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Effect of COMBinAtion therapy with remote ischemic conditioning and exenatide on the Myocardial Infarct size: a two-by-two factorial randomized trial (COMBAT-MI)

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An Editorial to this article was published on 25 January 2021

Abstract

Remote ischemic conditioning (RIC) and the GLP-1 analog exenatide activate different cardioprotective pathways and may have additive effects on infarct size (IS). Here, we aimed to assess the efficacy of RIC as compared with sham procedure, and of exenatide, as compared with placebo, and the interaction between both, to reduce IS in humans. We designed a two-by-two factorial, randomized controlled, blinded, multicenter, clinical trial. Patients with ST-segment elevation myocardial infarction receiving primary percutaneous coronary intervention (PPCI) within 6 h of symptoms were randomized to RIC or sham procedure and exenatide or matching placebo. The primary outcome was IS measured by late gadolinium enhancement in cardiac magnetic resonance performed 3–7 days after PPCI. The secondary outcomes were myocardial salvage index, transmurality index, left ventricular ejection fraction and relative microvascular obstruction volume. A total of 378 patients were randomly allocated, and after applying exclusion criteria, 222 patients were available for analysis. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. IS was similar between groups for the RIC (24 ± 11.8% in the RIC group vs 23.7 ± 10.9% in the sham group, P = 0.827) and the exenatide hypotheses (25.1 ± 11.5% in the exenatide group vs 22.5 ± 10.9% in the placebo group, P = 0.092). There were no effects with either RIC or exenatide on the secondary outcomes. Unexpected adverse events or side effects of RIC and exenatide were not observed. In conclusion, neither RIC nor exenatide, or its combination, were able to reduce IS in STEMI patients when administered as an adjunct to PPCI.

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Acknowledgements

The COMBAT-MI trial was conceived, designed and led by Prof. David Garcia-Dorado and represents the last contribution of his scientific and medical career dedicated entirely to the search for new and effective cardioprotective strategies that can benefit patients with ischemic heart disease. With this article, we want to pay a heartfelt tribute to his memory and express our gratitude to him. The authors also want to thank Prof. Aurora García-Dorado for her valuable and expert assistance in the statistical analysis. The trial was sponsored with a Grant from Instituto de Salud Carlos III (PIE 13/00027) and a grant from Generalitat de Catalunya (PERIS SLT/2381/2016).

Funding

The trial was sponsored with a Grant from Instituto de Salud Carlos III (PIE 13/00027) and a Grant from Generalitat de Catalunya (PERIS SLT/2381/2016). The sponsors have not been involved in the design, conduct, collection, analysis, interpretation of the data, nor in the preparation, review or approval of the manuscript.

Author information

Authors and Affiliations

  1. Cardiology Department, Vall D’Hebron Institut de Recerca (VHIR), Vall D’Hebron Hospital Universitari, Vall D’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Passeig Vall d’Hebron 119-129, 08035, Barcelona, Spain

    Bruno García del Blanco, Imanol Otaegui, José F. Rodríguez-Palomares, Antonio Rodríguez-Sinovas, Marisol Ruiz-Meana, Javier Inserte, Ignasi Barba, Gerard Martí, Bernat Serra, Neus Bellera, Manuel Ojeda-Ramos, Filipa Valente, Maria Ángeles Carmona, Elisabet Miró-Casas, Josep R. Marsal, Antonia Sambola, Rosa M. Lidón, Jordi Bañeras, José A. Barrabés, Ignacio Ferreira-González & David García-Dorado

  2. CIBERCV, Instituto de Salud Carlos III, Madrid, Spain

    Bruno García del Blanco, Imanol Otaegui, José F. Rodríguez-Palomares, Antoni Bayés-Genis, Eduard Fernández-Nofrerías, Victoria Vilalta del Olmo, Xavier Carrillo, Borja Ibáñez, Antonio Rodríguez-Sinovas, Marisol Ruiz-Meana, Javier Inserte, Ignasi Barba, Sandra Gómez-Talavera, Gerard Martí, Bernat Serra, Neus Bellera, Manuel Ojeda-Ramos, Filipa Valente, Maria Ángeles Carmona, Elisabet Miró-Casas, Antonia Sambola, Rosa M. Lidón, Jordi Bañeras, Jaime Elízaga, José A. Barrabés & David García-Dorado

  3. Institut de Cor, Hospital Univeristari Germans Trias i Pujol, Badalona, Spain

    Antoni Bayés-Genis, Eduard Fernández-Nofrerías, Victoria Vilalta del Olmo & Xavier Carrillo

  4. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

    Borja Ibáñez & Sandra Gómez-Talavera

  5. IIS-Fundación Jiménez Díaz, Madrid, Spain

    Borja Ibáñez & Sandra Gómez-Talavera

  6. Hospital Universitari Arnau de Vilanova, IRBLLEIDA, Lleida, Spain

    Fernando Worner, Juan Casanova & Eva Pueo

  7. Hospital Clínico Universitario de Santiago de Compostela, Santiago, Spain

    Jose R. González-Juanatey & Javier López-Pais

  8. Servicio de Cardiologia, Hospital Joan XXIII, Tarragona, Spain

    Alfredo Bardají, Gil Bonet MD & Mónica Fuertes

  9. Institut Diagnostic Per La Imatge, Hospital Vall D’Hebron, Barcelona, Spain

    Hug Cuellar

  10. Ciber de Epidemiologia Y Salud Pública, CIBERESP, Instituto de Salud Carlos III, Madrid, Spain

    Josep R. Marsal & Ignacio Ferreira-González

  11. Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Jaime Elízaga

  12. Cardiology Department, Hospital Universitari Mútua Terrassa, Terrassa, Spain

    Ferran Padilla

  13. Duke-National University of Singapore Medical School, Cardiovascular and Metabolic Disorders Program, Singapore, Singapore

    Derek J. Hausenloy

  14. National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore

    Derek J. Hausenloy

  15. Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore

    Derek J. Hausenloy

  16. The Hatter Cardiovascular Institute, University College London, London, UK

    Derek J. Hausenloy

  17. Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taichung, Taiwan

    Derek J. Hausenloy

Authors
  1. Bruno García del Blanco
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  2. Imanol Otaegui
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  3. José F. Rodríguez-Palomares
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  4. Antoni Bayés-Genis
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  5. Eduard Fernández-Nofrerías
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  6. Victoria Vilalta del Olmo
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  7. Xavier Carrillo
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  8. Borja Ibáñez
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  9. Fernando Worner
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  10. Juan Casanova
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  11. Eva Pueo
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  12. Jose R. González-Juanatey
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  13. Javier López-Pais
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  14. Alfredo Bardají
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  15. Gil Bonet MD
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  16. Mónica Fuertes
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  17. Antonio Rodríguez-Sinovas
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  18. Marisol Ruiz-Meana
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  19. Javier Inserte
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  20. Ignasi Barba
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  21. Sandra Gómez-Talavera
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  22. Gerard Martí
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  23. Bernat Serra
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  24. Neus Bellera
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  25. Manuel Ojeda-Ramos
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  26. Hug Cuellar
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  27. Filipa Valente
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  28. Maria Ángeles Carmona
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  29. Elisabet Miró-Casas
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  30. Josep R. Marsal
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  31. Antonia Sambola
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  32. Rosa M. Lidón
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  33. Jordi Bañeras
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  34. Jaime Elízaga
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  35. Ferran Padilla
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  36. José A. Barrabés
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  37. Derek J. Hausenloy
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  38. Ignacio Ferreira-González
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  39. David García-Dorado
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Contributions

Besides Prof. DG-D, all authors contributed to the study conception and design. Material preparation and data collection were performed by BGB, IO, JFR-P, AB-G, EF-N, VVO, XC, BI, FW, JC, EP, JRG-J, JL-P, AB, GB, MF, SG-T, GM, AC, EM, BS, NB, MO-R, HC, FV, AS, RML, JB, JE, FP and JAB. Analyses were performed by JRM, IF-G and DG-D. The first draft of the manuscript was written by IF-G, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Antonio Rodríguez-Sinovas or Ignacio Ferreira-González.

Ethics declarations

Conflict of interest

Authors declare that they have no conflict of interest.

Ethics approval

This study was conducted in accordance with the principles of the 1964 Declaration of Helsinki and its later amendments and the European guidelines for Good Clinical Practice and was approved by the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) and the Ethics Committees of the participant institutions.

Consent to participate

All participants provided written informed consent before randomization.

Consent for publication

The manuscript is not submitted elsewhere nor is under consideration for publication. All authors have read and agreed with the submission of the manuscript.

Additional information

In the memory of Professor García-Dorado, who passed away on August 16, 2019.

A comment to this article is available at https://doi.org/10.1007/s00395-021-00843-1.

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García del Blanco, B., Otaegui, I., Rodríguez-Palomares, J.F. et al. Effect of COMBinAtion therapy with remote ischemic conditioning and exenatide on the Myocardial Infarct size: a two-by-two factorial randomized trial (COMBAT-MI). Basic Res Cardiol 116, 4 (2021). https://doi.org/10.1007/s00395-021-00842-2

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  • DOI: https://doi.org/10.1007/s00395-021-00842-2

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