title: Atherothrombotic Risk Stratification and the Efficacy and Safety of Vorapaxar in Patients With Stable Ischemic Heart Disease and Previous Myocardial Infarction.
abstract: Patients with stable ischemic heart disease and previous myocardial infarction (MI) vary in their risk for recurrent cardiovascular events. Atherothrombotic risk assessment may be useful to identify high-risk patients who have the greatest potential to benefit from more intensive secondary preventive therapy such as treatment with vorapaxar.
  
  
  
  We identified independent clinical indicators of atherothrombotic risk among 8598 stable, placebo-treated patients with a previous MI followed up for 2.5 years (median) in TRA 2°P-TIMI 50 [Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50]. The efficacy and safety of vorapaxar (SCH 530348; MK-5348) were assessed by baseline risk among patients with previous MI without prior stroke or transient ischemic attack for whom there is a clinical indication for vorapaxar. End points were cardiovascular death, MI, or ischemic stroke and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding.
  
  
  
  The 9 independent risk predictors were age, diabetes mellitus, hypertension, smoking, peripheral arterial disease, previous stroke, previous coronary bypass grafting, heart failure, and renal dysfunction. A simple integer-based scheme using these predictors showed a strong graded relationship with the rate of cardiovascular death/MI/ischemic stroke and the individual components (P for trend <0.001 for all). High-risk patients (≥3 risk indicators; 20% of population) had a 3.2% absolute risk reduction in cardiovascular disease/MI/ischemic stroke with vorapaxar, and intermediate-risk patients (1-2 risk indicators; 61%) had a 2.1% absolute risk reduction (P<0.001 each), translating to a number needed to treat of 31 and 48. Bleeding increased across risk groups (P for trend<0.01); however, net clinical outcome was increasingly favorable with vorapaxar across risk groups. Fatal bleeding or intracranial hemorrhage was 0.9% with both treatments in high-risk patients.
  
  
  
  Stratification of baseline atherothrombotic risk can assist with therapeutic decision making for vorapaxar use for secondary prevention after MI.
  
  
  
  URL: https://www.clinicaltrials.gov. Unique identifier: NCT00526474.
authors.affiliation: From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., E.B., P.H., S.A.M., M.S.S., B.M.S., D.A.M.); South Australian Health and Research Institute, Flinders University and Medical Centre, Adelaide (P.E.A.); Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago (R.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion, Haifa, Israel (B.S.L.); and IV Divisione Cardiologia, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy (P.A.M.). ebohula@partners.org.
authors.forename: Erin A
authors.initials: EA
authors.lastname: Bohula
authors.affiliation: From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., E.B., P.H., S.A.M., M.S.S., B.M.S., D.A.M.); South Australian Health and Research Institute, Flinders University and Medical Centre, Adelaide (P.E.A.); Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago (R.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion, Haifa, Israel (B.S.L.); and IV Divisione Cardiologia, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy (P.A.M.).
authors.forename: Marc P
authors.initials: MP
authors.lastname: Bonaca
authors.affiliation: From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., E.B., P.H., S.A.M., M.S.S., B.M.S., D.A.M.); South Australian Health and Research Institute, Flinders University and Medical Centre, Adelaide (P.E.A.); Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago (R.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion, Haifa, Israel (B.S.L.); and IV Divisione Cardiologia, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy (P.A.M.).
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.affiliation: From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., E.B., P.H., S.A.M., M.S.S., B.M.S., D.A.M.); South Australian Health and Research Institute, Flinders University and Medical Centre, Adelaide (P.E.A.); Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago (R.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion, Haifa, Israel (B.S.L.); and IV Divisione Cardiologia, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy (P.A.M.).
authors.forename: Philip E
authors.initials: PE
authors.lastname: Aylward
authors.affiliation: From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., E.B., P.H., S.A.M., M.S.S., B.M.S., D.A.M.); South Australian Health and Research Institute, Flinders University and Medical Centre, Adelaide (P.E.A.); Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago (R.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion, Haifa, Israel (B.S.L.); and IV Divisione Cardiologia, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy (P.A.M.).
authors.forename: Ramon
authors.initials: R
authors.lastname: Corbalan
authors.affiliation: From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., E.B., P.H., S.A.M., M.S.S., B.M.S., D.A.M.); South Australian Health and Research Institute, Flinders University and Medical Centre, Adelaide (P.E.A.); Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago (R.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion, Haifa, Israel (B.S.L.); and IV Divisione Cardiologia, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy (P.A.M.).
authors.forename: Gaetano M
authors.initials: GM
authors.lastname: De Ferrari
authors.affiliation: From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., E.B., P.H., S.A.M., M.S.S., B.M.S., D.A.M.); South Australian Health and Research Institute, Flinders University and Medical Centre, Adelaide (P.E.A.); Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago (R.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion, Haifa, Israel (B.S.L.); and IV Divisione Cardiologia, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy (P.A.M.).
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.affiliation: From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., E.B., P.H., S.A.M., M.S.S., B.M.S., D.A.M.); South Australian Health and Research Institute, Flinders University and Medical Centre, Adelaide (P.E.A.); Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago (R.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion, Haifa, Israel (B.S.L.); and IV Divisione Cardiologia, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy (P.A.M.).
authors.forename: Basil S
authors.initials: BS
authors.lastname: Lewis
authors.affiliation: From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., E.B., P.H., S.A.M., M.S.S., B.M.S., D.A.M.); South Australian Health and Research Institute, Flinders University and Medical Centre, Adelaide (P.E.A.); Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago (R.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion, Haifa, Israel (B.S.L.); and IV Divisione Cardiologia, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy (P.A.M.).
authors.forename: Piera A
authors.initials: PA
authors.lastname: Merlini
authors.affiliation: From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., E.B., P.H., S.A.M., M.S.S., B.M.S., D.A.M.); South Australian Health and Research Institute, Flinders University and Medical Centre, Adelaide (P.E.A.); Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago (R.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion, Haifa, Israel (B.S.L.); and IV Divisione Cardiologia, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy (P.A.M.).
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., E.B., P.H., S.A.M., M.S.S., B.M.S., D.A.M.); South Australian Health and Research Institute, Flinders University and Medical Centre, Adelaide (P.E.A.); Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago (R.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion, Haifa, Israel (B.S.L.); and IV Divisione Cardiologia, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy (P.A.M.).
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
authors.affiliation: From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., E.B., P.H., S.A.M., M.S.S., B.M.S., D.A.M.); South Australian Health and Research Institute, Flinders University and Medical Centre, Adelaide (P.E.A.); Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago (R.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion, Haifa, Israel (B.S.L.); and IV Divisione Cardiologia, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy (P.A.M.).
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Scirica
authors.affiliation: From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., E.B., P.H., S.A.M., M.S.S., B.M.S., D.A.M.); South Australian Health and Research Institute, Flinders University and Medical Centre, Adelaide (P.E.A.); Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago (R.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of Medicine, Technion, Haifa, Israel (B.S.L.); and IV Divisione Cardiologia, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy (P.A.M.).
authors.forename: David A
authors.initials: DA
authors.lastname: Morrow
mesh_terms: D000368:Aged; D050197:Atherosclerosis / Q000150:complications / Q000453:epidemiology*; D004311:Double-Blind Method; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D053208:Kaplan-Meier Estimate; D007783:Lactones / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000209:etiology; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence; D018570:Risk Assessment; D055502:Secondary Prevention; D016896:Treatment Outcome
chemical_list: D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C530299:vorapaxar
keywords: atherosclerosis; receptors, thrombin; risk assessment; secondary prevention