variation in treatment effect that was due to between-study heterogeneity. A value of 0% meant no heterogeneity, and values of 25%, 50%, and 75% indicated low, moderate, and high, respectively. A fixed-effect model was used to test the overall effect unless there was marked heterogeneity (when the Cochrane Chi-square P < 0.1 or I 2 > 50%) in the studies, which required a random-effect model (Kahn and Sempos, 2000 2000 ). Meta-regression analyses were implemented to investigate potential effect modification by study characteristics (e.g. procedures, risk factors). Subgroup analyses should be conducted if a significant association of study characteristics with effect was identified in meta-regression analyses. Publication bias was assessed by examining the asymmetry of a funnel plot and weighted by the Egger regression test (Egger et al., 1997 1997 ). In order to assess the study quality, sensitivity analysis was performed by omitting each study at one time and calculating the remaining pooled effect. A two-tailed P < 0.05 was considered statistically significant. Statistical analysis was conducted by using Stata 12.0 (Stata Corporation, College Station, TX, USA) and Review Manager 5.2 (the Nordic Cochrane Centre, the Cochrane Collaboration, Copenhagen, Denmark). Results 1 Study characteristics 2 After screening a total of 341 eligible publications, we identified 25 potentially relevant articles based on titles and abstracts. Fifteen studies were excluded from the full text assessment for not observing clinical events. Finally, 10 studies were selected for meta-analysis (Fig. 1 1 ). These eligible studies contained 1346 patients, with 674 in the postconditioning group and 672 in the control group. The risk of the bias is presented as percentages across all included studies (Fig. 2 2 ). The characteristics of studies included in the meta-analysis are summarized in Tables 1 1 and 2 2 . The thrombectomy technique and glycoprotein (GP) IIb/IIIa inhibitor were used in five and seven studies, respectively (Table 2 2 ). Death and heart failure events were observed in all studies, and non-fatal reinfarction, TVR, stent thrombosis, and angina events were analyzed in six, five, four, and four trials, respectively (Table 3 3 ). The detailed information about outcomes of four trials was acquired by sending e-mails to the first author (Lønborg et al., 2010a 2010a ; 2010b 2010b ; Elżbieciak et al., 2013 2013 ; Sörensson et al., 2013 2013 ). Review authors’ judgments about each risk of bias item presented as percentages across all included studies P: postconditioning; C: control; TIMI: thrombolysis in myocardial infarction; PCI: percutaneous coronary intervention Data are expressed as duration of balloon inflation×number of inflations Lønborg et al. ( 2010a 2010a ; 2010b 2010b ) published two articles on the same trial, followed up at 3 and 15 months, respectively Study Country Number of P/C Ischemic time of P/C (min) Postconditioning Protocol * * Number of P/C at TIMI grade 0–1 before PCI Yang et al., 2007 2007 China 23/18 312/264 30 s×3 23/18 Lønborg et al., 2010a 2010a # # Denmark 59/59 241/255 30 s×4 59/59 Lønborg et al., 2010b 2010b # # Denmark 59/59 241/255 30 s×4 59/59 Garcia et al., 2011 2011 USA 22/21 270/264 30 s×4 22/21 Freixa et al., 2012 2012 Spain 39/40 326/330 60 s×4 39/37 Tarantini et al., 2012 2012 Italy 39/39 212/194 60 s×4 39/39 Hahn et al., 2013 2013 Korea 350/350 196/195 60 s×4 336/331 Elżbieciak et al., 2013 2013 Poland 18/21 318/226 60 s×4 18/21 Sörensson et al., 2013 2013 Sweden 33/35 180/165 60 s×4 33/35 Dong et al., 2013 China 32/30 300/294 30 s×3 32/30 P: postconditioning; C: control; TIMI: thrombolysis in myocardial infarction; GP: glycoprotein; NR: not reported P =0.0056, but major adverse events seem to be more frequent in postconditioning group irrespective of diabetic status ( P =0.053 for all patients; P =0.080 for patients without diabetes) 2 Study 2 Age (year) 5 Number of P/C 2 GP IIb/IIIa inhibitor 2 Thrombectomy Male Diabetes Hypertension Dyslipidaemia TIMI grade 3 after PCI Yang et al., 2007 2007 58.6/63.3 42328 42160 42324 42291 21/16 No No Lønborg et al., 2010a 2010a 61/62 45/47 42098 22/19 27/24 56/52 Yes Yes Lønborg et al., 2010b 2010b 61/62 45/47 42098 22/19 27/24 56/52 Yes Yes Garcia et al., 2011 2011 61/55 19/16 42008 42291 16/15 NR No No Freixa et al., 2012 2012 59/60 33/29 42254 19/20 17/14 35/36 Yes Yes Tarantini et al., 2012 2012 59.6/59.5 33/33 7/1 * * 23/19 20/19 38/38 Yes No Hahn et al., 2013 2013 60/60 276/261 84/87 161/159 139/159 321/306 Yes Yes Elżbieciak et al., 2013 2013 60.1/58.4 42356 42099 14/19 42326 18/21 Yes No Sörensson et al., 2013 2013 63/62 28/31 42257 42135 NR 31/30 Yes No Dong et al., 2013 70/68.4 20/22 42319 23/19 NR 26/17 No Yes TVR: target vessel revascularization Study Death Reinfarction Heart failure TVR Stent thrombosis Angina Stroke Follow-up Yang et al., 2007 2007 √ √ √ √ In hospital Lønborg et al., 2010a 2010a √ √ √ √ √ √ 3 months Lønborg et al., 2010b 2010b √ √ √ √ √ √ √ 15 months Garcia et al., 2011 2011 √ √ 3.4 years Freixa et al., 2012 2012 √ √ √ 6 months Tarantini et al., 2012 2012 √ √ √ √ 6 months Hahn et al., 2013 2013 √ √ √ √ √ 1 month Elżbieciak et al., 2013 2013 √ √ √ 24 months Sörensson et al., 2013 2013 √ √ √ √ 12 months Dong et al., 2013 √ √ √ 1 month Events of heart failure during follow-up 2 The occurrence of heart failure in patients treated with postconditioning was significantly lower than that in the control group as calculated using the fixed-effect model (RR 0.533, 95% CI 0.368–0.770, P =0.001; Fig. 3 3 ). I 2 of 0% indicated high homogeneity. The funnel plot had a symmetrical appearance (Fig. 4 4 ), consistent with Egger’s test that there was no publication bias (95% CI 1.242–0.838, P =0.659). Sensitivity analysis implemented by sequentially removing each included study and reanalyzing the remaining RR and 95% CI revealed the robustness of overall heart failure results (Fig. 5 5 ). Meta-regression analyses were performed to explore the possible effect of study characteristics on heart failure by using age, gender, percentage of hypertension or diabetes mellitus, use of thrombectomy or GP IIb/IIIa inhibitor, follow-up time, and postconditioning protocol. No significant relationship was found between the mentioned variables and heart failure events. The remaining RR and 95% CI are presented MACE during follow-up 2 Data on the outcomes of MACE in a follow-up from the hospitalization period to 3.4 years are presented in Fig. 6 6 . No significant difference in MACE was observed between the postconditioning and control groups (RR 0.876, 95% CI 0.671–1.144, P =0.330). Events of non-fatal reinfarction during follow-up 2 Six studies reported reinfarction events involving a total of 1084 patients, with 542 in each group in a follow-up of hospitalization period to 24 months. There was a marginal significant increase in non-fatal reinfarction events in the postconditioning group compared with the control group (RR 2.746, 95% CI 1.007–7.488, P =0.048; Fig. 7 7 ). Meta-regression was not performed because only six studies were included (Higgins and Green, 2011 2011 ). Other clinical events during follow-up 2 Table 4 4 shows data on the outcomes of death, TVR, stent thrombosis, and angina in a follow-up of in hospital to 3.4 years and no significant difference was observed between the postconditioning and control arm. P: postconditioning; C: control; TVR: target vessel revascularization Events Sample size of P/C I 2 (%) RR 95% CI P -value Death 674/672 0.0 1.642 0.853–3.159 0.138 TVR 530/525 0.0 1.667 0.611–4.546 0.318 Stent thrombosis 507/508 0.0 1.002 0.421–2.389 0.996 Angina 183/183 0.0 1.239 0.608–2.524 0.554 Discussion 1 Despite great improvement in the reperfusion treatment of STEMI with the introduction of thrombolysis and primary PCI, prompt opening of the culprit vessel may contribute to additional myocardial damage, such as myocardial stunning, no reflow and ventricular arrhythmia (Kloner and Jennings, 2001 2001 ; Piper et al., 2003 2003 ; Hausenloy and Yellon, 2008 2008 ). Unlike ischemic preconditioning, postconditioning can be easily performed during primary PCI. Although its cardioprotective effect has been well studied in different animal models (Argaud et al., 2005 2005 ; Tang et al., 2006 2006 ; Lim et al., 2007 2007 ; Mykytenko et al., 2007 2007 ), the clinical effect of postconditioning is still unclear from divergent results from clinical trials and small sample sizes. The current meta-analysis involving 1346 patients from 10 randomized trials reveals that postconditioning is associated with a significant decrease of heart failure and a slight increase of non-fatal reinfarction, as compared with the usual care. No remarkable difference is observed between two groups in terms of MACE and other events including death, TVR, stent thrombosis, and angina. Primary PCI is the most effective reperfusion therapeutic strategy for STEMI patients if it can be conducted within guideline-recommended time frames. The long-term clinical goal is the prevention of heart failure and improvement of LV contractile function, one of the predictors of long-term prognosis after PCI for AMI (de Silva et al., 2012 2012 ). A meta-analysis with a small size ( n =272) showed that postconditioning significantly reduced heart failure (Wei et al., 2012 2012 ). Our data confirm the conclusion with a larger sample size. Another meta-analysis revealed that the improvement of LVEF leveled off and became non-significant with the extension of follow-up (Wang et al., 2013 2013 ). Our meta-regression analysis finds no significant association of follow-up time with heart failure events. Hence, the protective effect of postconditioning on heart failure is sustainable. The inconsistent effect of postconditioning on LVEF and heart failure may be partly attributed to the fact that many patients with symptoms and signs of heart failure have preserved LVEF (Solomon et al., 2005 2005 ). The evidence of thrombectomy in STEMI has been well established (Bavry et al., 2008 2008 ; de Luca et al., 2008 2008 ; Burzotta et al., 2009 2009 ). Patients randomized to thrombus aspiration had a significantly increased rate of complete ST-segment resolution and improved myocardial blush grade. Although not powerful enough to evaluate the clinical outcome, cardiac mortality at one year was reduced (Vlaar et al., 2008 2008 ). However, thrombectomy was performed in relatively few patients in studies concerning postconditioning because the importance of thrombectomy during primary PCI in STEMI patients was acknowledged only after the trial design (Lønborg et al., 2010a 2010a ; Tarantini et al., 2012 2012 ), or for fear that use of thrombectomy might interfere with the postconditioning procedure, which should be implemented within 1 min after coronary reperfusion (Freixa et al., 2012 2012 ). Our meta-regression analysis shows no relationship between heart failure and use of thrombectomy, thus indicating that thrombectomy will not reduce the efficacy of postconditioning with respect to heart failure. Using GP IIb/IIIa inhibitors as a bailout therapy is reasonable in patients undergoing primary PCI in the event of angiographic evidence of a large thrombus, slow or no-reflow, and other thrombotic complications (Steg et al., 2012 2012 ). Data from a recent meta-analysis (Wang et al., 2013 2013 ) indicated the biomarker (creatine kinase, creatine kinase-myocardial band, troponin T/troponin I) for myocardial injury reduced significantly in studies not using GP IIb/IIIa inhibitors but not in those using the pharmacological substance. They explained that GP IIb/IIIa inhibitors and postconditioning achieved balance on protection by acting through a similar mechanism. We observe no significant relationship of heart failure in the use of GP IIb/IIIa inhibitors. A possible explanation of this ambivalence is that the troponin I value assessed at 72 h from the symptom onset rather than creatine kinase-myocardial band is associated with infarct volume (di Chiara et al., 2010 2010 ), a powerful indicator correlated with prognosis of STEMI (Eitel et al., 2013 2013 ). It is not conclusive whether different postconditioning protocols have different cardioprotective effect. Cohen et al. ( 2007 2007 ) suggested that a 30-s algorithm ensured that the pH did not increase abruptly and presented enough time to secure a proper production of reactive oxygen species. Additionally, Granfeldt et al. ( 2009 2009 ) proposed that brief cycles of reperfusion/reocclusion were recommended in small animal models, while longer periods (60 s) might be more effective in larger species. In the present meta-regression analysis, the protocols are not correlated with heart failure, suggesting that protocol is not a crucial factor in postconditioning’s beneficial effect on heart failure. Paradoxically, postconditioning appears to be harmful where non-fatal reinfarction is involved, with marginal significance. A higher rate of induced coronary embolization may be an explanation. Also, the cardiac protective role of postconditioning disappears when other adverse events including death, TVR, stent thrombosis, angina, and general MACE are selected as the end point. So we should express caution on the result because heart failure is a relatively subjective index compared to other end points. Several limitations in this study should be described. First, heterogeneity (such as different inclusion/exclusion criteria, postconditioning protocol, definition of heart failure, use of thrombectomy, and GP IIb/IIIa inhibitors) across studies did exist and might affect the generalization and interpretation of the meta-analysis results. However, we addressed this issue by regression analyses. Second, the hazard ratio (HR) should have been presented rather than RR because the follow-up duration in each trial was different and the time at which events occurred was important. But 7 of the 10 articles did not provide log-rank P -value, expected events, variance, survival curve, or time at which a certain event occurred, so HR could not be calculated (Tierney et al., 2007 2007 ). Third, our analysis was based on a relatively small sample. The small study effect has been well described in our previous work and the beneficial effect suggested by meta-analysis of small studies should be further validated in a meta-trial (Zhang et al., 2013 2013 ). Fourth, a recent prospective, randomized clinical trial about postconditioning with a sample size of 272 was not included because it published 21 d after the closing date of current meta-analysis (Limalanathan et al., 2014 2014 ). Conclusions 1 Our meta-analysis suggests that the use of postconditioning in STEMI patients undergoing primary PCI is associated with a significantly lower risk of heart failure, but the risk of non-fatal reinfarction may increase. The effect of postconditioning on other end points, including death, TVR, stent thrombosis, angina, as well as MACE during follow-up, is neutral. Future multicenter, prospective, randomized trials with the primary end point of clinical events are needed to clarify the prognostic effect of postconditioning. 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Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning We sincerely thank Prof. Sörensson (Karolinska Institutet, Department of Medicine, Unit of Cardiology, Karolinska University Hospital, Stockholm, Sweden), Elżbieciak (1st Department of Cardiology, Medical University of Silesia, Katowice, Poland), and Lønborg (Department of Cardiology, Rigshospitalet, Copenhagen, Denmark) for offering detailed information about clinical events. Compliance with ethics guidelines Xian-qing HU, Jian CHENG, Biao TANG, Zhong-heng ZHANG, Ke HUANG, Yi-ping YANG, Yan-yan MAO, Ming ZHONG, and Shen-wen FU declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. 10.1631/jzus.B1400237 Project supported by the Science and Technology Research Program of Jinhua Municipality (No. 2014-3-052), China 2014-08-31 2015-02-26 2015-01-08 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2015 2015 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 03 16