Summary
Background
Infarct size (IS) is a major determinant of patient outcome after acute ST-segment elevation myocardial infarction (STEMI). Interventions aimed at reducing reperfusion injury, such as cardiac ischaemic postconditioning (IPost), may reduce IS and improve clinical outcomes. IPost has been shown to be feasible in patients with STEMI treated by primary percutaneous coronary intervention (PPCI).
Aims
To provide an updated summary of the efficacy of IPost, assessed by analysing accurate surrogate markers of IS.
Methods
We performed a meta-analysis of randomized controlled trials that evaluated the efficacy of IPost in STEMI patients undergoing PPCI. The main outcome was area under the curve of serum creatine kinase release (CK-AUC). Secondary outcomes were other surrogate biomarkers of IS, complete ST-segment resolution, direct measurement of IS by single-photon emission computed tomography and estimation of IS by cardiac magnetic resonance (CMR-IS).
Results
Eleven studies were retrieved, including 1313 STEMI patients undergoing PPCI with or without IPost. Compared with controls, we observed a significant reduction in CK-AUC (standard mean difference [SMD] –2.84 IU/L, 95% CI –5.43 to –0.25 IU/L; P = 0.03). Other surrogate markers, such as CMR-IS (SMD –0.36, 95% CI –0.88 to 0.15; P = 0.16), showed a non-significant IS reduction in the IPost group.
Conclusions
This meta-analysis, dealing with accurate surrogate markers of IS, suggests that IPost reduces IS. However, results should be interpreted cautiously because of limited sample sizes and significant heterogeneity. Whether this translates into improvements in cardiac function and patient prognosis still needs to be demonstrated in larger prospective randomized controlled studies that are powered sufficiently.
Résumé
Objectifs
Synthétiser les données actuelles de la science concernant l’efficacité du postconditionnement ischémique sur la réduction de taille d’infarctus du myocarde (IDM).
Pré-requis
La taille d’IDM est un déterminant majeur du pronostic des patients au décours d’un STEMI. Les interventions visant à protéger des lésions de reperfusion comme le postconditionnement ischémique pourraient réduire la taille d’IDM et améliorer le pronostic. Des essais cliniques ont montré que le postconditionnement ischémique était réalisable chez les patients revascularisés par angioplastie primaire à la phase aiguë d’un STEMI.
Méthodes
Nous avons réalisé une méta-analyse des essais thérapeutiques randomisés et contrôlés évaluant l’efficacité du postconditionnement ischémique à la phase aiguë d’un STEMI revascularisé par angioplastie primaire. Le critère majeur était l’aire sous la courbe (AUC) des CPK. Les critères secondaires étaient d’autres biomarqueurs de taille d’IDM, la résolution du segment ST, et la taille d’IDM estimée par scintigraphie ou IRM myocardique.
Résultats
Onze études incluant 1313 patients ont été retenues. Notre analyse objective une réduction significative de l’AUC des CPK (SMD −2,84, 95 % CI −5,43, −0,25 IU/L, p = 0,03) dans le groupe actif. Elle montre une tendance non significative en faveur de cette même réduction dans le groupe actif sur les autres marqueurs de substitution comme l’IRM (SMD −0,36, 95 % CI −0,88, 0,15, p = 0,16).
Conclusions
Nos résultats suggèrent que le postconditionnement ischémique réalisé lors de la revascularisation d’un STEMI par angioplastie primaire permet d’obtenir une réduction de taille d’IDM. Ces résultats sont à interpréter avec prudence en raison de la petite taille des effectifs et d’une hétérogénéité significative. Des essais thérapeutiques contrôlés sur de larges effectifs sont nécessaires pour démontrer l’efficacité de cette réduction sur des critères cliniques et sur le pronostic des patients.
Background
Despite current optimal treatment, coronary heart disease morbidity and mortality remain significant, paving the way for the development of new cardioprotective therapies . Timely reperfusion is the most effective treatment to reduce the size of an infarct resulting from myocardial ischaemia. However, reperfusion has the potential to induce additional lethal injury, identified as reperfusion injury, which can be responsible for up to 40% of the final infarct size (IS). Because IS is known to be a major determinant of patient prognosis, any intervention that reduces its extent may result in a clinical benefit .
Ischaemic preconditioning and postconditioning are interventions with multiple and interacting components marshalled against myocardial reperfusion injury by endogenous cardioprotective mechanisms . Cardiac ischaemic postconditioning (IPost) is defined as rapid intermittent interruptions of blood flow in the early phase of myocardial reperfusion, feasible in patients with ST-segment elevation myocardial infarction (STEMI) revascularized by primary percutaneous coronary intervention (PPCI) .
Most clinical trials evaluating the benefit of IPost were small single-centre studies that reported conflicting results regarding IS reduction . Three meta-analyses investigating the effect of IPost have already been published . These meta-analyses either used suboptimal surrogate markers of myocardial IS, such as peak necrosis marker levels, or combined different markers in the same analysis. More evidence is needed before recommending IPost in routine clinical practice.
The aim of this systematic review and meta-analysis was to provide an updated summary of published randomized trials investigating the efficacy of IPost using reliable surrogate markers of IS reduction.
Methods
This review was conducted and reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) criteria .
Information sources and search strategy
We searched electronic databases (PubMed, Cochrane) for studies published before December 2013. In order to have comparable information from eligible studies, we collected additional data by communicating directly with the authors.
The following keywords were used: “ischaemic postconditioning”; “myocardial infarction”; and “acute coronary syndrome”. Our search was restricted to human and randomized controlled studies, without any language restriction. We also reviewed the reference lists of published meta-analyses and selected studies.
Eligibility criteria and study selection
The selection of eligible studies was done by two authors (C.T., D.A.), with disagreements resolved by consensus between these two authors.
Inclusion criteria were randomized controlled trials enrolling STEMI patients admitted during the acute phase for PPCI, comparing IPost (active group) with a routine intervention (control group), and evaluating one or more surrogate markers of IS. We decided a priori to exclude studies that systematically used intracoronary adenosine injection at the time of reperfusion, because adenosine is a known activator of cardioprotective signalling pathways, inducing potential pharmacological conditioning, which may dilute the effect of IPost on IS reduction .
The following surrogate markers of IS were considered: area under the curve (AUC) of serum creatine kinase (CK) release (CK-AUC); AUC of CK myocardial band release (CKMB-AUC); AUC of troponin (T or I isoforms) release (Tropo-AUC); complete ST-segment resolution (cSTR), defined as STR > 70% after reperfusion; direct measurement of IS by single-photon emission computed tomography (SPECT); or estimation of IS as a percentage of the area at risk by cardiac magnetic resonance (CMR).
Risk of bias in individual studies
One author (C.T.) assessed the methodological quality of the selected trials according to the Cochrane risk of bias criteria. We considered the following domains: random sequence generation and allocation concealment (selection bias); blinding of participants and personnel (performance bias); blinding of outcome assessment (detection bias); and completeness of the follow-up, intention-to-treat (ITT) analysis and dropouts (attrition bias).
Based on the above criteria, studies were divided into three categories: low (all criteria were at low risk of bias); high (at least one criterion was at high risk of bias); or unclear if otherwise.
Outcomes and comparisons
Our main outcome was the effect of IPost on CK-AUC. Secondary outcomes were: other biological surrogate markers (CKMB-AUC, Tropo-AUC); cSTR as a clinical surrogate marker of ischaemia resolution; and imaging surrogate markers of IS, measured by SPECT (SPECT-IS) or estimated by CMR (CMR-IS).
Data extraction process
Data from eligible trials were extracted by one author (C.T.). We contacted authors by e-mail whenever additional data were needed.
Statistical analysis
We extracted aggregate data from published reports. Summary measures are reported as standard mean difference (SMD) ± standard deviation for continuous variables (CK-AUC, CKMB-AUC, Tropo-AUC, SPECT-IS and CMR-IS) as studies assessed the same outcome but measured it in a variety of ways. Summary risk ratios (RRs) are reported for binary variables (cSTR) with 95% confidence intervals (CIs). We used a fixed-effects model, and if significant heterogeneity was observed, a random-effects model was performed. If heterogeneity persisted after using a random-effects model, we then performed a sensitivity analysis, by excluding one trial at a time. We tried to explore heterogeneity further by considering characteristics at both trial and patient levels. An inverse-variance model was used to pool the data. Statistical heterogeneity across trials was assessed with Chi 2 , I 2 and Tau 2 statistics. Heterogeneity was considered significant if the P value was < 0.1 and heterogeneity was considered high if I 2 was > 50%. Risk of bias assessment by visual inspection of funnel plot was not relevant due to the small number of included studies. Statistical analyses were performed using RevMan software (version 5.1).
Results
Included studies
The numbers of studies identified at each stage of the systemic review are shown in Fig. 1 . After removing duplicate references, the searches identified 595 records. Based on title and/or abstract, 37 relevant articles were retrieved for full-text reading. We excluded 22 articles for the following reasons: 16 were not randomized controlled trials; three were meta-analyses; one did not report any surrogate marker of IS; and two dealt with the same database as eligible studies. We excluded a further two trials that systematically used intracoronary adenosine injection at the time of reperfusion and two trials published in Chinese , as we did not succeed in obtaining data from the authors. Eleven studies were finally included in this review, corresponding to 1313 patients (646 randomized to the IPost group and 667 to the control group) ( Table 1 ). Additional data were obtained by contacting the authors of three studies . The studies by Lonborg et al. and Thuny et al./Mewton et al. were reported in two publications each, so we included the data as one study only for each group.
| Studies | Number of patients | Mean age (years) | Men/women ( n / n ) | Ischaemia duration (hours) | IPost protocol | Culprit artery a | Summary risk of bias | Outcomes reported | ||
|---|---|---|---|---|---|---|---|---|---|---|
| IPost | Control | IPost | Control | |||||||
| Yang et al., 2007 | 23 | 18 | 61 | 31/10 | 5.2 | 4.4 | 30 s × 3 | LAD > RCA > LCX | U | CK-AUC; cSTR; SPECT-IS |
| Ma et al., 2006 | 47 | 47 | 64 | 64/30 | 6.6 | 7.1 | 30 s × 3 | LAD > RCA > LCX | H | |
| Staat et al., 2005 | 16 | 14 | 57 | 25/5 | 5.3 | 5.5 | 60 s × 4 | RCA > LAD | U | CK-AUC |
| Thibault et al., 2008 | 17 | 21 | 56 | 25/13 | 4.7 | 4.9 | 60 s × 4 | LAD > RAD | L | CK-AUC; Tropo-AUC; SPECT-IS |
| Lonborg et al., 2010 | 59 b | 59 b | 62 | 92/26 | 4.0 | 4.3 | 30 s × 4 | RCA > LAD > LCX | U | cSTR; CMR-IS |
| Sorensson et al., 2010 | 45 b | 45 b | 63 | 65/25 | 2.8 | 3.1 | 60 s × 4 | RCA > LAD > LCX | U | CKMB-AUC; Tropo-AUC; CMR-IS |
| Freixa et al., 2012 | 39 b | 40 b | 60 | 62/17 | 5.4 | 5.0 | 60 s × 4 | LAD > RCA | L | cSTR c ; CMR-IS |
| Fan et al., 2011 | 22 | 28 | 66 | 31/19 | MD | MD | 30 s × 3 | MD | U | |
| Thuny et al., 2012 | 25 | 25 | 57 | 37/13 | 4.8 | 3.6 | 60 s × 4 | LAD > RCA > LCX | U | CMR-IS |
| Xue et al., 2010 | 23 | 20 | 58 | 41/2 | 4.1 | 5.4 | 60 s × 4 | LAD > RCA | U | CKMB-AUC; cSTR; SPECT-IS d |
| Hahn et al., 2013 | 350 | 350 | 60 | 537/163 | 3.3 | 3.2 | 60 s × 4 | LAD > RCA > LCX | L | cSTR |
| Total | 646 | 667 | 60.4 | |||||||
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