Translational failure of anti-inflammatory compounds for myocardial infarction: a meta-analysis of large animal models.
OBJECTIVE
Numerous anti-inflammatory drugs have been tested in large animal studies of myocardial infarction (MI). Despite positive results, translation of anti-inflammatory strategies into clinical practice has proved to be difficult. Critical disparities between preclinical and clinical study design that influence efficacy may partly be responsible for this translational failure. The aim of the present systematic review was to better understand which factors underlie the failure of transition towards the clinic.


RESULTS
Meta-analysis and regression of large animal studies were performed to identify sources that influenced effect size of anti-inflammatory compounds in large animal models of MI. We included 183 studies, containing 3331 large animals. Infarct size (IS) as a ratio of the area at risk (12.7%; 95% confidence interval, CI 11.1-14.4%, P < 0.001) and IS as a ratio of the left ventricle (3.9%; 95% CI 3.1-4.7%, P < 0.001) were reduced in treatment compared with control groups. Effect size was higher when outcome was assessed early after MI (P = 0.013) and where studies included only male animals (P < 0.001). Mortality in treated animals was higher in studies that blinded the investigator during the experiment (P = 0.041) and depended on the type of drug used (P < 0.001).


CONCLUSIONS
As expected, treatment with anti-inflammatory drugs leads to smaller infarct size in large animal MI models. Timing of outcome assessment, sex, and study quality are significantly associated with outcome and may explain part of the translational failure in clinical settings. Effect size depends on the type of drug used, enabling identification of compounds for future clinical testing.
Experimental Cardiology Laboratory, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands G.P.J.vanHout@umcutrecht.nl.
Gerardus P J
GP
van Hout
Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Sanne J
SJ
Jansen of Lorkeers
Systematic Review Centre for Laboratory Animal Experimentation, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Kimberly E
KE
Wever
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
Emily S
ES
Sena
Experimental Cardiology Laboratory, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands.
Lisanne H J A
LH
Kouwenberg
Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
Wouter W
WW
van Solinge
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
Malcolm R
MR
Macleod
Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Pieter A
PA
Doevendans
Experimental Cardiology Laboratory, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
Gerard
G
Pasterkamp
Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Steven A J
SA
Chamuleau
Experimental Cardiology Laboratory, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
Imo E
IE
Hoefer
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000187:drug effects*; D009203:Myocardial Infarction / Q000188:drug therapy*; D039781:PubMed; D057170:Translational Research, Biomedical / Q000379:methods
D000893:Anti-Inflammatory Agents
Anti-inflammatory; Infarct size reduction; Large animal model; Myocardial infarction; Translational failure