Efficacy and Safety of Vorapaxar With and Without a Thienopyridine for Secondary Prevention in Patients With Previous Myocardial Infarction and No History of Stroke or Transient Ischemic Attack: Results from TRA 2°P-TIMI 50.
BACKGROUND
Vorapaxar antagonizes protease-activated receptor 1, the primary receptor for thrombin on human platelets, and reduces recurrent thrombotic events in stable patients with a previous myocardial infarction (MI). We wished to determine whether the efficacy and safety of antiplatelet therapy with vorapaxar was modified by concurrent thienopyridine use.


RESULTS
The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50 (TRA 2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in 26,449 patients with previous atherothrombosis. This prespecified analysis included 16,897 patients who qualified with a MI in the preceding 2 weeks to 12 months and was restricted to patients without a history of stroke or transient ischemic attack given its contraindication in that population. Randomization was stratified on the basis of planned thienopyridine use. Thienopyridine was planned at randomization in 12,410 (73%). Vorapaxar significantly reduced the composite of cardiovascular death, MI, and stroke in comparison with placebo regardless of planned thienopyridine therapy (planned thienopyridine, hazard ratio, 0.80, 0.70-0.91, P<0.001; no planned thienopyridine, hazard ratio, 0.75; 0.60-0.94, P=0.011; P-interaction=0.67). Findings were similar when patients were stratified by actual thienopyridine use at baseline (P-interaction=0.82) and through 18 months (P-interaction=0.44). Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate or severe bleeding risk was increased with vorapaxar and was not significantly altered by planned thienopyridine (planned, hazard ratio, 1.50; 1.18-1.89, P<0.001; no planned, hazard ratio, 1.90, 1.17-3.07, P=0.009; P-interaction=0.37) or actual thienopyridine use (P-interaction=0.24).


CONCLUSIONS
Vorapaxar reduced cardiovascular death, MI, or stroke in stable patients with a history of previous MI, whether treated concomitantly with a thienopyridine or not. The relative risk of moderate or severe bleeding was similarly increased irrespective of thienopyridine use.


BACKGROUND
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00526474.
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., S.A.M., B.M.S., E.B., D.A.M.); Department of Cardiovascular Medicine, Flinders Cardiovascular Center, Adelaide, Australia (P.E.A.); Cardiovascular Division, Pontificia Universidad Catolica de Chile, Santiago, Chile (R.L.C.); Department of Cardiology, Military Hospital, Budapest, Hungary (R.G.K.); and Green Lane Cardiovascular Research Unit, Auckland City Hospital, Auckland, New Zealand (H.W.). ebohula@partners.org.
Erin A
EA
Bohula
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., S.A.M., B.M.S., E.B., D.A.M.); Department of Cardiovascular Medicine, Flinders Cardiovascular Center, Adelaide, Australia (P.E.A.); Cardiovascular Division, Pontificia Universidad Catolica de Chile, Santiago, Chile (R.L.C.); Department of Cardiology, Military Hospital, Budapest, Hungary (R.G.K.); and Green Lane Cardiovascular Research Unit, Auckland City Hospital, Auckland, New Zealand (H.W.).
Philip E
PE
Aylward
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., S.A.M., B.M.S., E.B., D.A.M.); Department of Cardiovascular Medicine, Flinders Cardiovascular Center, Adelaide, Australia (P.E.A.); Cardiovascular Division, Pontificia Universidad Catolica de Chile, Santiago, Chile (R.L.C.); Department of Cardiology, Military Hospital, Budapest, Hungary (R.G.K.); and Green Lane Cardiovascular Research Unit, Auckland City Hospital, Auckland, New Zealand (H.W.).
Marc P
MP
Bonaca
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., S.A.M., B.M.S., E.B., D.A.M.); Department of Cardiovascular Medicine, Flinders Cardiovascular Center, Adelaide, Australia (P.E.A.); Cardiovascular Division, Pontificia Universidad Catolica de Chile, Santiago, Chile (R.L.C.); Department of Cardiology, Military Hospital, Budapest, Hungary (R.G.K.); and Green Lane Cardiovascular Research Unit, Auckland City Hospital, Auckland, New Zealand (H.W.).
Ramon L
RL
Corbalan
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., S.A.M., B.M.S., E.B., D.A.M.); Department of Cardiovascular Medicine, Flinders Cardiovascular Center, Adelaide, Australia (P.E.A.); Cardiovascular Division, Pontificia Universidad Catolica de Chile, Santiago, Chile (R.L.C.); Department of Cardiology, Military Hospital, Budapest, Hungary (R.G.K.); and Green Lane Cardiovascular Research Unit, Auckland City Hospital, Auckland, New Zealand (H.W.).
Robert G
RG
Kiss
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., S.A.M., B.M.S., E.B., D.A.M.); Department of Cardiovascular Medicine, Flinders Cardiovascular Center, Adelaide, Australia (P.E.A.); Cardiovascular Division, Pontificia Universidad Catolica de Chile, Santiago, Chile (R.L.C.); Department of Cardiology, Military Hospital, Budapest, Hungary (R.G.K.); and Green Lane Cardiovascular Research Unit, Auckland City Hospital, Auckland, New Zealand (H.W.).
Sabina A
SA
Murphy
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., S.A.M., B.M.S., E.B., D.A.M.); Department of Cardiovascular Medicine, Flinders Cardiovascular Center, Adelaide, Australia (P.E.A.); Cardiovascular Division, Pontificia Universidad Catolica de Chile, Santiago, Chile (R.L.C.); Department of Cardiology, Military Hospital, Budapest, Hungary (R.G.K.); and Green Lane Cardiovascular Research Unit, Auckland City Hospital, Auckland, New Zealand (H.W.).
Benjamin M
BM
Scirica
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., S.A.M., B.M.S., E.B., D.A.M.); Department of Cardiovascular Medicine, Flinders Cardiovascular Center, Adelaide, Australia (P.E.A.); Cardiovascular Division, Pontificia Universidad Catolica de Chile, Santiago, Chile (R.L.C.); Department of Cardiology, Military Hospital, Budapest, Hungary (R.G.K.); and Green Lane Cardiovascular Research Unit, Auckland City Hospital, Auckland, New Zealand (H.W.).
Harvey
H
White
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., S.A.M., B.M.S., E.B., D.A.M.); Department of Cardiovascular Medicine, Flinders Cardiovascular Center, Adelaide, Australia (P.E.A.); Cardiovascular Division, Pontificia Universidad Catolica de Chile, Santiago, Chile (R.L.C.); Department of Cardiology, Military Hospital, Budapest, Hungary (R.G.K.); and Green Lane Cardiovascular Research Unit, Auckland City Hospital, Auckland, New Zealand (H.W.).
Eugene
E
Braunwald
From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., M.P.B., S.A.M., B.M.S., E.B., D.A.M.); Department of Cardiovascular Medicine, Flinders Cardiovascular Center, Adelaide, Australia (P.E.A.); Cardiovascular Division, Pontificia Universidad Catolica de Chile, Santiago, Chile (R.L.C.); Department of Cardiology, Military Hospital, Budapest, Hungary (R.G.K.); and Green Lane Cardiovascular Research Unit, Auckland City Hospital, Auckland, New Zealand (H.W.).
David A
DA
Morrow
D000368:Aged; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D038622:Internationality; D002546:Ischemic Attack, Transient; D007783:Lactones / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000175:diagnosis / Q000517:prevention & control*; D011725:Pyridines / Q000008:administration & dosage*; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors; D055502:Secondary Prevention / Q000379:methods*; D020521:Stroke; D016896:Treatment Outcome; D010975:Platelet Aggregation Inhibitors
D007783:Lactones; D011725:Pyridines; D018179:Receptors, Thrombin; C446540:thienopyridine; C530299:vorapaxar; D010975:Platelet Aggregation Inhibitors
atherosclerosis; receptors, thrombin; thienoypyridine