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Multi-proteomic approach to predict specific cardiovascular events in patients with diabetes and myocardial infarction: findings from the EXAMINE trial

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Abstract

Background

Patients with diabetes who had a recent myocardial infarction (MI) are at high risk of cardiovascular events. Therefore, risk assessment is important for treatment and shared decisions. We used data from EXAMINE trial to investigate whether a multi-proteomic approach would provide specific proteomic signatures and also improve the prognostic capacity for determining the risk of cardiovascular death, MI, stroke, heart failure [HF], all-cause death, and combinations of these outcomes.

Methods

93 circulating proteins (92 from the Olink® CVDII plus troponin) were assessed in 5131 patients. Cox, competing risks, and reclassification measures were applied.

Results

The clinical model showed good discrimination and calibration for all outcomes. On top of the clinical model that included age, sex, smoking, diabetes duration, history of MI (prior to the index MI of inclusion), history of HF hospitalization, history of stroke, atrial fibrillation, hypertension, systolic blood pressure, statin therapy, estimated glomerular filtration rate, and study treatment (alogliptin or placebo), troponin and BNP added prognostic information to the composite of cardiovascular death, MI, or stroke (∆C-index + 5%) and cardiovascular death alone (∆C-index + 7%). Troponin, BNP, and TRAILR2 added prognostic information on all-cause death and the composite of cardiovascular death or HF hospitalization. HF hospitalization alone was improved by adding BNP and Gal-9. For MI, troponin, FGF23, and AMBP added prognostic value; whereas for stroke, only troponin added prognostic value (multi-proteomics improved C-index > 3% [p < 0.001] for all the studied outcomes). The addition of the final biomarker selection to the clinical model improved event reclassification (cNRI from + 23% to + 64%). Specifically, the addition of the biomarkers allowed a better classification of patients at low risk (as having “true” low risk) and patients and high risk (as having “true” high risk). These results were consistent for all the studied outcomes with even more marked differences in the fatal events.

Conclusions

The addition of multi-proteomic biomarkers to a clinical model in this population with diabetes and a recent MI allowed a better risk prediction and event reclassification, potentially helping for better risk assessment and targeted treatment decisions.

Graphic abstract

T2D type 2 diabetes, MI myocardial infarction, CV cardiovascular, HFH heart failure hospitalization, Δ delta, cNRI continuous net reclassification index, BNP brain natriuretic peptide, TRAILR2 trail receptor 2 (or death receptor 5), Gal-9 galectin-9, FGF23 fibroblast growth factor 23.

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The data and materials may be available upon reasonable request.

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Acknowledgements

EXAMINE is a clinical trial sponsored by Takeda Global Research and Development Center, Inc., Deerfield, IL. The authors are solely responsible for the design of the study, all study analyses, and the drafting and editing of the manuscript and its final contents. Clinical trials identifier: Clinicaltrials.gov-NCT00968708. JPF, PR, FZ are supported by a public grant overseen by the French National Research Agency (ANR) as part of the second “Investissements d’Avenir” program (ANR-15-RHU-0004). All the other authors have nothing to disclose with regards to this manuscript. JPF wrote the manuscript, performed the statistical analysis and made critical revisions; AS contributed to discussion and reviewed/edited the manuscript; CM contributed to discussion and reviewed/edited the manuscript including the revision of the statistical methods and analysis; GB reviewed/edited the manuscript; PR reviewed/edited the manuscript; WBW reviewed/edited the manuscript; FZ contributed to discussion and reviewed/edited the manuscript. Dr. João Pedro Ferreira is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

A.S is supported by a research grant from the Fonds de Recherche Sante – Quebec Junior Award, Alberta Innovates Health Solution Clinician Scientist fellowship, the European Society of Cardiology Young Investigator research grant, and has received research support from Roche Diagnostics, Boeringer-Ingelheim, Takeda, Akcea, and the Canadian Cardiovascular Society Bayer Vascular award. G.L.B., has received personal fees from Takeda Development Center, is a consultant for Merck, Relypsa, and is on the steering committee for international renal/CV outcomes trials for Janssen, Bayer, Vascular Dynamics. W.B.W has received research support from the National Institute of Aging (NIH) and personal fees from Takeda Development Center (Deerfield, IL, USA) during the conduct of the EXAMINE trial (Steering Committee Chair). F.Z has received fees for serving on the board of Boston Scientific; consulting fees from Novartis, Takeda, AstraZeneca, Boehringer Ingelheim, GE Healthcare, Relypsa, Servier, Boston Scientific, Bayer, Johnson & Johnson, and Resmed; and speaking fees from Pfizer and AstraZeneca. No other potential conflicts of interest relevant to this article were reported.

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Authors and Affiliations

  1. Université de Lorraine, Centre D’Investigation Clinique- Plurithématique Inserm CIC-P 1433, Inserm U1116, CHRU Nancy Hopitaux de Brabois, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France

    João Pedro Ferreira, Patrick Rossignol & Faiez Zannad

  2. Division of Cardiology, McGill University Health Centre, Montreal, QC, Canada

    Abhinav Sharma

  3. Cytel Corporation, Cambridge, MA, USA

    Cyrus Mehta

  4. Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Cyrus Mehta

  5. Department of Medicine, American Heart Association Comprehensive Hypertension Center, University of Chicago, Chicago, USA

    George Bakris

  6. Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, Connecticut, USA

    William B. White

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  1. João Pedro Ferreira
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  2. Abhinav Sharma
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  3. Cyrus Mehta
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  4. George Bakris
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  5. Patrick Rossignol
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  7. Faiez Zannad
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Correspondence to João Pedro Ferreira.

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Ferreira, J.P., Sharma, A., Mehta, C. et al. Multi-proteomic approach to predict specific cardiovascular events in patients with diabetes and myocardial infarction: findings from the EXAMINE trial. Clin Res Cardiol 110, 1006–1019 (2021). https://doi.org/10.1007/s00392-020-01729-3

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