Vorapaxar in the secondary prevention of atherothrombotic events

David A Morrow; Eugene Braunwald; Marc P Bonaca; Sebastian F Ameriso; Anthony J Dalby; Mary Polly Fish; Keith A A Fox; Leslie J Lipka; Xuan Liu; José Carlos Nicolau; A J Oude Ophuis; Ernesto Paolasso; Benjamin M Scirica; Jindrich Spinar; Pierre Theroux; Stephen D Wiviott; John Strony; Sabina A Murphy; TRA 2P–TIMI 50 Steering Committee and Investigators; Helle Klingenberg Iversen

doi:10.1056/NEJMoa1200933

Vorapaxar in the secondary prevention of atherothrombotic events

David A Morrow, Eugene Braunwald, Marc P Bonaca, Sebastian F Ameriso, Anthony J Dalby, Mary Polly Fish, Keith A A Fox, Leslie J Lipka, Xuan Liu, José Carlos Nicolau, A J Oude Ophuis, Ernesto Paolasso, Benjamin M Scirica, Jindrich Spinar, Pierre Theroux, Stephen D Wiviott, John Strony, Sabina A Murphy, TRA 2P–TIMI 50 Steering Committee and Investigators, Helle Klingenberg Iversen

Department of Clinical Medicine

667 Citations (Scopus)

Abstract

BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS:At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P = 0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS:Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)

Original language	English
Journal	New England Journal of Medicine
Volume	366
Issue number	15
Pages (from-to)	1404-13
Number of pages	10
ISSN	0028-4793
DOIs	https://doi.org/10.1056/NEJMoa1200933
Publication status	Published - 12 Apr 2012

Keywords

Aged
Brain Ischemia
Cardiovascular Diseases
Double-Blind Method
Female
Hemorrhage
Humans
Intracranial Hemorrhages
Kaplan-Meier Estimate
Lactones
Male
Middle Aged
Myocardial Infarction
Peripheral Arterial Disease
Platelet Aggregation Inhibitors
Pyridines
Receptor, PAR-1
Retreatment
Risk
Secondary Prevention
Stroke

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10.1056/NEJMoa1200933

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Morrow, D. A., Braunwald, E., Bonaca, M. P., Ameriso, S. F., Dalby, A. J., Fish, M. P., Fox, K. A. A., Lipka, L. J., Liu, X., Nicolau, J. C., Ophuis, A. J. O., Paolasso, E., Scirica, B. M., Spinar, J., Theroux, P., Wiviott, S. D., Strony, J., Murphy, S. A., TRA 2P–TIMI 50 Steering Committee and Investigators, & Iversen, H. K. (2012). Vorapaxar in the secondary prevention of atherothrombotic events. New England Journal of Medicine, 366(15), 1404-13. https://doi.org/10.1056/NEJMoa1200933

Morrow, DA, Braunwald, E, Bonaca, MP, Ameriso, SF, Dalby, AJ, Fish, MP, Fox, KAA, Lipka, LJ, Liu, X, Nicolau, JC, Ophuis, AJO, Paolasso, E, Scirica, BM, Spinar, J, Theroux, P, Wiviott, SD, Strony, J, Murphy, SA, TRA 2P–TIMI 50 Steering Committee and Investigators & Iversen, HK 2012, 'Vorapaxar in the secondary prevention of atherothrombotic events', New England Journal of Medicine, vol. 366, no. 15, pp. 1404-13. https://doi.org/10.1056/NEJMoa1200933

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title = "Vorapaxar in the secondary prevention of atherothrombotic events",

abstract = "BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS:At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P = 0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS:Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)",

keywords = "Aged, Brain Ischemia, Cardiovascular Diseases, Double-Blind Method, Female, Hemorrhage, Humans, Intracranial Hemorrhages, Kaplan-Meier Estimate, Lactones, Male, Middle Aged, Myocardial Infarction, Peripheral Arterial Disease, Platelet Aggregation Inhibitors, Pyridines, Receptor, PAR-1, Retreatment, Risk, Secondary Prevention, Stroke",

author = "Morrow, {David A} and Eugene Braunwald and Bonaca, {Marc P} and Ameriso, {Sebastian F} and Dalby, {Anthony J} and Fish, {Mary Polly} and Fox, {Keith A A} and Lipka, {Leslie J} and Xuan Liu and Nicolau, {Jos{\'e} Carlos} and Ophuis, {A J Oude} and Ernesto Paolasso and Scirica, {Benjamin M} and Jindrich Spinar and Pierre Theroux and Wiviott, {Stephen D} and John Strony and Murphy, {Sabina A} and {TRA 2P–TIMI 50 Steering Committee and Investigators} and Iversen, {Helle Klingenberg}",

year = "2012",

month = apr,

day = "12",

doi = "10.1056/NEJMoa1200933",

language = "English",

volume = "366",

pages = "1404--13",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "15",

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TY - JOUR

T1 - Vorapaxar in the secondary prevention of atherothrombotic events

AU - Morrow, David A

AU - Braunwald, Eugene

AU - Bonaca, Marc P

AU - Ameriso, Sebastian F

AU - Dalby, Anthony J

AU - Fish, Mary Polly

AU - Fox, Keith A A

AU - Lipka, Leslie J

AU - Liu, Xuan

AU - Nicolau, José Carlos

AU - Ophuis, A J Oude

AU - Paolasso, Ernesto

AU - Scirica, Benjamin M

AU - Spinar, Jindrich

AU - Theroux, Pierre

AU - Wiviott, Stephen D

AU - Strony, John

AU - Murphy, Sabina A

AU - TRA 2P–TIMI 50 Steering Committee and Investigators

AU - Iversen, Helle Klingenberg

PY - 2012/4/12

Y1 - 2012/4/12

N2 - BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS:At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P = 0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS:Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)

AB - BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS:At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P = 0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS:Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)

KW - Aged

KW - Brain Ischemia

KW - Cardiovascular Diseases

KW - Double-Blind Method

KW - Female

KW - Hemorrhage

KW - Humans

KW - Intracranial Hemorrhages

KW - Kaplan-Meier Estimate

KW - Lactones

KW - Male

KW - Middle Aged

KW - Myocardial Infarction

KW - Peripheral Arterial Disease

KW - Platelet Aggregation Inhibitors

KW - Pyridines

KW - Receptor, PAR-1

KW - Retreatment

KW - Risk

KW - Secondary Prevention

KW - Stroke

U2 - 10.1056/NEJMoa1200933

DO - 10.1056/NEJMoa1200933

M3 - Journal article

C2 - 22443427

SN - 0028-4793

VL - 366

SP - 1404

EP - 1413

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 15

ER -

Vorapaxar in the secondary prevention of atherothrombotic events

Abstract

Keywords

UN SDGs

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