Scholarly article on topic 'Short-and long-term effects of ischemic postconditioning in STEMI patients: a meta-analysis'

Short-and long-term effects of ischemic postconditioning in STEMI patients: a meta-analysis Academic research paper on "Basic medicine"

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Academic research paper on topic "Short-and long-term effects of ischemic postconditioning in STEMI patients: a meta-analysis"

Gao et al. Lipids in Health and Disease (2015) 14:147 DOI 10.1186/s12944-015-0151-x

LIPIDS IN HEALTH AND DISEASE

RESEARCH

Open Access

Short-and long-term effects of ischemic postconditioning in STEMI patients: a meta-analysis

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Jing Gao1,2,3+, Junyi Luo1,2T, Fen Liu2, Yingying Zheng ',2, Bangdang Chen2, Qingjie Chen1,2 and Yining Yang1

Abstract

Background: Compelling evidence from large randomized trials demonstrates the salutary effects of ischemic postconditioning on cardioprotection against ischemic/reperfusion injury. However, some studies appear negative findings.

This study was designed to assess the short-and long-term effects of postconditioning (Poc) in studies including evolving ST-elevation myocardial infarction (STEMI).

Methods: Relevant studies were identified through an electronic literature search from the PubMed, Library of Congress, Embase, Cochrane Central Register of Controlled Trials, and ISI Web of Science. Studies published up to December 2014 were eligible for inclusion. Patients older than 18 years presenting within 12 h of the first STEMI and eligible for angioplasty were considered for the study.

Results: The 25 trials allocated 1136 patients to perform locational postconditioning cycles at the onset of reperfusion and 1153 patients to usual percutaneous coronary intervention (PCI). Ischemic postconditioning demonstrated a decrease in serum cardiac enzymes creatine kinase (CK) and CK-MB (P < 0.00001 and P =0.25, respectively) in the subgroup analysis based on direct stenting. Reduction in infarct size by imaging was showed during7 days after myocardial infarction (P =0.01), but not in the longterm (P = 0.08). The wall motion score index was improved in both the short term within 7 days (P = 0.009) and the long term over 6 months after receiving Poc (P = 0.02). All included studies were limited by the high risk of performance and publication bias. Conclusions: Ischemic postconditioning by brief interruptions of coronary blood flow at the onset of reperfusion after PCI appears to be superior to PCI alone in reducing myocardial injury and improving left ventricular function, especially in patients who have received direct stenting in PCI.

Keywords: Ischemic postconditioning, STEMI, Ischemic/reperfusion injury, Cardioprotection, Infarct size

Background

Ischemic/reperfusion injury appearing after primary percutaneous coronary intervention (PCI) abrogates myo-cardial salvage and may increase infarct size [1]. It was proved that ischemic preconditioning, which involved a series of brief ischemia/reperfusion cycles and performed before ischemia, was explicitly a cardioprotective

* Correspondence: yangyn5126@163.com +Equalcontributors

department of Cardiology, First Affiliated Hospitalof Xinjiang Medical University, Urumqi 830054, P.R., China

2Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi 830054, P.R., China

Fulllist of author information is available at the end of the article

Bio Med Central

strategy [2-4]. Unlike preconditioning, ischemic post-conditioning, which involves brief episodes of ischemia/ reperfusion during early reperfusion, has been demonstrated to be effective in many studies [5-9]. Ischemic postconditioning has a promising potential to be applied in the clinic. However, some studies suggest that ische-mic postconditioning during primary PCI does not reduce infarct size or improve myocardial function recovery [10, 11]. The purpose of this paper was to further summarize the evidence supporting cardioprotection of ischemic postconditioning in patients with acute STEMI by conducting a meta-analysis of the published literature.

© 2015 Gao et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Methods

Search strategy

To avoid insufficient number of studies, an electronic literature search was simultaneously conducted across the PubMed, Library of Congress, Embase, Cochrane Central Register of Controlled Trials, and ISI Web of Science. Two independent evaluators reviewed all English language articles published up to 2014. The following key words were used as search terms: ischemic postcon-ditioning, reperfusion, ischemic reperfusion injury, primary percutaneous intervention, controlled trials, and randomized controlled trials (RCTs). All prospective, randomized, single-center, or multicenter clinical trials were included.

Eligibility criteria

Criteria for inclusion were as follows:(1) subjects with explicit STEMI, (2) two reperfusion strategies, PCI with postconditioning (Poc) or conventional (Con) PCI, were compared, (3) a similar baseline between Poc and the control group, with a good match of age, gender, ische-mic time, and risk factors, (4) one or more myocardial injury-related indicators, which involve peak creatine kinase (CK), peak CK-MB, ST-segment resolution, infarct size (IS), left ventricular ejection fraction (LVEF), and wall motion score index (WMSI). Continuous variables were reported as mean ± standard deviation (SD). Only the latest study was included in the meta-analysis for identical or largely similar articles.

Study selection and quality assessment

Two investigators independently assessed the eligibility of identified studies. The studies that were evaluated were RCTs that focused on the role of Poc in STEMI. Published abstracts or without data were excluded. Disagreement resolved by discussion or by referral to a third assess or if necessary. Complete consensus among the authors on the final results was achieved. Studies included in the meta-analysis had to fulfill the aforementioned eligibility criteria. The criteria for study quality outlined by the Cochrane Reviewer's Handbook 4.2were adopted for quality assessment of included RCTs. These criteria were as follows: (1) correct random methods, (2) randomization, (3) blindness assessment, (4) completeness of the follow-up and using ITT (intention-to-treat) analysis to deal with the dropouts.

Statistical analysis

Continuous data were reported either as mean (SD) or median (interquartile range). For continuous data, mean difference was calculated where same scale was used to measure relevant outcomes (peak CK, peak CK-MB, LV EF, and WMSI). A random effects model was used to pool data, and the corresponding forest plots were

constructed. The Cochran's Q test was used to assess the heterogeneity among studies and was complemented by the I2 statistic [12]. All analyses were conducted using the statistical software Review Manager (RevMan) version 5.3. The authors are solely responsible for the design and conduct of this study and its final contents.

Results

Identification of studies

A total of 25 eligible publications were screened by the investigators. The studies that were excluded were as follows: (1) 949 manuscripts based on titles and abstracts and (2) 27 articles that either lacked original data [5, 13, 14], or were with inaccurate data [15], or involved remote postconditioning [16-18] and pharmacological postconditioning [19-24], or involved patients who were not suffering from STEMI and treated with PCI [6, 25-37]. The studies were excluded based on the full-text review. Twenty-five studies [7-11, 38-57] were included in this meta-analysis (Fig. 1).

Study characteristics

Among the 2289 participants included in the meta-analysis, 1136 patients were in the postconditioning group and 1153 in the conventional care group. Characteristics of studies and patients are summarized in Tables 1 and 2.

The Poc protocol (cycles x ischemia/reperfusion in seconds) varied between studies, being 2x90 "/180" in 1 study, 10x30"/30" in 1 study, 3x30"/30" to 4x 30 "/30" in 9 studies, and 3x60 "/60" to 4x60 "/60" in 14 studies. The follow-up in the trials varied from 3 days to 3.4 years. The relevant outcomes in all studies include markers of cardiac injury and left ventricular function (Table 2).

Table 1 Characteristics of studies included in the meta-analysis

Author Country Year Number (Poc/Con) Male (%) (Poc/Con) Age (y) (Poc/Con) Dyslipidemia (%) (Poc/Con) Diabetes (%) (Poc/Con) Smokers (%) (Poc/Con) Hypertension (%) (Poc/Con)

Staat [38] France 2005 16/14 75/93 58/56 80/50 20/13 57/56 38/36

Ma [9] China 2006 47/47 66/71 64/64 NR 38/45 NR 62/55

Ma [39] China 2007 32/29 66/70 64/64 NR 38/45 NR 59/55

Yang [7] China 2007 23/18 87/61 59/63 61/56 26/28 61/50 70/61

Laskey [40] USA 2008 12/12 58/58 60/58 58/75 42/42 NR 75/83

Thibault [41] France 2008 17/21 76/78 56/56 52/49 10/12 65/65 29/35

Linl [42]a China 2010 25/26 84/65 59/63 56/42 24/27 56/50 52/54

Lin2 [42]a China 2010 24/26 71/65 58/63 67/42 21/27 67/50 58/54

Lonborg [43, 44]b Denmark 2010 59/59 69/74 61/62 46/41 7/7 61/49 37/32

Sorensson [45] Sweden 2010 38/38 82/89 63/62 77/62 NR 26/29 16/29

Xue [46] China 2010 23/20 95/94 54/62 16/24 21/29 63/71 37/71

Garcia [47] USA 2011 22/21 86/76 61/55 73/71 5/19 23/43 73/71

Liu [48] China 2011 30/34 73/68 59/59 NR 30/32 57/61 37/39

Freixa [10] Spain 2012 39/40 84/72 59/60 44/35 23/17 51/62 49/50

Tarantini [49] Italy 2012 37/38 85/85 60/60 51/49 18/3 67/77 59/49

Thuny [8] France 2102 25/25 76/72 57/57 36/48 20/14 68/64 40/48

Zhao [50] China 2012 30/32 97/87 57/62 31/17 13/27 69/77 50/67

Dwyer [51] Canada 2013 50/52 88/89 57/57 36/29 6/14 44/44 42/33

Elzbieciak [52] Poland 2013 18/21 67/86 60/58 61/86 22/24 67/52 78/91

Hahn [53] Korea 2013 350/350 79/75 60/60 40/46 24/25 53/52 46/46

Mewton [54] France 2013 25/25 76/72 57/57 NR 20/14 68/64 48/40

Sorensson [55] Sweden 2013 33/35 85/89 63/62 NR 29/32 27/26 15/31

Dong [56] China 2014 32/30 63/73 70/68 NR 34/37 41/50 72/63

Limalanathan [11] Norway 2014 120/129 84/80 61/60 NR 4/2 49/54 29/25

Waltenberger [57] Germany 2014 25/27 68/70 60/60 12/11 12/7 60/55 48/33

aLonborg et al. published 2 articles on the same trial

bLin et al. compared 60-s postconditioning with 30-s postconditioning and no postconditioning (routine) in this study

PCI was performed by direct stenting in some studies [7-9, 11, 38-42, 47-49, 52, 56]. However, in other studies [10, 43-46, 50, 51, 53, 55, 57], the choice of stent was left to the discretion of the operator. Balloon angio-plasty or thrombus aspiration was also allowed if a stent could not be deployed or was considered harmful.

In the eligible studies, troponin levels were measured in eight studies [10, 11, 41, 44, 45, 49, 52, 56]. Eighteen [7, 9, 10, 38-42, 45-49, 51, 53, 54, 56, 57] studies contained data on peak or the area under the curve of CK or CK-MB. IS was measured by single-photon emission computed tomography (SPECT) or cardiovascular magnetic resonance (CMR) in eleven studies [7, 8, 10, 11, 41, 44, 46, 49, 51, 52, 57]. Global left ventricular function as determined by LVEF was measured in nine studies by echocardiography [7, 41, 42, 46, 47, 49-52], in eight studies by CMR [8, 11, 44, 45, 51, 54, 55, 57], and in one study by both echocardiography and CMR [10]. Regional

left ventricular function was measured by WMSI in six studies [9, 39, 42, 46, 48, 50].

Study quality

The analysis of the study quality in the 25 eligible studies is presented in Table 3. Baselines between the Poc group and the control group in all the studies were comparable. The measurement data was compared by the Student t test, and count data was compared by X test between the two groups. In terms of quality, each of these studies would be graded level B according to the Cochrane Reviewer's Handbook 4.2 for quality assessment of included RCTs.

Biomarkers of acute myocardial injury

The commonly measured myocardial injury biochemical markers of acute myocardialinfarction (AMI) are CK

Table 2 Characteristics of studies included in the meta-analysis

Author Country Year Chest pain Elapsed time (m) Culprit lesion Protocal Endpoint Follow-up i s n

Staat France 2005 <12 h NR LAD (38/43); RCA (62/57) 60"/60" x4 CKAUC;peak CK; blush grade; STR 3d H a

Ma China 2006 <12 h 395 ±150/426 ±150 LAD (49/53); LCX (23/17); RCA (28/30) 30"/30" x 3 peak CK;peak CK-MB; WMSI 7d;2 m h

Ma China 2007 <12 h NR LAD (53/52); LCX (22/17); RCA (25/31) 30"/30" x 3 peak CK;peak CK-MB; WMSI 7d;2 m Q 3 Q.

Yang China 2007 NR 312 ±48/264 ±42 LAD (65/61); LCX (9/6); RCA (26/33) 30"/30" x 3 peakCK; CKAUC;IS; LVEF 3d;1w is e

Laskey USA 2008 <6 h 228 ±43/222 ±54 LAD (100/100); LCX (0); RCA (0) 90"/180" x 2 peak CK; STR NR s e 2

Thibault France 2008 <6 h 283 ± 82/297 ± 104 NR 60"/60" x4 CKAUC; TnI;IS; LVEF 6 m;12 m 1

Lin China 2010 <12 h NR LAD (64/62); LCX (8/8); RCA (28/30) 30"/30" x 3 TNFa; LV EF (7d, 1y);WMSI 7d;1y 5)

Lin China 2010 <12 h NR LAD (54/62); LCX (8/77); RCA (38/31) 60"/60" x 3 TNFa;LV EF (7dN 1y);WMSI 7d;1y 47

Lonborg Denmark 2010 <12 h 241 ±148.9/255 ±196 LAD (44/39); LCX (8/19); RCA (47/42) 30"/30" x4 IS;IS/AAR;LVEF;peak TnT 3m

Sorensson Sweden 2010 <6 h 165 ± 63.7/185 ± 87.41 LAD (37/37); LCX (11/3); RCA (53/61) 60"/60" x4 IS/AAR; TnTAUC; LVEF 6-9d

Xue China 2010 <12 h 4.1 ±3.0/5.4 ±3.7 LAD (42/59); LCX (0); RCA (58/41) 60"/60" x4 CK-MB, IS, LVEF, STR 7d

Garcia USA 2011 <12 h 4.5/4.4 LAD (36/24); LCX (23/10); RCA (41/67) 30"/30" x4 peakCK; CK-MB;LVEF 3.4y

Liu China 2011 <12 h 312 ±102/324 ±108 LAD (53/59); LCX (10/12); RCA (37/29) 30"/30" x 3 peak CK; Peak CK-MB; WMSI;LVEF; 7d

Freixa

326 ±180/330 ±211

LAD (51/39); LCX (NR) RCA (45/47)

blush grade;IS

60"/60" x4 peak CK; Peak CK-MB; TnT; STR; IS (7d,6 m)

7d;6 m

Tarantini Italy 2012 <6 h 212 ±85/194 ±80 LAD (41/44); LCX (18/8); RCA (41/49) 60"/60" x4 peak TnI; LVEF;IS; 30d

Thuny France 2102 <12 h 289 ±31/215 ± 20 LAD (56/56); LCX (0/8); RCA (44/36) 60"/60" x4 IS;peak CK 3d

Zhao China 2012 <12 h 309 ± 201/404 ± 191 LAD (53/53); LCX:NR; RCA:NR 60"/60" x4 LVEF; WMSI 1w;6 m

Dwyer Canada 2013 <6 h 150 ± 70/170 ± 84 LAD (50/46); LCX:(12/14); RCA:(38/40) 30"/30" x4 IS; AAR; PeakCK; LVEF 3d

Elzbieciak Poland 2013 <12 h 225.6 ±139.4/317.6 ±195.8 1 LAD (100/100); LCX (0) RCA (0) 60"/60" x4 IS; AAR; PeakCK-MB; peak TnT; LVEF;IS/AAR 3d;6 m

Hahn Korea 2013 <12 h 196 ±51/195 ±171 LAD (47/45); LCX:(11/11); RCA:(42/44) 60"/60" x4 peakCK-MB; STR; blush grade 30d

Mewton France 2013 <12 h 289 ±31 /215 ±20 LAD (56/56); LCX (0/8); RCA (44/36) 60"/60" x4 LVEF;IS;IS/AAR 4d

Sorensson Sweden 2013 <6 h 165 ± 51/180 ± 84 LAD (33/37); LCX (9/3); RCA (57/60) 60"/60" x4 IS; LVEF 12 m

Dong China 2014 <12 h 300 ± 90/294 ± 66 LAD (56/43); LCX (6/10); RCA (38/47) 30"/30" x 3 blush grade; STR; CK- MB; TnT; LVEF 7d;30d

Limalanathan Norway 2014 <6 h NR LAD (46/51); LCX (13/9); RCA (41/41) 60"/60" x4 IS (CECMR); STR; TnT; LVEF 2d;4 m

Waltenberger Germany 2014 <6 h NR LAD (28/26); LCX (NR); RCA (64/74) 30"/30" x 10 CKAUC;IS; LVEF 4d;4 m;12

NR,not related; LAD,left anterior descending branch; RCA,right coronary arterry; LCX,left circumflex artery; CK,creatine kinase; CKAUC,CK area under the curve; CK-MB,creatine kinase isoenzyme; STR,ST resolution; WMSI, wall motion score index; IS, infarct size; LVEF, left ventricular ejection fraction; TnI,troponin I; TNFa,tumor necrosis factor; AAR,area at risk; TnT, troponin T

Table 3 Quality assessments of studies included in the meta-analysis

Study Year Randomization Blinded assessment Dropout rate (%) Similar baseline

Staat 2005 yes no unclear yes

Ma 2006 yes no unclear yes

Ma 2007 yes no unclear yes

Yang 2007 yes unclear unclear yes

Laskey 2008 yes unclear 0 yes

Thibault 2008 yes single-blind 0 yes

Linl 2010 yes no unclear yes

Lin2 2010 yes no unclear yes

Lonborg 2010 yes unclear 0.26 yes

Sorensson 2010 yes no 0.15 yes

Xue 2010 yes unclear 0 yes

Garcia 2011 yes unclear 0 yes

Liu 2011 yes unclear 0 yes

Freixa 2012 yes no 0 yes

Tarantini 2012 yes no 0.04 yes

Thuny 2102 yes no 0.19 yes

Zhao 2012 yes no 0.09 yes

Dwyer 2013 yes unclear 0.23 yes

Elzbieciak 2013 yes no 0 yes

Hahn 2013 yes no 0.04 yes

Mewton 2013 yes no 0 yes

Sorensson 2013 yes no 0 yes

Dong 2014 yes unclear 0 yes

Limalanathan 2014 yes no 0.08 yes

Waltenberger 2014 yes single-blind 0.13 yes

and CK-MB, which are associated with infarct size. Compared with the Con group, the Poc group showed no apparent decrease in the level of peak CK after AMI [standard mean difference (SMD) = -0.49; 95 % confidence interval (CI), -1.09 to-0.1; I2 = 91 %; P =0.11). There was substantial between-study heterogeneity (Cochran Q test, P < 0.00001, I2 = 91 %). Subgroup analysis based on the method of PCI (PCI was performed only by direct stenting in some studies,and by other methods including direct stenting,balloon dilatation,and thrombus aspiration in rest of studies) showed that not only the decrease in CK became more significant but the heterogeneity also dropped with direct stenting (SMD = -0.82; 95 % CI, -1.18 to-0.47;I2 = 64 %;P < 0.00001) as compared with other methods (SMD = 0.96; 95 % CI, -0.66 to 2.58;I2 = 96 %;P =0.25) (Fig. 2). The CK-MB result was similar to those of CK (Fig. 3). The funnel plots with respect to the end point of CK and CK-MB showed no significant publication bias (Fig. 4). Publication bias measured by Egger's test was not significant (P = 0.21, P = 0.68, respectively). These results showed that Poc can

reduce ischemic necrosis of myocardium after acute infarction when patients received direct stenting.

Myocardial infarct size measured by imaging

The meta-analysis of the studies demonstrated that the perfusion defect index on SPECT or CMR,an estimate of infarct size during 72 h after AMI, significantly reduced in the Poc group compared to the Con group. The pooled outcome of studies suggested a reduction in IS as measured by imaging (SMD = -0.82; 95 % CI, -1.44 to -0.19; I2 = 91 %; P =0.01). There was substantial between-study heterogeneity (Cochran Q test, P < 0.00001, I2 = 91 %) during 72 h after AMI. Subgroup analysis based on direct stenting showed that the heterogeneity dropped with direct stenting (SMD = -0.6; 95 % CI, -1.09 to-0.11;/2 = 75 %;P = 0.02) as compared with other methods (SMD = -1.12; 95 % CI, -2.9 to 0.65;/2 = 96 %; P =0.22) (Fig. 5). However, no significant difference was noted between the two groups more than 4 months after AMI (SMD = -0.43; 95 % CI, -0.9 to -0.04; I2 = 87 %; P = 0.08), while there was a trend

Study or Subgroup_Mean

Рос Con Std. Mean Difference _SD Total Mean_SD Total Weight_IV, Random, 95% CI

Std. Mean Difference IV, Random, 95% CI

1.2.1 Direct stenting

Garcia 2011 Laskey 2008 Liu 2011 Ma 2006 Ma 2007 Staat 2005 Thuny 2012 Yang 2007 Subtotal (95% CI) Heterogeneity: Tau2 = Test for overall effect:

2,182 1,717 22 1,524 435 12 1,162 548 30

1.236 813 47

1.237 813 32 2,831 404 16 1,695 1,907 25 2,229 255 23

0.16; Chi2 = 19.66, df = Z = 4.54 (P< 0.00001)

2,444 1,862 1,732 1,697 1,697 4,234 3,505 2,699

1,928 561 480 966 966 722 1,942 634

21 10.0%

12 9.2%

34 10.3%

47 10.6%

29 10.3%

14 8.6%

25 10.1%

18 9.8% 79.0%

7 (P = 0.006);

I2 = 64%

1.2.2 other methods

Dwyer 2013 2,944 1,984 50

Freixa 2012 3,909 485 39

Subtotal (95% CI) 89

Heterogeneity: Tau2 = 1.31; Chi2 = 24.48, df = Test for overall effect: Z = 1.16 (P = 0.25)

2,660 3,122

1,982 379

52 40 92

10.7% 10.3% 21.0%

: 1 (P< 0.00001); I2 = 96%

Total (95% CI) 296 292 100.0%

Heterogeneity: Tau2 = 0.83; Chi2 = 103.73, df = 9 (P < 0.00001); I2 = 91% Test for overall effect: Z = 1.62 (P = 0.11)

Test for subgroup differences: Chi2 = 4.44, df = 1 (P = 0.04), I2 = 77.5%

Fig. 2 Effect of postconditioning on CK release during 72 h after PCI

-0.14 [-0.74, 0.46] -0.65 [-1.48, 0.17] -1.10 [-1.63,-0.57] -0.51 [-0.92, -0.10] -0.51 [-1.02,0.00] -2.38 [-3.34, -1.41] -0.93 [-1.51,-0.34] -1.00 [-1.66,-0.34] -0.82 [-1.18, -0.47]

0.14 [-0.25, 0.53] 1.79 [1.27,2.32] 0.96 [-0.66, 2.58]

-0.49 [-1.09, 0.10]

■ -2 0 2 4 Favours [Рос] Favours [Con]

toward the reduction of IS. Subgroup analysis based on direct stenting showed that the heterogeneity dropped with direct stenting (SMD = -0.16; 95 % CI, -0.43 to-0.11; I2 = 16 %; P = 0.24) as compared with other methods (SMD = -0.61; 95 % CI, -0.1.5 to 0.28; I2 = 93 %; P =0.18) (Fig. 6). No significant change in

heterogeneity was noted when the studies were grouped based on geographic region.

Cardiac function measures

LVEF was significantly improved in the Poc group in the short term within 7 days after AMI (SMD = 0.41; 95 % CI,

Рос

Std. Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight IV. Random. 95% CI

Std. Mean Difference IV. Random. 95% CI

2.2.1 Direct stenting

Xue 2010 232 172 350 229 204 350 16.0%

Subtotal (95% CI) 739 740 45.4%

Heterogeneity: Tau2 = 0.30; Chi2 = 59.56, df = 2 (P < 0.00001); I2 = 97% Test for overall effect: Z = 2.02 (P = 0.04)

Total (95% CI) 888 871 100.0%

Heterogeneity: Tau2 = 0.39; Chi2 = 113.05, df = 6 (P < 0.00001); I2 = 95% Test for overall effect: Z = 0.81 (P = 0.42)

Test for subgroup differences: Chi2 = 17.62, df = 1 (P < 0.0001), I2 = 94.3%

Fig. 3 Effect of postconditioning on CK-MB release during 72 h after PCI

0.02 [-0.13, 0.16] 0.67 [0.02,1.32]

-0.21 [-0.70, 0.29]

Elzbieciak 2013 241.6 166.8 18 188 240.2 0 Not estimable

Garcia 2011 195 33 22 242 40 21 12.6% -1.26 [-1.92,-0.60]

Liu 2011 165 70 30 280 99 34 13.6% -1.31 [-1.86,-0.77] —"—

Ma 2006 117 76 47 172 93 47 14.6% -0.64 [-1.06, -0.23]

Ma 2007 117 76 32 172 93 29 13.8% -0.64 [-1.16,-0.13]

Subtotal (95% CI) 149 131 54.6% -0.92 [-1.29, -0.56]

Heterogeneity: Tau2 = 0.07; Chi2 = 5.76, df = 3 (P = 0.12); l2 = 48%

Test for overall effect: Z = 4.98 (P < 0.00001 )

2.2.2 other methods

Freixa 2012 251 28.9 39 195 17.6 40 13.3% 2.32 [1.75, 2.90]

Hahn 2013 232 172 350 229 204 350 16.0% 0.02 [-0.13, 0.16]

-2-1012 Favours [Рос] Favours [Con]

Fig. 4 Funnelplot for the analysis of acute myocardialinjury biomarkers

0.16 to 0.65 I2 = 73 %; P = 0.001) (Fig. 7). LVEF also improved in the Poc group than in the Con group over 4 months after AMI (SMD =0.48; 95 % CI, 0.11 to 0.85; P =0.01). However, subgroup analysis showed that improvement in LVEF was not significant. The heterogeneity dropped with the involvement of direct stenting (SMD =0.2; 95 % CI, -0.02 to 0.42; I2 = 0 %;P =0.07) as compared with other methods (SMD = 0.57; 95 % CI, 0.02 to 1.W2 = 88 %;P =0.04) (Fig. 8). Patients receiving Poc had a lower WMSI (a value of 1 is normal segmental motion and

higher values indicate poorer contraction) than those receiving usual primary PCI in both the short term within 7 days (SMD = -2.65; 95 % CI-4.63 to-0.67; P =0.009) (Fig. 9) and the long term over 6 months (SMD = -3.48; 95 % CI,-6.47 to-0.5; P = 0.02) (Fig. 10).

Discussion

The current meta-analysis included data from 25 randomized trials involving 2289 participants. The results gave rise to a view that postconditioning following PCI

Poc Con Std. Mean Différence Std. Mean Différence

Study or Subgroup Mean SD Total Mean SD Total Weight IV. Random. 95% CI IV. Rando m. 95% CI

3.2.1 direct stenting

Llmalanathan 2014 16.2 12.52 120 17.4 13.04 129 15.8% -0.09 [-0.34, 0.16]

Mewton 2013 18 9.2 25 27.6 16 25 14.3% -0.72 [-1.30,-0.15]

Thuny2012 13 7 25 21 14 25 14.3% -0.71 [-1.28,-0.14]

Yang 2007 22.8 6.7 23 31.3 8.6 18 13.7% -1.10 [-1.76,-0.43] —■—

Subtotal (95% CI) 193 197 58.1% -0.60 [-1.09, -0.11]

Heterogeneity: Tau2 = 0.18; Chi2 =12.10, df = 3(P = 0.007); I2 = 75%

Test for overall effect: Z = 2.38 (P = 0.02)

3.2.2 other methods

Freixa 2012 27.5 17.2 39 22.1 10.2 40 15.0% 0.38 [-0.07, 0.82]

Waltenberger2014 15.4 2.1 25 21.7 2.3 27 13.0% -2.81 [-3.59, -2.03]

Xue 2010 13 11.2 23 24.2 10.6 20 13.9% -1.01 [-1.65,-0.37] -

Subtotal (95% CI) 87 87 41.9% -1.12 [-2.90, 0.65]

Heterogeneity: Tau2 = 2.36; Chi2 = 50.81, df = Test for overall effect: Z = 1.24 (P = 0.22)

2 (P< 0.00001); I2 = 96%

Total (95% CI) 280 284 100.0%

Heterogeneity: Tau2 = 0.63; Chi2 = 64.18, df = 6 (P < 0.00001); I2 = 91%

Test for overall effect: Z = 2.56 (P = 0.01)

Test for subgroup differences: Chi2 = 0.31, df = 1 (P = 0.58), I2 = 0%

Fig. 5 Effect of postconditioning on IS reduction during 7 days after PCI

-0.82 [-1.44, -0.19]

-2 0 2 4 Favours [Poc] Favours [Con]

Рос Con Std. Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight IV. Random. 95% CI

4.2.1 direct stenting

Elzbieciak2013 25.26 12.88 18 26.18 23 21 13.2% -0.05 [-0.68, 0.58]

Llmalanathan 2014 13.5 8.3 120 14.4 12.52 129 16.4% -0.08 [-0.33, 0.16]

Thibault 2008 11.8 10.3 17 19.5 13.3 21 12.9% -0.63 [-1.28, 0.03]

Subtotal (95% CI) 155 171 42.5% -0.16 [-0.43, 0.11]

Heterogeneity: Tau2 = 0.01; Chi2 = 2.38, df = 2 (P = 0.30); I2 = 16%

Test for overall effect: Z = 1.16 (P = 0.24)

4.2.2 other methods

Dwyer 2013 9 3 50 9 5 52 15.4% 0.00 [-0.39, 0.39]

Freixa 2012 21.8 13.2 39 18.7 10.6 40 14.9% 0.26 [-0.19, 0.70]

Lonborg 2010 14.7 7 43 17.7 7 43 15.1% -0.42 [-0.85, 0.00]

Waitenberger 2014 13.9 1.7 25 18.6 2 27 12.1% -2.49 [-3.22, -1.75]

Subtotal (95% CI) 157 162 57.5% -0.61 [-1.50, 0.28]

Heterogeneity: Tau2 = 0.76; Chi2 = 42.50, df = = 3(P< 0.00001); l2 = 93%

Test for overall effect: Z = 1.35 (P = 0.18)

Total (95% CI) 312 333 100.0% -0.43 [-0.90, 0.04]

Heterogeneity: Tau2 = 0.34; Chi2 = 45.79, df = = 6(P< 0.00001); l2 = 87%

Std. Mean Difference IV. Random. 95% CI

Test for overall effect: Z = 1.77 (P = 0.08)

Test for subgroup differences: Chi2 = 0.91, df = 1 (P = 0.34), I2 = 0%

Fig. 6 Effect of postconditioning on IS 4-12months after myocardialinfarction

-2-1012 Favours [Рос] Favours [Con]

/ Рос Con Std. Mean Difference Std. Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IVr Rande mr 95% CI

6.2.1 Direct stenting

Dong 2014 55.1 9.8 32 42.9 10.7 30 6.8% 1.18 [0.63, 1.72]

Garcia 2011 52 9 22 43 15 21 6.2% 0.72 [0.10, 1.34]

Llmalanathan 2014 51 10.37 120 50 13.23 129 9.3% 0.08 [-0.17, 0.33]

Lin1 2010 58 3 24 58 3 26 6.7% 0.00 [-0.55, 0.55]

Liu 2011 55 8 30 47 10 34 7.0% 0.87 [0.35, 1.38]

Mewton 2013 52 8 25 50 12 25 6.7% 0.19 [-0.36, 0.75]

Tarantini 2012 49.4 7.4 37 49.9 7 38 7.6% -0.07 [-0.52, 0.38]

Thuny2012 52 8 25 50 25 38 7.1% 0.10 [-0.41, 0.60]

Subtotal (95% CI) 315 341 57.3% 0.36 [0.05, 0.67]

Heterogeneity: Tau2 = 0.13; Chi2 = 23.64, df = 7(P = 0.001); I2 = 70%

Test for overall effect: Z = 2.29 (P = 0.02)

6.2.2 other methods

Dwyer 2013 56 10 50 52 10 52 8.1% 0.40 [0.00, 0.79] ■

Freixa 2012 42.7 9.8 39 43.7 8.9 40 7.7% -0.11 [-0.55, 0.34]

Sorensson 2010 50 9.63 38 50 11.11 38 7.6% 0.00 [-0.45, 0.45]

Waitenberger 2014 55.3 1.9 25 52.2 2.2 27 6.2% 1.48 [0.86, 2.10]

Xue 2010 57 9 23 47 11 20 6.0% 0.98 [0.35, 1.62]

Zhao 2012 55.19 10.42 30 51.87 9.3 32 7.1% 0.33 [-0.17, 0.83]

Subtotal (95% CI) 205 209 42.7% 0.48 [0.04, 0.91]

Heterogeneity: Tau2 = 0.22; Chi2 = 23.02, df = 5(P = 0.0003); 2 = 78%

Test for overall effect: Z = 2.16 (P = 0.03)

Total (95% CI) 520 13 (P = 1 (P 550 100.0% 0.41 [0.16, 0.65] ♦

Heterogeneity: Tau2 = 0.15; Chi2 = 47.34, df = Test for overall effect: Z = 3.27 (P = 0.001) Test for subgroup differences: Chi2 = 0.19, df <0.00001); l2 = = 0.67), I2 = 0% 73% -2 -1 Favours [Con] 1 2 Favours [Рос]

Fig. 7 Effect of postconditioning on LV EF during 7 days after PCI

Poc Con Std. Mean Difference Std. Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight IV. Random. 95% CI IV. Rande m. 95% CI

10.2.1 Direct stenting 9.1 21 9.2% 0.18 [-0.45, 0.81]

Elzbieciak 2013 49.52 13.03 18 47.5

Limalanathan 2014 56.5 10.37 120 55 10.37 129 11.8% 0.14 [-0.10, 0.39]

Thibault 2008 56 8 17 49 13 21 9.0% 0.62 [-0.04, 1.28]

Subtotal (95% CI) 155 171 29.9% 0.20 [-0.02, 0.42]

Heterogeneity: Tau2 = 0.00; Chi2 = 1.77, df = 2 (P = 0.41); I2 = 0%

Test for overall effect: Z = 1.80 (P = 0.07)

10.2.2 other methods

Dwyer 2013 54 8 50 53 7 52 10.9% 0.13 [-0.26, 0.52]

Freixa 2012 43.4 10.4 39 47.95 12.6 40 10.5% -0.39 [-0.83, 0.06]

Lonborg 2010 53 10 43 53 10 43 10.7% 0.00 [-0.42, 0.42]

Sorensson 2013 47 5.19 33 38 5.93 35 9.8% 1.59 [1.04, 2.14]

Thibault 2008 56 8 17 49 13 21 9.0% 0.62 [-0.04, 1.28]

Waltenberger 2014 53.6 2.3 25 49.6 2.3 27 9.1% 1.71 [1.07, 2.36] -■-►

Zhao 2012 56.45 8.54 30 51.19 11.22 32 10.1% 0.52 [0.01, 1.03]

Subtotal (95% CI) 237 250 70.1% 0.57 [0.02,1.13]

Heterogeneity: Tau2 = 0.49; Chi2 = 52.10, df = 6(P< 0.00001); l2 = 88%

Test for overall effect: Z = 2.03 (P = 0.04)

Total (95% CI) 392 9 (P < 421 100.0% 0.48 [0.11, 0.85] I I I I

Heterogeneity: Tau2 = 0.29; Chi2 = 55.79, df = Tect for nvprall affprt- 7 = 9ЦЧ?Р = ПП"П 0.00001); l2 = 84% 1 1 -2 -1 1 1 1 2

1 CoL IUI UVCldN BMCU. i— — ¿.ЭО ^Г — U.U 1 J Test for subgroup differences: Chi2 = 1.50, df = 1 (P = 0.22), I2 = 33.3% Favours [Con] Favours [Poc]

Fig. 8 Effect of postconditioning on LV EF 4 months after myocardialinfarction

induced by transient coronary ischemia in STEMI patients may reduce myocardial injury biomarkers and improve cardiac function, compared with the usual care group. This cardioprotection was more apparent when direct stenting was performed in PCI compared with other methods of PCI, including balloon angioplasty and thrombus aspiration. The lack of substantial effect of Poc when PCI was completed by angioplasty or thrombus aspiration was most likely due to inadequate revascularization. However, despite the trend in IS reduction, no significant decrease was noted in IS over 4 months after AMI.

Reperfusion therapy is an effective therapeutic approach during the early stage of STEMI patients to prevent heart failure and other cardiovascular events. Many studies have verified that immediate reperfusion is critical to rescue the ischemic myocardium. However, reperfusion has the potential exacerbation of myocardium

injury, including myocardial stunning, no reflow, and ventricular arrhythmias [58-60]. Therefore, attenuating reperfusion injury has become an urgent challenge for salvaging myocardium during reperfusion in STEMI patients. Poc performed during angioplasty is technically simple and safe, for cycles of "ischemia/reperfusion" can be easily achieved by repeatedly deflating and inflating the balloon in the culprit artery. A number of studies [7-9, 38-44, 46, 48, 50, 54, 56, 57] described salutary effects of Poc on ischemic/reperfusion injury. In contrast, other studies [10, 11, 45, 47, 49, 51-53, 55] show negative effect of postconditioning, even harmful for myocardium salvage. These studies present high heterogeneity of result due to the difference of Poc protocol, measurement, culprit artery, chest pain elapsed time, endpoints, and the type of PCI. For example, IS can be measured by SPECT or CMR, assessed by percentage of the area at risk, a percentage of the left ventricular mass,or in

Std. Mean Difference

Study or Subgroup_Mean_SD Total Mean_SD Total Weight_IV. Random. 95% CI

Std. Mean Difference IV. Random. 95% CI

Lin1 2010 Lin2 2010 Xue 2010 Zhao 2012

1.51 1.26 1.2 1.24

0.1 0.03 0.2 0.19

25 24 23 30

1.8 1.81 1.4 1.31

0.1 0.1

0.3 0.23

26 26 20 32

25.4% 22.7% 25.8% 26.1%

Total (95% CI) 102 104 100.0%

Heterogeneity: Tau2 = 3.86; Chi2 = 85.91, df = 3 (P < 0.00001); I2 = 97% Test for overall effect: Z = 2.62 (P = 0.009)

-2.86 [-3.65, -2.06] -7.21 [-8.78, -5.64] -0.78 [-1.40, -0.16] -0.33 [-0.83, 0.17]

-2.65 [-4.63, -0.67]

Fig. 9 Effect of postconditioning on WMSIduring 7 days after myocardialinfarction

-10 -5 0 5 10 Favours [Poc] Favours [Con]

Poc Con Std. Mean Difference Std. Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight IV. Random. 95% CI IV. Rande m. 95% CI

Lin1 2010 1.27 0.05 25 1.53 0.09 26 33.6% -3.50 [-4.39, -2.60] »

Lin2 2010 1.1 0.02 24 1.53 0.09 26 32.1% -6.37 [-7.79, -4.96]

Zhao 2012 1.2 0.17 30 1.4 0.32 32 34.3% -0.76 [-1.28, -0.25] ■

Total (95% CI) 79 84 100.0% -3.48 [-6.47, -0.50]

Heterogeneity: Tau2 = 6.70; Chi2 = 69.20, df = 2 (P < 0.00001); I2 = 97% Test for overall effect: Z = 2.29 (P = 0.02) -10 -5 Favours [Poc] 5 10 Favours [Con]

Fig. 10 Effect of postconditioning on WMSI6 months after myocardialinfarction

grams. A pooled analysis of RCTs has shown that involvement of the left anterior descending (LAD) is one of the strongest predictors of IS [61]. This study revealed that postconditioning presents cardioprotection in patients with STEMI, especially in whom PCI was performed by direct stenting. The reason may be that reperfusion is more adequate by direct stenting than other methods. Appropriate trials are needed to answer this question. Eleven studies performed follow-up from 3 months to 3.4 year [10, 11, 41, 42, 44, 47, 50-52, 55, 57]. The short-term (within 7 days after PCI) beneficial effect in the Poc group included reduced biomarkers of myocardium injury, reduced IS measured by imaging,and the left ventricular function assessed by LVEF or WMSI. Unfortunately, the remarkable decrease of IS did not appear after the long-term follow up. In both short- or long-term follow-up, the global left ventricular function as determined by LVEF improved. Although the analysis suggest that regional left ventricular function assessed by WMSI showed positive result in both short- and long-term follow-up,only several studies cover WMSI. Due to the limited sample size, the results should not be considered conclusive.

Poc could improve myocardial reperfusion in patients with ST-elevation AMI undergoing PCI by reducing no reflow. However, the mechanisms of Poc are not clear. Previos study revealed that high concentrations of inorganic phosphate, reactive oxygen species, and reactive nitrogen species are all present during myocardial ischemia and during reperfusion [62]. Due to the importance of oxidative stress and inflammation in atherosclerotic plaques development and Cardiovascular disease progression, therapeutic of antioxidant seems to be very important [63]. So the cardioprotective effect of Poc partly depend on antioxidant and anti-inflammatory.

Moreover, the question is whether different protocols have different cardioprotective effects. Many different protocols of postconditioning existed, such as 60 s x 3circles, 60 s x 4circles, 30 s x 4circles, and so on, used in available studies. However, only one study tested the hypothesis that postconditioning of 60 s x 3 was more protective than postconditioning of 30 s x 3 [42]. Therefore, additional trials of a large scale are needed to

determine the optimal protocol. It is also reported that ischemic postconditioning reduced infarct size in normotensive but not hypertensive rat hearts [64, 65]. Experimental animal data suggest that the presence of diabetes and related conditions, such as obesity and metabolic syndrome, may affect the cardioprotective efficacy of both ischemic and pharmacologic postcondi-tioning. Przyklenk et al. [66] found that ischemic post-conditioning cannot play a protective role in reducing infarct size by isolated perfused heart of murine model compared with the normoglycemic heart. In a retrospective analysis, postconditioning the human heart by multiple balloon inflations failed to reduce irreversible injury in patients above the age of 65 years [67]. Yellon and colleagues demonstrated a decline in the effectiveness of RISK pathway signaling with age [68]. They suggested that cardioprotection associated with postcon-ditioning may be affected by age, comorbidities, medications, and the method selection of PCI. Therefore, future strategies will need to focus on the quality of reperfusion. Appropriate trial design is required to provide clearer answers.

Limitations

Compared with previous studies, the analysis of the present study involves a comprehensive literature search including a large number of relevant studies. Postcondi-tioning was associated with a reduction of infarct size as determined by biochemical quantification and imaging. Cardiac function was assessed by LVEF and WMSI. In this meta-analysis, the long-term (over than 3 month) effect of postconditioning was analyzed as well as the short-term effect. Besides, method selection of PCI was based on subgroup analysis. However, the limitations inherent to the studies contained in the analysis impact the present-study results, such as small sample size, heterogeneity between studies, and risk of performance bias.

Conclusion

Ischemic postconditioning during PCI in STEMI seems to be superior to the conventional PCI alone in reducing acute myocardial injury, infarction size, and left

ventricular function including global and regional function, especially in patients who have received direct stenting in PCI. Given the limitations of the current available evidence, additional data involving potential risk factors of restricting postconditioning from large RCTs are needed.

Competing interests

The authors declare that they have no competing interests. Authors' contributions

Yining Yang put forwad the design. Jing Gao and Junyi Luo completed the work of data analysis. Yingying Zheng, Bangdang Chen and Qingjie Chen performed collecting related papers. The manuscript was drafted by Jing Gao and Fen Liu, and revised by Junyi Luo. Finally, Jing Gao performed submitting. All authors read and approved the final manuscript.

Acknowledgements

This study was supported by the High Technology Research and Development Projects of Xinjiang (No. 201417102).

Author details

1Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P.R., China. 2Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi 830054, P.R., China. 3Department of endocrinology, Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, P.R.China.

Received: 15 October 2015 Accepted: 6 November 2015 Published online: 16 November 2015

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