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Biomarkers of platelet activation and cardiovascular risk in the DAPT trial

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Abstract

Prolonged use of dual antiplatelet therapy (DAPT) post-percutaneous coronary intervention (PCI) has been shown to reduce the risk of major adverse cardiovascular events (MACE), but with increased bleeding. It remains unknown whether biomarkers of platelet activation may be useful for identifying patients at increased risk of MACE. The DAPT study was a randomized trial of 12 versus 30 months of DAPT in patients who underwent PCI. Serum biomarkers [myeloid-related protein (MRP)-8/14, P-selectin, soluble CD-40 ligand (sCD40L)] were assessed in 1399 patients early post-PCI. On-treatment platelet reactivity index (PRI) using VASP phosphorylation was assessed in 443 patients randomized to continued DAPT at 1 year. MACE was defined as CV death, MI, or ischemic stroke. Multivariable models were adjusted for baseline characteristics, index event, and stent type. A stepwise increase in the risk of MACE was observed with increasing tertiles of both MRP-8/14 and P-selectin (p-trend = 0.04 for both). After multivariable adjustment, the adjusted HR (95% CI) for MACE in patients in the top tertile was 1.94 (1.14–3.30) for MRP-8/14 and 1.62 (0.99–2.64) for P-selectin. In contrast, baseline sCD40L was not associated with CV risk. Among patients randomized to continued DAPT, higher on-treatment platelet reactivity was not significantly associated with risk of MACE (p-trend = 0.32; adj-HR T3 vs. T1 1.54, 95% CI 0.20–12.18) or bleeding (P-trend = 0.17; adj-HR 0.25, 95% CI 0.05–1.21). MRP-8/14 and soluble P-selectin may be useful for identifying patients at increased risk of MACE after PCI. The utility of on-treatment platelet function testing requires further study.

Clinical Trial Registration https://www.clinicaltrials.gov. Unique identifier NCT00977938.

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Funding

Dr. Berg is supported by a T32 postdoctoral training grant from the National Heart, Lung, and Blood Institute (T32 HL007604). Dr. Sabatine and Dr. O’Donoghue were supported by grant R01HL098082 from the National Heart, Lung, and Blood Institute for this investigation.

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Authors and Affiliations

  1. TIMI Study Group, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    David D. Berg, David A. Morrow, Abby L. Cange, Marc S. Sabatine & Michelle L. O’Donoghue

  2. Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Robert W. Yeh

  3. Medtronic, Minneapolis, MN, USA

    Laura Mauri

  4. The Christ Hospital Heart and Vascular Center, The Lindner Research Center, Cincinnati, OH, USA

    Dean J. Kereiakes

  5. Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Donald E. Cutlip

  6. Baim Clinical Research Institute, Boston, MA, USA

    Qi Gao

  7. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Petr Jarolim

  8. Center for Platelet Research Studies, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA

    Alan D. Michelson & Andrew L. Frelinger III

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  1. David D. Berg
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Correspondence to David D. Berg.

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Conflict of interest

Dr. Berg has nothing to disclose. Dr. Yeh has received Consulting Fees and Research Grants from Abbott Vascular, AstraZeneca, Boston Scientific and Medtronic. Laura Mauri is currently a Full-Time Employee of Medtronic. Dr. Morrow has received Grants and Personal Fees from Abbott Laboratories, AstraZeneca, Roche Diagnostics, and Bayer Pharma; Grants from Novartis, BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Takeda, Pfizer, Quark, The Medicines Company, Merck, and Zora Diagnostics; Personal Fees from InCarda, Aralez, Peloton, and Verseon. He is a Member of the TIMI Study Group, for which he has received Institutional Research Grant support through Brigham and Women’s Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences. Dr. Cutlip has received Consulting Fees from Celonova. Ms. Gao has nothing to disclose. Dr. Jarolim has received Research Grants through his institution from Abbott Laboratories, Amgen, Inc., AstraZeneca, LP, Daiichi-Sankyo, Inc., GlaxoSmithKline, Merck and Co, Inc., Roche Diagnostics Corporation, Takeda Global Research and Development Center, and Waters Technologies Corporation; and Consulting Fees from Roche Diagnostics Corporation. Dr. Michelson has received Research Grants from Ironwood Pharmaceuticals. Dr. Frelinger has received Research Grants from Ironwood Pharmaceuticals. Dr. Cange has nothing to disclose. Dr. Sabatine reports Grants from AstraZeneca during the conduct of the study; Grants and Personal Fees from Amgen, Personal Fees from Anthos Therapeutics, Grants and Personal Fees from AstraZeneca, Grants from Bayer, Personal Fees from Bristol-Myers Squibb, Personal Fees from CVS Caremark, Grants from Daiichi-Sankyo, Personal Fees from DalCor, Personal Fees from Dyrnamix, Grants from Eisai, Personal Fees from Esperion, Grants from GlaxoSmithKline, Personal Fees from IFM Therapeutics, Grants and Personal Fees from Intarcia, Personal Fees from Ionis, Grants and Personal Fees from Janssen Research and Development, Grants and Personal Fees from Medicines Company, Grants and Personal Fees from MedImmune, Grants and Personal Fees from Merck, Grants and Personal Fees from Novartis, Grants from Pfizer, Grants from Poxel, Grants from Quark Pharmaceuticals, Grants from Takeda, outside the submitted work; and is a Member of the TIMI Study Group, which has also received Institutional Research Grant support through Brigham and Women’s Hospital from: Abbott, Aralez, Roche, and Zora Biosciences. Dr. O’Donoghue has received Research Grants from GlaxoSmithKline, Janssen, The Medicines Company, and Merck.

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Berg, D.D., Yeh, R.W., Mauri, L. et al. Biomarkers of platelet activation and cardiovascular risk in the DAPT trial. J Thromb Thrombolysis 51, 675–681 (2021). https://doi.org/10.1007/s11239-020-02221-5

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