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Importance of infarct size versus other variables for clinical outcomes after PPCI in STEMI patients

  • Thomas Bochaton
  • Marc J. Claeys
  • David Garcia-Dorado
  • Nathan Mewton
  • Cyrille Bergerot
  • Claire Jossan
  • Camille Amaz
  • Inesse Boussaha
  • Hélène Thibault
  • Michel OvizeEmail author
Original Contribution

Abstract

Despite promising experimental studies and encouraging proof-of-concept clinical trials, interventions aimed at limiting infarct size have failed to improve clinical outcomes in patients with ST-elevation myocardial infarction (STEMI). Our objective was to examine whether variables (cardiovascular risk factors, comorbidities, post-procedural variables, cotreatments) might be associated with clinical outcomes in STEMI patients independently from infarct size reduction. The present study was based on a post hoc analysis of the CIRCUS trial database (Clinicaltrials.gov NCT01502774) that assessed the clinical benefit of a single intravenous bolus of cyclosporine in 969 patients with anterior STEMI. Since cyclosporine had no detectable effect on clinical outcomes as well as on any measured variable, we here considered the whole study population as one group. Multivariate analysis was performed to address the respective weight of infarct size and variables in clinical outcomes. Multivariate analysis revealed that several variables (including gender, hypertension, renal dysfunction, TIMI flow grade post-PCI < 3, and treatment administered after PCI with betablockers and angiotensin-converting enzyme inhibitors) had per se a significant influence on the occurrence of [death or hospitalization for heart failure] at 1 year. The relative weight of infarct size and variables on the composite endpoint of [death or hospitalization for heart failure] at 1 year was 18% and 82%, respectively. Several variables contribute strongly to the clinical outcomes of STEMI patients suggesting that cardioprotective strategy might not only focus on infarct size reduction.

Keywords

Cardio-protection Infarct size Comorbidities ischemia–reperfusion injury STEMI 

Notes

Acknowledgements

The CIRCUS study was supported by grants from the French Ministry of Health and Research National Program (Programme Hospitalier de Recherche Clinique National 2010) and NeuroVive Pharmaceutical. M. Ovize has been supported by the OPeRa (ANR-10-IBHU-0004 OPeRa) and the RHU MARVELOUS (ANR-16- RHUS-0009) programs.

Funding

David Garcia-Dorado is recipient of grants from ‘Instituto de Salud Carlos III’, the European Regional Development Fund (ERDF-FEDER), and European Union CARDIOPROTECTION COST Action (CA16225).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M (2005) Postconditioning inhibits mitochondrial permeability transition. Circulation 111:194–197.  https://doi.org/10.2217/14796678.1.4.457 CrossRefPubMedGoogle Scholar
  2. 2.
    Bolognese L, Neskovic AN, Parodi G, Cerisano G, Buonamici P, Santoro GM, Antoniucci D (2002) Left ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilation and long-term prognostic implications. Circulation 106:2351–2357CrossRefGoogle Scholar
  3. 3.
    Bøtker HE, Kharbanda R, Schmidt MR, Bøttcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sørensen HT, Redington AN, Nielsen TT (2010) Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 375:727–734.  https://doi.org/10.1016/S0140-6736(09)62001-8 CrossRefPubMedGoogle Scholar
  4. 4.
    Bulluck H, Zheng H, Chan MY, Foin N, Foo DC, Lee CW, Lim ST, Sahlen A, Tan HC, Tan JW, Tong KL, Wong AS, Wong PE, Yeo KK, Foo LL, Chua TS, Koh TH, Hausenloy DJ (2019) Independent predictors of cardiac mortality and hospitalization for heart failure in a multi-ethnic asian ST-segment elevation myocardial infarction population treated by primary percutaneous coronary intervention. Sci Rep 9:10072.  https://doi.org/10.1038/s41598-019-46486-0 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, Bonnefoy-Cudraz E, Guérin P, Elbaz M, Delarche N, Coste P, Vanzetto G, Metge M, Aupetit JF, Jouve B, Motreff P, Tron C, Labeque JN, Steg PG, Cottin Y, Range G, Clerc J, Claeys MJ, Coussement P, Prunier F, Moulin F, Roth O, Belle L, Dubois P, Barragan P, Gilard M, Piot C, Colin P, De Poli F, Morice MC, Ider O, Dubois-Randé JL, Unterseeh T, Le Breton H, Béard T, Blanchard D, Grollier G, Malquarti V, Staat P, Sudre A, Elmer E, Hansson MJ, Bergerot C, Boussaha I, Jossan C, Derumeaux G, Mewton N, Ovize M (2015) Cyclosporine before PCI in Patients with acute myocardial infarction. N Engl J Med 373:1021–1031.  https://doi.org/10.1056/NEJMoa1505489 CrossRefPubMedGoogle Scholar
  6. 6.
    Davidson SM, Ferdinandy P, Andreadou I, Bøtker HE, Heusch G, Ibáñez B, Ovize M, Schulz R, Yellon DM, Hausenloy DJ, Garcia-Dorado D (2019) Cardioprotection cost on behalf of the European Union cardioprotection cost action (CA16225). Multitarget strategies to reduce myocardial ischemia/reperfusion injury. J Am Coll Cardiol 73:89–99.  https://doi.org/10.1016/j.jacc.2018.09.086 CrossRefPubMedGoogle Scholar
  7. 7.
    De Waha S, Patel MR, Granger CB, Ohman EM, Maehara A, Eitel I, Ben-Yehuda O, Jenkins P, Thiele H, Stone GW (2017) Relationship between microvascular obstruction and adverse events following primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: an individual patient data pooled analysis from seven randomized trials. Eur Heart J 38:3502–3510.  https://doi.org/10.1093/eurheartj/ehx414 CrossRefPubMedGoogle Scholar
  8. 8.
    Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R (2014) Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev 66:1142–1174.  https://doi.org/10.1124/pr.113.008300 CrossRefPubMedGoogle Scholar
  9. 9.
    Garber L, McAndrew TC, Chung ES, Stancak B, Svendsen JH, Monteiro J, Fischer TM, Kueffer F, Ryan T, Bax J, Leon AR, Stone GW (2018) Predictors of left ventricular remodeling after myocardial infarction in patients with a patent infarct related coronary artery after percutaneous coronary intervention (from the post-myocardial infarction remodeling prevention therapy [PRomPT] trial). Am J Cardiol 121:1293–1298.  https://doi.org/10.1016/j.amjcard.2018.02.007 CrossRefPubMedGoogle Scholar
  10. 10.
    Garcia-Dorado D, García-del-Blanco B, Otaegui I, Rodríguez-Palomares J, Pineda V, Gimeno F, Ruiz-Salmerón R, Elizaga J, Evangelista A, Fernandez-Avilés F, San-Román A, Ferreira-González I (2014) Intracoronary injection of adenosine before reperfusion in patients with ST-segment elevation myocardial infarction: a randomized controlled clinical trial. Int J Cardiol 177:935–941.  https://doi.org/10.1016/j.ijcard.2014.09.203 CrossRefPubMedGoogle Scholar
  11. 11.
    Gnavi R, Rusciani R, Dalmasso M, Giammaria M, Anselmino M, Roggeri DP, Roggeri A (2014) Gender, socioeconomic position, revascularization procedures and mortality in patients presenting with STEMI and NSTEMI in the era of primary PCI. Differences or inequities? Int J Cardiol 176:724–730.  https://doi.org/10.1016/j.ijcard.2014.07.107 CrossRefPubMedGoogle Scholar
  12. 12.
    Hausenloy DJ, Candilio L, Evans R, Ariti C, Jenkins DP, Kolvekar S, Knight R, Kunst G, Laing C, Nicholas J, Pepper J, Robertson S, Xenou M, Clayton T, Yellon DM (2015) ERICCA trial investigators. remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med 373:1408–1417.  https://doi.org/10.1056/NEJMoa1413534 CrossRefPubMedGoogle Scholar
  13. 13.
    Hausenloy DJ, Garcia-Dorado D, Bøtker HE, Davidson SM, Downey J, Engel FB, Jennings R, Lecour S, Leor J, Madonna R, Ovize M, Perrino C, Prunier F, Schulz R, Sluijter JPG, Van Laake LW, Vinten-Johansen J, Yellon DM, Ytrehus K, Heusch G, Ferdinandy P (2017) Novel targets and future strategies for acute cardioprotection: position paper of the european society of cardiology working group on cellular biology of the heart. Cardiovasc Res 113:564–585.  https://doi.org/10.1093/cvr/cvx049 CrossRefPubMedGoogle Scholar
  14. 14.
    Hausenloy DJ, Kharbanda RK, Møller UK, Ramlall M, Aarøe J, Butler R, Bulluck H, Clayton T, Dana A, Dodd M, Engstrom T, Evans R, Lassen JF, Christensen EF, Garcia-Ruiz JM, Gorog DA, Hjort J, Houghton RF, Ibanez B, Knight R, Lippert FK, Lønborg JT, Maeng M, Milasinovic D, More R, Nicholas JM, Jensen LO, Perkins A, Radovanovic N, Rakhit RD, Ravkilde J, Ryding AD, Schmidt MR, Riddervold IS, Sørensen HT, Stankovic G, Varma M, Webb I, Terkelsen CJ, Greenwood JP, Yellon DM, Bøtker HE (2019) CONDI-2/ERIC-PPCI investigators. Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial. Lancet 394(10207):1415–1424.  https://doi.org/10.1016/s0140-6736(19),32039-2 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Heusch G (2018) Cardioprotection research must leave its comfort zone. Eur Heart J 39:3393–3395.  https://doi.org/10.1093/eurheartj/ehy253 CrossRefPubMedGoogle Scholar
  16. 16.
    Heusch G (2016) The coronary circulation as a target of cardioprotection. Circ Res 118:1643–1658.  https://doi.org/10.1161/CIRCRESAHA.116.308640 CrossRefPubMedGoogle Scholar
  17. 17.
    Heusch G (2018) 25 years of remote ischemic conditioning: from laboratory curiosity to clinical outcome. Basic Res Cardiol 113:15.  https://doi.org/10.1007/s00395-018-0673-2 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Heusch G, Gersh BJ (2017) The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J 38:774–784.  https://doi.org/10.1093/eurheartj/ehw224 CrossRefPubMedGoogle Scholar
  19. 19.
    Heusch G, Kleinbongard P, Rassaf T (2019) Cardioprotection beyond infarct size reduction. Circ Res 124:679–680.  https://doi.org/10.1161/CIRCRESAHA.119.314679 CrossRefPubMedGoogle Scholar
  20. 20.
    Ibáñez B, Heusch G, Ovize M, Van de Werf F (2015) Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol 65:1454–1471.  https://doi.org/10.1016/j.jacc.2015.02.032 CrossRefPubMedGoogle Scholar
  21. 21.
    Ibanez B, Macaya C, Sánchez-Brunete V, Pizarro G, Fernández-Friera L, Mateos A, Fernández-Ortiz A, García-Ruiz JM, García-Álvarez A, Iñiguez A, Jiménez-Borreguero J, López-Romero P, Fernández-Jiménez R, Goicolea J, Ruiz-Mateos B, Bastante T, Arias M, Iglesias-Vázquez JA, Rodriguez MD, Escalera N, Acebal C, Cabrera JA, Valenciano J, Pérez de Prado A, Fernández-Campos MJ, Casado I, García-Rubira JC, García-Prieto J, Sanz-Rosa D, Cuellas C, Hernández-Antolín R, Albarrán A, Fernández-Vázquez F, de la Torre-Hernández JM, Pocock S, Sanz G, Fuster V (2013) Effect of early metoprolol on infarct size in st-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the effect of metoprolol in cardioprotection during an acute myocardial infarction (METOCARD-CNIC) trial. Circulation 128:1495–1503.  https://doi.org/10.1161/CIRCULATIONAHA.113.003653 CrossRefPubMedGoogle Scholar
  22. 22.
    Ibanez B, Rossello X (2019) Left ventricular remodeling is no longer a relevant outcome after myocardial infarction. JACC Cardiovasc Imaging.  https://doi.org/10.1016/j.jcmg.2019.04.004 CrossRefPubMedGoogle Scholar
  23. 23.
    Cavanaugh JE, Neath AA (2019) The Akaike information criterion: Background, derivation, properties, application, interpretation, and refinements. Wiley Interdiscip Rev Computat Stat.  https://doi.org/10.1002/wics.1460 CrossRefGoogle Scholar
  24. 24.
    Kleinbongard P, Bøtker HE, Ovize M, Hausenloy DJ, Heusch G (2019) Co-morbidities and co-medications as confounders of cardioprotection–does it matter in the clinical setting? Br J Pharmacol.  https://doi.org/10.1111/bph.14839 [Epub ahead of print] CrossRefPubMedGoogle Scholar
  25. 25.
    Kosmidou I, Redfors B, Selker HP, Thiele H, Patel MR, Udelson JE, Magnus Ohman E, Eitel I, Granger CB, Maehara A, Kirtane A, Généreux P, Jenkins PL, Ben-Yehuda O, Mintz GS, Stone GW (2017) Infarct size, left ventricular function, and prognosis in women compared to men after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: results from an individual patient-level pooled analysis of 10 randomized trials. Eur Heart J 38:1656–1663.  https://doi.org/10.1093/eurheartj/ehx159 CrossRefPubMedGoogle Scholar
  26. 26.
    Lønborg J, Vejlstrup N, Kelbæk H, Bøtker HE, Kim WY, Mathiasen AB, Jørgensen E, Helqvist S, Saunamäki K, Clemmensen P, Holmvang L, Thuesen L, Krusell LR, Jensen JS, Køber L, Treiman M, Holst JJ, Engstrøm T (2012) Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 33:1491–1499.  https://doi.org/10.1093/eurheartj/ehr309 CrossRefPubMedGoogle Scholar
  27. 27.
    Mewton N, Ovize M (2013) Remote preconditioning and all-cause mortality. Lancet 382:579–580.  https://doi.org/10.1016/S0140-6736(13)61607-4 CrossRefPubMedGoogle Scholar
  28. 28.
    Mewton N, Revel D, Bonnefoy E, Ovize M, Croisille P (2011) Comparison of visual scoring and quantitative planimetry methods for estimation of global infarct size on delayed enhanced cardiac MRI and validation with myocardial enzymes. Eur J Radiol 78:87–92.  https://doi.org/10.1016/j.ejrad.2009.09.027 CrossRefPubMedGoogle Scholar
  29. 29.
    Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, Coburn M, Schaelte G, Böning A, Niemann B, Roesner J, Kletzin F, Strouhal U, Reyher C, Laufenberg-Feldmann R, Ferner M, Brandes IF, Bauer M, Stehr SN, Kortgen A, Wittmann M, Baumgarten G, Meyer-Treschan T, Kienbaum P, Heringlake M, Schön J, Sander M, Treskatsch S, Smul T, Wolwender E, Schilling T, Fuernau G, Hasenclever D, Zacharowski K (2015) RIPHeart study collaborators. a multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med 373:1397–1407.  https://doi.org/10.1056/NEJMoa1413579 CrossRefPubMedGoogle Scholar
  30. 30.
    Moghaddam N, Wong GC, Cairns JA, Goodman SG, Perry-Arnesen M, Tocher W, Mackay M, Singer J, Lee T, Rao SV, Fordyce CB (2018) Association of anemia with outcomes among st-segment-elevation myocardial infarction patients receiving primary percutaneous coronary intervention. Circ Cardiovasc Interv 11:e007175.  https://doi.org/10.1161/CIRCINTERVENTIONS.118.007175 CrossRefPubMedGoogle Scholar
  31. 31.
    Niccoli G, Montone RA, Ibanez B, Thiele H, Crea F, Heusch G, Bulluck H, Hausenloy DJ, Berry C, Stiermaier T, Camici PG, Eitel I (2019) Optimized treatment of ST-elevation myocardial infarction. Circ Res 125(2):245–258.  https://doi.org/10.1161/CIRCRESAHA.119.315344 CrossRefPubMedGoogle Scholar
  32. 32.
    Pfeffer MA, Braunwald E (1990) Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 81:1161–1172CrossRefGoogle Scholar
  33. 33.
    Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, André-Fouët X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M (2008) Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 359:473–481.  https://doi.org/10.1056/NEJMoa071142 CrossRefPubMedGoogle Scholar
  34. 34.
    Piper HM, Garcia-Dorado D, Ovize M (1998) A fresh look at reperfusion injury. Cardiovasc Res 38:291–300CrossRefGoogle Scholar
  35. 35.
    Rathod KS, Jones DA, Rathod VS, Bromage D, Guttmann O, Gallagher SM, Mohiddin S, Rothman MT, Knight C, Jain AK, Kapur A, Mathur A, Timmis AD, Amersey R, Wragg A (2014) Prognostic impact of anaemia on patients with ST-elevation myocardial infarction treated by primary PCI. Coron Artery Dis 25:52–59.  https://doi.org/10.1097/MCA.0000000000000038 CrossRefPubMedGoogle Scholar
  36. 36.
    Rodriguez-Palomares JF, Gavara J, Ferreira-González I, Valente F, Rios C, Rodríguez-García J, Bonanad C, García Del Blanco B, Miñana G, Mutuberria M, Nuñez J, Barrabés J, Evangelista A, Bodí V, García-Dorado D (2019) Prognostic value of initial left ventricular remodeling in patients with reperfused STEMI. JACC Cardiovasc Imaging.  https://doi.org/10.1016/j.jcmg.2019.02.025 CrossRefPubMedGoogle Scholar
  37. 37.
    Saad M, Stiermaier T, Fuernau G, Pöss J, de Waha-Thiele S, Desch S, Thiele H, Eitel I (2019) Impact of direct stenting on myocardial injury assessed by cardiac magnetic resonance imaging and prognosis in ST-elevation myocardial infarction. Int J Cardiol 283:88–92.  https://doi.org/10.1016/j.ijcard.2018.11.141 CrossRefPubMedGoogle Scholar
  38. 38.
    Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L’Huillier I, Aupetit JF, Bonnefoy E, Finet G, André-Fouët X, Ovize M (2005) Postconditioning the human heart. Circulation 112:2143–2148CrossRefGoogle Scholar
  39. 39.
    Thibault H, Piot C, Staat P, Bontemps L, Sportouch C, Rioufol G, Cung TT, Bonnefoy E, Angoulvant D, Aupetit JF, Finet G, André-Fouët X, Macia JC, Raczka F, Rossi R, Itti R, Kirkorian G, Derumeaux G, Ovize M (2008) Long-term benefit of postconditioning. Circulation 117:1037–1044.  https://doi.org/10.1161/CIRCULATIONAHA.107.729780 CrossRefPubMedGoogle Scholar
  40. 40.
    Thuny F, Lairez O, Roubille F, Mewton N, Rioufol G, Sportouch C, Sanchez I, Bergerot C, Thibault H, Cung TT, Finet G, Argaud L, Revel D, Derumeaux G, Bonnefoy-Cudraz E, Elbaz M, Piot C, Ovize M, Croisille P (2012) Post-conditioning reduces infarct size and edema in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 59:2175–2181.  https://doi.org/10.1016/j.jacc.2012.03.026 CrossRefPubMedGoogle Scholar
  41. 41.
    Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357:1121–1135.  https://doi.org/10.1056/NEJMra071667 CrossRefPubMedGoogle Scholar
  42. 42.
    Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285:H579–H588CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Thomas Bochaton
    • 1
  • Marc J. Claeys
    • 4
  • David Garcia-Dorado
    • 5
    • 6
  • Nathan Mewton
    • 1
  • Cyrille Bergerot
    • 1
    • 2
  • Claire Jossan
    • 2
  • Camille Amaz
    • 2
  • Inesse Boussaha
    • 2
  • Hélène Thibault
    • 1
    • 2
  • Michel Ovize
    • 1
    • 2
    • 3
    Email author
  1. 1.INSERM UMR 1060, CarMeN LaboratoryUniversity Claude Bernard Lyon1, IHU OPeRa, Hôpital Louis Pradel, Hospices Civils de LyonLyonFrance
  2. 2.Service d’Explorations Fonctionnelles Cardiovasculaires CIC 1407 de LyonHôpital Louis Pradel, Hospices Civils de LyonLyonFrance
  3. 3.Service d’Explorations Fonctionnelles CardiovasculairesHôpital Louis PradelBronFrance
  4. 4.Department of CardiologyAntwerp University HospitalAntwerpBelgium
  5. 5.Hospital Universitari Vall d´Hebron, Department of CardiologyVall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de BarcelonaBarcelonaSpain
  6. 6.Centro de Investigación Biomédica en Red-CVBarcelonaSpain

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