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Meta-Analysis
. 2015 Nov 18;10(11):e0142021.
doi: 10.1371/journal.pone.0142021. eCollection 2015.

Determinants of the Efficacy of Cardiac Ischemic Preconditioning: A Systematic Review and Meta-Analysis of Animal Studies

Kimberley E Wever  1 , Carlijn R Hooijmans  1 , Niels P Riksen  2 , Thomas B Sterenborg  3 , Emily S Sena  4 , Merel Ritskes-Hoitinga  1 , Michiel C Warlé  3
Affiliations
Meta-Analysis

Determinants of the Efficacy of Cardiac Ischemic Preconditioning: A Systematic Review and Meta-Analysis of Animal Studies

Kimberley E Wever et al. PLoS One. .

Abstract

Background: Ischemic preconditioning (IPC) of the heart is a protective strategy in which a brief ischemic stimulus immediately before a lethal ischemic episode potently limits infarct size. Although very promising in animal models of myocardial infarction, IPC has not yet been successfully translated to benefit for patients.

Objective: To appraise all preclinical evidence on IPC for myocardial infarction and identify factors hampering translation.

Methods and results: Using systematic review and meta-analysis, we identified 503 animal studies reporting infarct size data from 785 comparisons between IPC-treated and control animals. Overall, IPC reduced myocardial infarction by 24.6% [95%CI 23.5, 25.6]. Subgroup analysis showed that IPC efficacy was reduced in comorbid animals and non-rodents. Efficacy was highest in studies using 2-3 IPC cycles applied <45 minutes before myocardial infarction. Local and remote IPC were equally effective. Reporting of study quality indicators was low: randomization, blinding and a sample size calculation were reported in 49%, 11% and 2% of publications, respectively.

Conclusions: Translation of IPC to the clinical setting may be hampered by the observed differences between the animals used in preclinical IPC studies and the patient population, regarding comorbidity, sex and age. Furthermore, the IPC protocols currently used in clinical trials could be optimized in terms of timing and the number of ischemic cycles applied. In order to inform future clinical trials successfully, future preclinical studies on IPC should aim to maximize both internal and external validity, since poor methodological quality may limit the value of the preclinical evidence.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist. NPR served on a Scientific Advisory Board of Astra Zeneca, which is unrelated to the current paper. KEW performed part of this work on a travelling fellowship from the Company of Biologists. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Flow chart of the study selection process.
A systematic search in PubMed and EMBASE yielded 6237 unique publications. After application of inclusion and exclusion criteria, data from 503 publications were included in the meta-analysis and quality assessment.
Fig 2
Fig 2. Reporting of study quality indicators and risk of bias in 503 included studies.
A, Reporting of three key study quality indicators was found to be poor in many cases. B, Using SYRCLE's risk of bias tool, the risks of selection, performance, detection, attrition and other biases were assessed. Lack of (adequate) reporting of measures to reduce bias resulted in a high percentage of unclear risk of bias for most items.
Fig 3
Fig 3. Impact of animal characteristics on IPC efficacy.
Data are presented as raw difference in means (MD) in infarct size as a percentage of the area at risk (IS/AAR%). Horizontal white line and grey bar represent the pooled effect estimate and its 95% confidence interval. The number of comparisons contributing data is indicated in each bar. *differs from dog; **differs from rat; #differs from total conditions; ##differs from all other groups.
Fig 4
Fig 4. Impact of IPC protocol characteristics on IPC efficacy.
Data are presented as raw difference in means (MD) in infarct size as a percentage of the area at risk (IS/AAR%). Horizontal white line and grey bar represent the pooled effect estimate and its 95% confidence interval. The number of comparisons contributing data is indicated in each bar. *differs from 7–17 min; **differs from 0–6 and 7–44 min; ***differs from 45–278 min; #differs from 1 cycle; ##differs from 4 cycles.
Fig 5
Fig 5. Assessment of publication bias.
Visual inspection of funnel (A) and precision (B) plots suggested an underrepresentation of studies with moderate precision and small effect sizes, but this was not confirmed by trim and fill analysis. Dotted line represents the overall effect size of 24.6. C-D: Egger's regression test revealed that small study effects are likely present, since the regression line does not intercept at the origin. ES = effect size; SE = standard error; MD = raw difference in means.
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References

    1. Organisation WH (2011) Global atlas on cardiovascular disease prevention and control In: Shanthi Mendis PPaBN, editor. Policies, strategies and interventions: World Health Organization; World Heart Federation; World Stroke Organization; pp. 164.
    1. Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 3: e442 - PMC - PubMed
    1. Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357: 1121–1135. - PubMed
    1. Healy DA, Moloney MC, McHugh SM, Grace PA, Walsh SR (2014) Remote ischaemic preconditioning as a method for perioperative cardioprotection: Concepts, applications and future directions. Int J Surg. - PubMed
    1. Brevoord D, Kranke P, Kuijpers M, Weber N, Hollmann M, Preckel B (2012) Remote ischemic conditioning to protect against ischemia-reperfusion injury: a systematic review and meta-analysis. PLoS One 7: e42179 10.1371/journal.pone.0042179 - DOI - PMC - PubMed

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Grants and funding

This work was supported by The Netherlands Organization for Health Research and Development (ZonMW, project #104024065). KEW performed part of this work with support of the Laboratory Animal Science Association and The Company of Biologists Ltd. NPR is supported by a Clinical Fellowship of ZonMW and the Netherlands Heart Foundation (dr. Dekker fellowship). ES’ contribution was funded by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) infrastructure award: ivSyRMAF, the CAMARADES–NC3Rs in vivo systematic review and meta-analysis facility. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.