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Characterising and predicting bleeding in high-risk patients with an acute coronary syndrome
  1. Razi Khan1,
  2. Renato D Lopes2,
  3. Megan L Neely2,
  4. Susanna R Stevens2,
  5. Robert A Harrington3,
  6. Rafael Diaz4,
  7. Frank Cools5,
  8. Petr Jansky6,
  9. Gilles Montalescot7,
  10. Dan Atar8,
  11. Jose Lopez-Sendon9,
  12. Marcus Flather10,
  13. Danny Liaw11,
  14. Lars Wallentin12,
  15. John H Alexander2,
  16. Shaun G Goodman13
  17. for the Apixaban for Prevention of Acute Ischemic Safety Events (APPRAISE)-2 Steering Committee and Investigators
  1. 1Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada
  2. 2Duke Clinical Research Institute, Duke Medicine, Durham, North Carolina, United States
  3. 3Stanford School of Medicine, Stanford, California, USA
  4. 4ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina
  5. 5Academisch Ziekenhuis Klina, Brasschaat, Belgium
  6. 6University Hospital Motol, Prague, Czech Republic
  7. 7Institute of Cardiology, Pitié-Salpêtrière University Hospital, Paris, France
  8. 8Oslo University Hospital, and Institute of Clinical Sciences, University of Oslo, Oslo, Norway
  9. 9University Hospital La Paz, Madrid, Spain
  10. 10Clinical Trials and Evaluation Unit, Royal Brompton Hospital and Harefield NHS Foundation Trust, London, UK
  11. 11Bristol-Myers Squibb, Princeton, New Jersey, USA
  12. 12Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
  13. 13Terrence Donnelly Heart Centre, St Michael's Hospital, University of Toronto, and the Canadian Heart Research Centre, Toronto, Ontario, Canada
  1. Correspondence to Dr Renato D Lopes, Duke Clinical Research Institute, Duke University Medical Center, 2400 Pratt Street, Room 0311 Terrace Level, Durham NC 27705, USA; renato.lopes{at}duke.edu

Abstract

Objective In the Apixaban for Prevention of Acute Ischemic Events (APPRAISE-2) trial, the use of apixaban, when compared with placebo, in high-risk patients with a recent acute coronary syndrome (ACS) resulted in a significant increase in bleeding without a reduction in ischaemic events. The aim of this analysis was to provide further description of these bleeding events and to determine the baseline characteristics associated with bleeding in high-risk post-ACS patients.

Methods APPRAISE-2 was a multinational clinical trial including 7392 high-risk patients with a recent ACS randomised to apixaban (5 mg twice daily) or placebo. Bleeding including Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding, International Society on Thrombosis and Haemostasis (ISTH) major or clinically relevant non-major (CRNM) bleeding, and any bleeding were analysed using an on-treatment analysis. Kaplan–Meier curves were plotted to describe the timing of bleeding, and a Cox proportional hazards model was used to identify predictors of ISTH major or CRNM bleeding and any bleeding. Median follow-up was 241 days.

Results The proportion of patients who experienced TIMI major or minor, ISTH major or CRNM, and any bleeding was 1.5%, 2.2% and 13.3%, respectively. The incidence of bleeding was highest in the immediate post-ACS period (0.11 in the first 30 days vs 0.03 after 30 days events per 1 patient-year); however, >60% of major bleeding events occurred >30 days after the end of the index hospitalisation. Gastrointestinal bleeding was the most common cause of major bleeding, accounting for 45.9% of TIMI major or minor and 39.5% of ISTH major or CRNM bleeding events. Independent predictors of ISTH major or CRNM bleeding events included older age, renal dysfunction, dual oral antiplatelet therapy, smoking history, increased white cell count and coronary revascularisation.

Conclusions When compared with placebo, the use of apixaban is associated with an important short-term and long-term risk of bleeding in high-risk post-ACS patients, with gastrointestinal bleeding being the most common source of major bleeding. The baseline predictors of major bleeding appear to be consistent with those identified in lower-risk ACS populations with shorter-term follow-up.

Clinical trial No NCT00831441.

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