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Original research article
Predicting the risk of bleeding during dual antiplatelet therapy after acute coronary syndromes
  1. Joakim Alfredsson1,2,
  2. Benjamin Neely1,
  3. Megan L Neely1,
  4. Deepak L Bhatt3,
  5. Shaun G Goodman4,5,
  6. Pierluigi Tricoci1,6,
  7. Kenneth W Mahaffey7,
  8. Jan H Cornel8,
  9. Harvey D White9,
  10. Keith AA Fox10,
  11. Dorairaj Prabhakaran11,
  12. Kenneth J Winters12,
  13. Paul W Armstrong5,
  14. E Magnus Ohman1,6,
  15. Matthew T Roe1,6
  16. for the TRILOGY ACS Investigators
  1. 1 Duke Clinical Research Institute, Durham, USA
  2. 2 Department of Cardiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
  3. 3 Brigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School, Boston, USA
  4. 4 Division of Cardiology, Department of Medicine, St. Michael’s Hospital, Toronto, Canada
  5. 5 Canadian VIGOUR Centre and Division of Cardiology, University of Alberta, Edmonton, Canada
  6. 6 Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, USA
  7. 7 Department of Medicine, Stanford University, Stanford, USA
  8. 8 Medisch Centrum Alkmaar, Alkmaar, The Netherlands
  9. 9 Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
  10. 10 Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
  11. 11 Centre for Chronic Disease Control and Public Health Foundation of India, New Delhi, India
  12. 12 Eli Lilly and Company, Indianapolis, USA
  1. Correspondence to Dr Matthew T Roe, Duke Clinical Research Institute, Duke University, 2400 Pratt Street – Room 7035, Durham, North Carolina 27705, USA; matthew.roe{at}


Objectives Dual antiplatelet therapy (DAPT) with aspirin + a P2Y12 inhibitor is recommended for at least 12 months for patients with acute coronary syndrome (ACS), with shorter durations considered for patients with increased bleeding risk. However, there are no decision support tools available to predict an individual patient’s bleeding risk during DAPT treatment in the post-ACS setting.

Methods To develop a longitudinal bleeding risk prediction model, we analy sed 9240 patients with unstable angina/non-ST segment elevation myocardial infarction (NSTEMI) from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial, who were managed without revasculari sation and treated with DAPT for a median of 14.8 months.

Results We identified 10 significant baseline predictors of non-coronary artery bypass grafting (CABG)-related Global Use of Strategies to Open Occluded Arteries (GUSTO) severe/life-threatening/moderate bleeding: age, sex, weight, NSTEMI (vs unstable angina), angiography performed before randomi sation, prior peptic ulcer disease, creatinine, systolic blood pressure, haemoglobin and treatment with beta-blocker. The five significant baseline predictors of Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding included age, sex, angiography performed before randomi sation, creatinine and haemoglobin. The models showed good predictive accuracy with Therneau’s C-indices: 0.78 (SE = 0.024) for the GUSTO model and 0.67 (SE = 0.023) for the TIMI model. Internal validation with bootstrapping gave similar C-indices of 0.77 and 0.65, respectively. External validation demonstrated an attenuated C-index for the GUSTO model (0.69) but not the TIMI model (0.68).

Conclusions Longitudinal bleeding risks during treatment with DAPT in patients with ACS can be reliably predicted using selected baseline characteristics. The TRILOGY ACS bleeding models can inform risk –benefit considerations regarding the duration of DAPT following ACS.

Trial registration identifier:

  • platelets
  • risk factors
  • hemorrhage

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  • Contributors Conceived/designed research: JA, MR, Performed stat analysis: BN, MN, Handled funding and supervision: MR, Acquired data: MR, Drafted: JA, MR, Made critical revision for key intellectual content: All.

  • Funding The TRILOGY ACS study was supported by Daiichi Sankyo and Eli Lilly and Company. The TRACER trial was supported by Merck & Co. The study sponsors had no role in the conception and design of this study or in drafting the initial version of this manuscript. An employee of Eli Lilly (K.J. Winters) participated as an author on subsequent drafts of the manuscript. All data analyses were performed independently by the Duke Clinical Research Institute, Durham, North Carolina, USA.

  • Competing interests JA: consulting fees: Bristol-Myers Squibb, Sanofi-Aventis and Eli Lilly. Lecture fees: AstraZeneca, Novartis, Merck, Sharp & Dohme and Sanofi-Aventis. Research funding: AstraZeneca. BN and MN: none. DLB: advisory board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences. Board of directors: Boston VA Research Institute, Society of Cardiovascular Patient Care. Chair: American Heart Association Get With The Guidelines Steering Committee. Data monitoring committees: Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute. Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News,, Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), WebMD (CME steering committees). Other: Clinical Cardiology (Deputy Editor). Research funding: Amarin, AstraZeneca, Biotronik, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi-Aventis, St. Jude Medical, The Medicines Company. Trustee: American College of Cardiology. Unfunded research: FlowCo, PLx Pharma, Takeda. SGG: consulting fees: AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Merck and Sanofi-Aventis. Research grants: AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Johnson & Johnson, Merck and Sanofi-Aventis. All other disclosures (unrelated to this manuscript) are listed at: PT: research grants: Merck, Sanofi-Aventis, CSL and Regeneron. Consulting payments: Merck and CSL. KWM: grant funding: Medtronic and St. Jude. Consulting payments: American College of Cardiology, AstraZeneca, Bayer, Boehringer Ingelheim, Cubist, Eli Lilly, Elsevier, Forest, GlaxoSmithKline, Johnson and Johnson, Medtronic, Merck, Omthera, Portola, Spring Publishing, The Medicines Company and WebMD. JHC: consulting payments: Eli Lilly, Merck Sharp and Dohme, AstraZeneca and Merck. HDW: grant support from Sanofi-Aventis, Eli Lilly, The Medicines Company, NIH, Pfizer, Roche, Johnson & Johnson, Schering-Plough, Merck Sharp & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo Pharma Development and Bristol-Myers Squibb. Advisory boards: Merck Sharpe & Dohme, Roche and Regado Biosciences. KAAF: research grants: Lilly, Bayer, Johnson & Johnson and AstraZeneca. Speakers bureau: Bayer, Johnson & Johnson, AstraZeneca and Sanofi-Aventis. Consulting/other: Lilly, Bayer, Johnson & Johnson, AstraZeneca, Sanofi-Aventis, Boehringer Ingelheim and Eli Lilly. DP: research grants: Eli Lilly and the Medtronic Foundation. Honoraria: Eli Lilly. KJW: employee and minor stockholder of Eli Lilly and Company. PWA: consulting fees: Eli Lilly, Hoffmann-La Roche, Merck, Axio Research and Orexigen. Grant support: Boehringer Ingelheim, Hoffmann-La Roche, Sanofi-Aventis, Scios, Ortho Biotech, Johnson & Johnson, Janssen Pharmaceuticals, GlaxoSmithKline, Amylin Pharmaceuticals and Merck. Payment for developing educational presentations: AstraZeneca and Eli Lilly and Company. EMO: grant support and travel expenses: Daiichi Sankyo and Eli Lilly. Consulting fees: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Liposcience, Merck, Pozen, Hoffmann-La Roche, Sanofi-Aventis, The Medicines Company and Web MD. Grant support: Gilead Sciences. Lecture fees: Gilead Sciences, Boehringer Ingelheim and The Medicines Company. MTR: research funding: Eli Lilly, Sanofi-Aventis, Daiichi Sankyo, Janssen Pharmaceuticals, Ferring Pharmaceuticals, American College of Cardiology, the American Heart Association and the Familial Hypercholesterolemia Foundation. Consulting payments or honoraria: AstraZeneca, Boehringer Ingelheim, Merck, Amgen, Pri-Med and Elsevier Publishers. All conflicts of interest are listed at

  • Provenance and peer review Not commissioned; externally peer reviewed.

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