Vorapaxar

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David A Morrow - One of the best experts on this subject based on the ideXlab platform.

  • effect of Vorapaxar on cardiovascular and limb outcomes in patients with peripheral artery disease with and without coronary artery disease analysis from the tra 2 p timi 50 trial
    Vascular Medicine, 2020
    Co-Authors: Arman Qamar, Benjamin M Scirica, Marc P. Bonaca, Sabina A Murphy, David A Morrow, Mark A. Creager, Jeffrey W. Olin, Joshua A Beckman
    Abstract:

    Intensive antithrombotic therapy reduces major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with peripheral artery disease (PAD). Recent studies have suggested heterogeneity in risk and benefit in those with and without concomitant coronary artery disease (CAD) and peripheral revascularization. We evaluated the risk of MACE and MALE in patients with PAD stratified by history of concomitant CAD and prior peripheral revascularization and whether the efficacy and safety of Vorapaxar were similar in these subgroups. The TRA 2°P-TIMI 50 trial randomized 26,449 patients with prior MI, ischemic stroke, or PAD to Vorapaxar or placebo. This analysis examined the effect of Vorapaxar in a broad population of 6136 patients with PAD. Overall, Vorapaxar significantly reduced MACE (HR 0.85, 95% CI 0.73, 0.99; p = 0.034) and MALE (HR 0.70, 95% CI 0.53, 0.92; p = 0.011) in patients with PAD. The absolute risk reduction (ARR) for MACE was greater in patients with PAD and CAD versus those with PAD alone (-2.2% vs 0.1%: number needed to treat (NNT) 45 vs 1000). Conversely, the ARR for MALE was higher in those with prior lower extremity revascularization (2.5% vs 0.2%: NNT 40 vs 500). Vorapaxar increased major bleeding (HR 1.39, 95% CI 1.12, 1.71; p = 0.003). The net clinical outcome in all patients with PAD was reduced with Vorapaxar (HR 0.82, 95% CI 0.72, 0.94; p = 0.004), with benefits driven by reductions in MACE for those with CAD and by reductions in MALE for those with prior peripheral revascularization. Among patients with PAD, Vorapaxar resulted in a net clinical benefit; however, the drivers of benefit were heterogeneous, with greater reductions in MACE in those with concomitant CAD and greater reductions in MALE in those with prior lower extremity revascularization, and unclear benefit in patients with neither. These clinical characteristics may be useful in identifying the subgroups of patients with PAD most likely to benefit from potent antithrombotic therapies. ClinicalTrials.gov Identifier: NCT00526474.

  • Efficacy and safety of more potent antiplatelet therapy with Vorapaxar in patients with impaired renal function
    Journal of Thrombosis and Thrombolysis, 2019
    Co-Authors: Simon Correa, Benjamin M Scirica, Marc P. Bonaca, Sabina A Murphy, David A Morrow, Erica L. Goodrich, Michelle L. O’donoghue
    Abstract:

    Patients with renal disease are often undertreated with antiplatelet therapy due to concerns about bleeding. Vorapaxar blocks platelet activation via the PAR-1 receptor and reduces cardiovascular events in patients with stable atherosclerosis, but with increased bleeding. We examined the efficacy and safety of Vorapaxar in patients with impaired renal function. TRA2°P-TIMI 50 randomized patients with stable atherosclerosis to Vorapaxar or. We analyzed patients with eGFR assessed who qualified with a history of MI or PAD (without stroke or TIA) (n = 19,932). Cox models assessed the risk of CV events and bleeding by quartile of baseline eGFR in the placebo arm and then by randomized assignment. Net clinical outcome (NCO) was predefined as CV death, MI, stroke, or GUSTO severe bleeding. Patients with lower eGFR tended to be older, female, have hypertension, hyperlipidemia or prior PAD. In the placebo arm, baseline eGFR in the lowest quartile was associated with a 26% higher risk of CV death, MI or stroke (Q1:Q4 HR_adj 1.26, 1.03–1.55) and 73% higher risk of GUSTO moderate or severe bleeding (HR_adj 1.73, 1.12–2.65). Vorapaxar reduced the risk of MACE to a similar extent (14–26%) across quartiles of baseline eGFR (P interaction = 0.70) and increased the relative risk of GUSTO moderate or severe bleeding (P interaction = 0.54). NCO was similar across quartiles of eGFR (P interaction = 0.65). Intensification of antiplatelet therapy with Vorapaxar offers comparable net clinical benefit regardless of baseline renal function. These data support the use of more potent antiplatelet regimens in patients with renal dysfunction.

  • Peripheral Revascularization in Patients With Peripheral Artery Disease With Vorapaxar: Insights From the TRA 2°P-TIMI 50 Trial.
    JACC. Cardiovascular interventions, 2016
    Co-Authors: Marc P. Bonaca, Benjamin M Scirica, Sabina A Murphy, Eugene Braunwald, Mark A. Creager, Jeffrey W. Olin, Ian C. Gilchrist, Erica L. Goodrich, David A Morrow
    Abstract:

    Abstract Objectives The aim of this study was to determine whether the reduction in peripheral revascularization with Vorapaxar in patients with peripheral artery disease (PAD) is directionally consistent across indications, including acute limb ischemia, progressively disabling symptoms, or both. Background The protease-activated receptor–1 antagonist Vorapaxar reduces peripheral revascularization in patients with PAD. Methods The TRA 2°P–TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50) trial randomized 26,449 patients with histories of myocardial infarction, stroke, or symptomatic PAD to Vorapaxar or placebo on a background of standard therapy. A total of 5,845 patients had a known history of PAD at randomization. Peripheral revascularization procedures reported by the site were a pre-specified outcome. We explored whether the benefit of Vorapaxar was consistent across indication and type of procedure. Results Of the 5,845 patients with known PAD, a total of 934 (16%) underwent at least 1 peripheral revascularization over 2.5 years (median). More than one-half (55%) were for worsening claudication, followed by critical limb ischemia (24%), acute limb ischemia (16%), and asymptomatic severe stenosis (4%). Vorapaxar significantly reduced peripheral revascularization (19.3% for placebo, 15.4% for Vorapaxar; hazard ratio: 0.82; 95% confidence interval: 0.72 to 0.93; p = 0.003), with a consistent pattern of efficacy across indication. Conclusions Vorapaxar reduces peripheral revascularization in patients with PAD. This benefit of Vorapaxar is directionally consistent across type of procedure and indication. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2°P - TIMI 50] [P04737]; NCT00526474)

  • Outcomes in Stable Patients With Previous Atherothrombotic Events Receiving Vorapaxar Who Experience a New Acute Coronary Event (from TRA2°P-TIMI 50).
    The American journal of cardiology, 2016
    Co-Authors: David D. Berg, Benjamin M Scirica, Ramón Corbalán, Marc P. Bonaca, Sabina A Murphy, Robert Gabor Kiss, Eugene Braunwald, Shinya Goto, Jindrich Spinar, David A Morrow
    Abstract:

    Vorapaxar is a first-in-class protease-activated receptor-1 antagonist indicated for secondary prevention in stable patients with previous myocardial infarction (MI) or peripheral artery disease and no cerebrovascular disease. Vorapaxar is not recommended for initiation in the acute phase of acute coronary syndromes (ACS) because of an unfavorable balance between bleeding and efficacy when started in that setting. The aim of this analysis was to investigate outcomes in patients who experienced a new ACS while receiving Vorapaxar for long-term secondary prevention. Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic ischemic Events-Thrombolysis In Myocardial Infarction 50 was a randomized, double-blind, placebo-controlled trial of Vorapaxar (n = 26,449). We evaluated bleeding and ischemic events during the acute care of patients with a new ACS during the trial. During a median follow-up of 30 months, 799 patients (8.9%) randomized to Vorapaxar and 913 (10.0%) to placebo had a new ACS event (p = 0.003); 87% and 86%, respectively, were on study therapy at the time of the event. In a landmark analysis through 7 days after ACS, the rates of Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding were 0.8% versus 0.8% (hazard ratio [HR] 0.99, 95% CI 0.33 to 2.94) and GUSTO moderate/severe bleeding were 2.5% versus 1.6% (HR 1.59, 95% CI 0.78 to 3.24) with Vorapaxar versus placebo. The effect of Vorapaxar on cardiovascular death, MI, or stroke (2.4% vs 4.4%; HR 0.54, 95% CI 0.31 to 0.93; p = 0.027) was consistent with the overall trial result. In conclusion, in patients who experience a new ACS event while receiving Vorapaxar for secondary prevention, continuing therapy was associated with favorable efficacy without excess severe bleeding during the period of acute ACS management.

  • the efficacy and safety of Vorapaxar with and without a thienopyridine for secondary prevention in patients with prior myocardial infarction and no history of stroke or tia results from tra 2 p timi 50
    Circulation, 2015
    Co-Authors: Erin A. Bohula, Philip E Aylward, Benjamin M Scirica, Ramón Corbalán, Marc P. Bonaca, Sabina A Murphy, Harvey D White, Robert Gabor Kiss, Eugene Braunwald, David A Morrow
    Abstract:

    Background —Vorapaxar antagonizes protease-activated receptor (PAR)-1, the primary receptor for thrombin on human platelets, and reduces recurrent thrombotic events in stable patients with a prior myocardial infarction (MI). We wished to determine whether the efficacy and safety of antiplatelet therapy with Vorapaxar was modified by concurrent thienopyridine use. Methods and Results —TRA 2°P-TIMI 50 was a randomized, double-blind, placebo-controlled trial of Vorapaxar in 26,449 patients with prior atherothrombosis. This pre-specified 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 TIA 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 when compared to placebo regardless of planned thienopyridine therapy (planned thienopyridine HR 0.80, 0.70-0.91, p<0.001; no planned thienopyridine HR 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). GUSTO moderate or severe bleeding risk was increased with Vorapaxar and was not significantly altered by planned thienopyridine (planned HR 1.50, 1.18-1.89, p<0.001; no planned HR 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 prior MI, whether treated concomitantly with a thienopyridine or not. The relative risk of moderate or severe bleeding was similarly increased irrespective of thienopyridine use. Clinical Trial Registration Information —http://www.clinicaltrials.gov. Identifier: [NCT00526474][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00526474&atom=%2Fcirculationaha%2Fearly%2F2015%2F09%2F03%2FCIRCULATIONAHA.114.015042.atom

Marc P. Bonaca - One of the best experts on this subject based on the ideXlab platform.

  • effect of Vorapaxar on cardiovascular and limb outcomes in patients with peripheral artery disease with and without coronary artery disease analysis from the tra 2 p timi 50 trial
    Vascular Medicine, 2020
    Co-Authors: Arman Qamar, Benjamin M Scirica, Marc P. Bonaca, Sabina A Murphy, David A Morrow, Mark A. Creager, Jeffrey W. Olin, Joshua A Beckman
    Abstract:

    Intensive antithrombotic therapy reduces major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with peripheral artery disease (PAD). Recent studies have suggested heterogeneity in risk and benefit in those with and without concomitant coronary artery disease (CAD) and peripheral revascularization. We evaluated the risk of MACE and MALE in patients with PAD stratified by history of concomitant CAD and prior peripheral revascularization and whether the efficacy and safety of Vorapaxar were similar in these subgroups. The TRA 2°P-TIMI 50 trial randomized 26,449 patients with prior MI, ischemic stroke, or PAD to Vorapaxar or placebo. This analysis examined the effect of Vorapaxar in a broad population of 6136 patients with PAD. Overall, Vorapaxar significantly reduced MACE (HR 0.85, 95% CI 0.73, 0.99; p = 0.034) and MALE (HR 0.70, 95% CI 0.53, 0.92; p = 0.011) in patients with PAD. The absolute risk reduction (ARR) for MACE was greater in patients with PAD and CAD versus those with PAD alone (-2.2% vs 0.1%: number needed to treat (NNT) 45 vs 1000). Conversely, the ARR for MALE was higher in those with prior lower extremity revascularization (2.5% vs 0.2%: NNT 40 vs 500). Vorapaxar increased major bleeding (HR 1.39, 95% CI 1.12, 1.71; p = 0.003). The net clinical outcome in all patients with PAD was reduced with Vorapaxar (HR 0.82, 95% CI 0.72, 0.94; p = 0.004), with benefits driven by reductions in MACE for those with CAD and by reductions in MALE for those with prior peripheral revascularization. Among patients with PAD, Vorapaxar resulted in a net clinical benefit; however, the drivers of benefit were heterogeneous, with greater reductions in MACE in those with concomitant CAD and greater reductions in MALE in those with prior lower extremity revascularization, and unclear benefit in patients with neither. These clinical characteristics may be useful in identifying the subgroups of patients with PAD most likely to benefit from potent antithrombotic therapies. ClinicalTrials.gov Identifier: NCT00526474.

  • Efficacy and safety of more potent antiplatelet therapy with Vorapaxar in patients with impaired renal function
    Journal of Thrombosis and Thrombolysis, 2019
    Co-Authors: Simon Correa, Benjamin M Scirica, Marc P. Bonaca, Sabina A Murphy, David A Morrow, Erica L. Goodrich, Michelle L. O’donoghue
    Abstract:

    Patients with renal disease are often undertreated with antiplatelet therapy due to concerns about bleeding. Vorapaxar blocks platelet activation via the PAR-1 receptor and reduces cardiovascular events in patients with stable atherosclerosis, but with increased bleeding. We examined the efficacy and safety of Vorapaxar in patients with impaired renal function. TRA2°P-TIMI 50 randomized patients with stable atherosclerosis to Vorapaxar or. We analyzed patients with eGFR assessed who qualified with a history of MI or PAD (without stroke or TIA) (n = 19,932). Cox models assessed the risk of CV events and bleeding by quartile of baseline eGFR in the placebo arm and then by randomized assignment. Net clinical outcome (NCO) was predefined as CV death, MI, stroke, or GUSTO severe bleeding. Patients with lower eGFR tended to be older, female, have hypertension, hyperlipidemia or prior PAD. In the placebo arm, baseline eGFR in the lowest quartile was associated with a 26% higher risk of CV death, MI or stroke (Q1:Q4 HR_adj 1.26, 1.03–1.55) and 73% higher risk of GUSTO moderate or severe bleeding (HR_adj 1.73, 1.12–2.65). Vorapaxar reduced the risk of MACE to a similar extent (14–26%) across quartiles of baseline eGFR (P interaction = 0.70) and increased the relative risk of GUSTO moderate or severe bleeding (P interaction = 0.54). NCO was similar across quartiles of eGFR (P interaction = 0.65). Intensification of antiplatelet therapy with Vorapaxar offers comparable net clinical benefit regardless of baseline renal function. These data support the use of more potent antiplatelet regimens in patients with renal dysfunction.

  • Peripheral Revascularization in Patients With Peripheral Artery Disease With Vorapaxar: Insights From the TRA 2°P-TIMI 50 Trial.
    JACC. Cardiovascular interventions, 2016
    Co-Authors: Marc P. Bonaca, Benjamin M Scirica, Sabina A Murphy, Eugene Braunwald, Mark A. Creager, Jeffrey W. Olin, Ian C. Gilchrist, Erica L. Goodrich, David A Morrow
    Abstract:

    Abstract Objectives The aim of this study was to determine whether the reduction in peripheral revascularization with Vorapaxar in patients with peripheral artery disease (PAD) is directionally consistent across indications, including acute limb ischemia, progressively disabling symptoms, or both. Background The protease-activated receptor–1 antagonist Vorapaxar reduces peripheral revascularization in patients with PAD. Methods The TRA 2°P–TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50) trial randomized 26,449 patients with histories of myocardial infarction, stroke, or symptomatic PAD to Vorapaxar or placebo on a background of standard therapy. A total of 5,845 patients had a known history of PAD at randomization. Peripheral revascularization procedures reported by the site were a pre-specified outcome. We explored whether the benefit of Vorapaxar was consistent across indication and type of procedure. Results Of the 5,845 patients with known PAD, a total of 934 (16%) underwent at least 1 peripheral revascularization over 2.5 years (median). More than one-half (55%) were for worsening claudication, followed by critical limb ischemia (24%), acute limb ischemia (16%), and asymptomatic severe stenosis (4%). Vorapaxar significantly reduced peripheral revascularization (19.3% for placebo, 15.4% for Vorapaxar; hazard ratio: 0.82; 95% confidence interval: 0.72 to 0.93; p = 0.003), with a consistent pattern of efficacy across indication. Conclusions Vorapaxar reduces peripheral revascularization in patients with PAD. This benefit of Vorapaxar is directionally consistent across type of procedure and indication. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2°P - TIMI 50] [P04737]; NCT00526474)

  • atherothrombotic risk stratification and the efficacy and safety of Vorapaxar in patients with stable ischemic heart disease and previous myocardial infarction
    Circulation, 2016
    Co-Authors: Erin A. Bohula, Philip E Aylward, Ramón Corbalán, Marc P. Bonaca, Sabina A Murphy, Eugene Braunwald, Gaetano M De Ferrari, Basil S Lewis, Piera Angelica Merlini, Marc S Sabatine
    Abstract:

    Background —Patients with stable ischemic heart disease and prior MI vary in their risk for recurrent CV events. Atherothrombotic risk assessment may be useful to identify high-risk patients who have the greatest potential for benefit from more intensive secondary preventative therapy such as treatment with Vorapaxar. Methods —We identified independent clinical indicators of atherothrombotic risk among 8,598 stable, placebo-treated patients with a prior MI followed for 2.5 years (median) in TRA 2°P-TIMI 50. The efficacy and safety of Vorapaxar was assessed by baseline risk among patients with prior MI without prior stroke or TIA for whom there is a clinical indication for Vorapaxar. Endpoints were CV death, MI, or ischemic stroke (CVD/MI/iCVA) and GUSTO severe bleeding. Results —The 9 independent risk predictors were age, diabetes, hypertension, smoking, peripheral arterial disease, prior stroke, prior 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 CVD/MI/iCVA and the individual components (p-trend<0.001 for all). High-risk patients (≥3 risk indicators; 20% of population) had a 3.2% absolute risk reduction (ARR) in CVD/MI/iCVA with Vorapaxar and intermediate-risk (1-2; 61%) had a 2.1% ARR (p<0.001 each), translating to a number-needed-to-treat of 31 and 48. Bleeding increased across risk groups (p-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. Conclusions —Stratification of baseline atherothrombotic risk can assist with therapeutic decision-making regarding Vorapaxar use for secondary prevention after MI. Clinical Trial Registration —http://www.clinicaltrials.gov; [NCT00526474][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00526474&atom=%2Fcirculationaha%2Fearly%2F2016%2F07%2F20%2FCIRCULATIONAHA.115.019861.atom

  • Outcomes in Stable Patients With Previous Atherothrombotic Events Receiving Vorapaxar Who Experience a New Acute Coronary Event (from TRA2°P-TIMI 50).
    The American journal of cardiology, 2016
    Co-Authors: David D. Berg, Benjamin M Scirica, Ramón Corbalán, Marc P. Bonaca, Sabina A Murphy, Robert Gabor Kiss, Eugene Braunwald, Shinya Goto, Jindrich Spinar, David A Morrow
    Abstract:

    Vorapaxar is a first-in-class protease-activated receptor-1 antagonist indicated for secondary prevention in stable patients with previous myocardial infarction (MI) or peripheral artery disease and no cerebrovascular disease. Vorapaxar is not recommended for initiation in the acute phase of acute coronary syndromes (ACS) because of an unfavorable balance between bleeding and efficacy when started in that setting. The aim of this analysis was to investigate outcomes in patients who experienced a new ACS while receiving Vorapaxar for long-term secondary prevention. Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic ischemic Events-Thrombolysis In Myocardial Infarction 50 was a randomized, double-blind, placebo-controlled trial of Vorapaxar (n = 26,449). We evaluated bleeding and ischemic events during the acute care of patients with a new ACS during the trial. During a median follow-up of 30 months, 799 patients (8.9%) randomized to Vorapaxar and 913 (10.0%) to placebo had a new ACS event (p = 0.003); 87% and 86%, respectively, were on study therapy at the time of the event. In a landmark analysis through 7 days after ACS, the rates of Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding were 0.8% versus 0.8% (hazard ratio [HR] 0.99, 95% CI 0.33 to 2.94) and GUSTO moderate/severe bleeding were 2.5% versus 1.6% (HR 1.59, 95% CI 0.78 to 3.24) with Vorapaxar versus placebo. The effect of Vorapaxar on cardiovascular death, MI, or stroke (2.4% vs 4.4%; HR 0.54, 95% CI 0.31 to 0.93; p = 0.027) was consistent with the overall trial result. In conclusion, in patients who experience a new ACS event while receiving Vorapaxar for secondary prevention, continuing therapy was associated with favorable efficacy without excess severe bleeding during the period of acute ACS management.

Sabina A Murphy - One of the best experts on this subject based on the ideXlab platform.

  • effect of Vorapaxar on cardiovascular and limb outcomes in patients with peripheral artery disease with and without coronary artery disease analysis from the tra 2 p timi 50 trial
    Vascular Medicine, 2020
    Co-Authors: Arman Qamar, Benjamin M Scirica, Marc P. Bonaca, Sabina A Murphy, David A Morrow, Mark A. Creager, Jeffrey W. Olin, Joshua A Beckman
    Abstract:

    Intensive antithrombotic therapy reduces major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with peripheral artery disease (PAD). Recent studies have suggested heterogeneity in risk and benefit in those with and without concomitant coronary artery disease (CAD) and peripheral revascularization. We evaluated the risk of MACE and MALE in patients with PAD stratified by history of concomitant CAD and prior peripheral revascularization and whether the efficacy and safety of Vorapaxar were similar in these subgroups. The TRA 2°P-TIMI 50 trial randomized 26,449 patients with prior MI, ischemic stroke, or PAD to Vorapaxar or placebo. This analysis examined the effect of Vorapaxar in a broad population of 6136 patients with PAD. Overall, Vorapaxar significantly reduced MACE (HR 0.85, 95% CI 0.73, 0.99; p = 0.034) and MALE (HR 0.70, 95% CI 0.53, 0.92; p = 0.011) in patients with PAD. The absolute risk reduction (ARR) for MACE was greater in patients with PAD and CAD versus those with PAD alone (-2.2% vs 0.1%: number needed to treat (NNT) 45 vs 1000). Conversely, the ARR for MALE was higher in those with prior lower extremity revascularization (2.5% vs 0.2%: NNT 40 vs 500). Vorapaxar increased major bleeding (HR 1.39, 95% CI 1.12, 1.71; p = 0.003). The net clinical outcome in all patients with PAD was reduced with Vorapaxar (HR 0.82, 95% CI 0.72, 0.94; p = 0.004), with benefits driven by reductions in MACE for those with CAD and by reductions in MALE for those with prior peripheral revascularization. Among patients with PAD, Vorapaxar resulted in a net clinical benefit; however, the drivers of benefit were heterogeneous, with greater reductions in MACE in those with concomitant CAD and greater reductions in MALE in those with prior lower extremity revascularization, and unclear benefit in patients with neither. These clinical characteristics may be useful in identifying the subgroups of patients with PAD most likely to benefit from potent antithrombotic therapies. ClinicalTrials.gov Identifier: NCT00526474.

  • Efficacy and safety of more potent antiplatelet therapy with Vorapaxar in patients with impaired renal function
    Journal of Thrombosis and Thrombolysis, 2019
    Co-Authors: Simon Correa, Benjamin M Scirica, Marc P. Bonaca, Sabina A Murphy, David A Morrow, Erica L. Goodrich, Michelle L. O’donoghue
    Abstract:

    Patients with renal disease are often undertreated with antiplatelet therapy due to concerns about bleeding. Vorapaxar blocks platelet activation via the PAR-1 receptor and reduces cardiovascular events in patients with stable atherosclerosis, but with increased bleeding. We examined the efficacy and safety of Vorapaxar in patients with impaired renal function. TRA2°P-TIMI 50 randomized patients with stable atherosclerosis to Vorapaxar or. We analyzed patients with eGFR assessed who qualified with a history of MI or PAD (without stroke or TIA) (n = 19,932). Cox models assessed the risk of CV events and bleeding by quartile of baseline eGFR in the placebo arm and then by randomized assignment. Net clinical outcome (NCO) was predefined as CV death, MI, stroke, or GUSTO severe bleeding. Patients with lower eGFR tended to be older, female, have hypertension, hyperlipidemia or prior PAD. In the placebo arm, baseline eGFR in the lowest quartile was associated with a 26% higher risk of CV death, MI or stroke (Q1:Q4 HR_adj 1.26, 1.03–1.55) and 73% higher risk of GUSTO moderate or severe bleeding (HR_adj 1.73, 1.12–2.65). Vorapaxar reduced the risk of MACE to a similar extent (14–26%) across quartiles of baseline eGFR (P interaction = 0.70) and increased the relative risk of GUSTO moderate or severe bleeding (P interaction = 0.54). NCO was similar across quartiles of eGFR (P interaction = 0.65). Intensification of antiplatelet therapy with Vorapaxar offers comparable net clinical benefit regardless of baseline renal function. These data support the use of more potent antiplatelet regimens in patients with renal dysfunction.

  • Peripheral Revascularization in Patients With Peripheral Artery Disease With Vorapaxar: Insights From the TRA 2°P-TIMI 50 Trial.
    JACC. Cardiovascular interventions, 2016
    Co-Authors: Marc P. Bonaca, Benjamin M Scirica, Sabina A Murphy, Eugene Braunwald, Mark A. Creager, Jeffrey W. Olin, Ian C. Gilchrist, Erica L. Goodrich, David A Morrow
    Abstract:

    Abstract Objectives The aim of this study was to determine whether the reduction in peripheral revascularization with Vorapaxar in patients with peripheral artery disease (PAD) is directionally consistent across indications, including acute limb ischemia, progressively disabling symptoms, or both. Background The protease-activated receptor–1 antagonist Vorapaxar reduces peripheral revascularization in patients with PAD. Methods The TRA 2°P–TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50) trial randomized 26,449 patients with histories of myocardial infarction, stroke, or symptomatic PAD to Vorapaxar or placebo on a background of standard therapy. A total of 5,845 patients had a known history of PAD at randomization. Peripheral revascularization procedures reported by the site were a pre-specified outcome. We explored whether the benefit of Vorapaxar was consistent across indication and type of procedure. Results Of the 5,845 patients with known PAD, a total of 934 (16%) underwent at least 1 peripheral revascularization over 2.5 years (median). More than one-half (55%) were for worsening claudication, followed by critical limb ischemia (24%), acute limb ischemia (16%), and asymptomatic severe stenosis (4%). Vorapaxar significantly reduced peripheral revascularization (19.3% for placebo, 15.4% for Vorapaxar; hazard ratio: 0.82; 95% confidence interval: 0.72 to 0.93; p = 0.003), with a consistent pattern of efficacy across indication. Conclusions Vorapaxar reduces peripheral revascularization in patients with PAD. This benefit of Vorapaxar is directionally consistent across type of procedure and indication. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2°P - TIMI 50] [P04737]; NCT00526474)

  • atherothrombotic risk stratification and the efficacy and safety of Vorapaxar in patients with stable ischemic heart disease and previous myocardial infarction
    Circulation, 2016
    Co-Authors: Erin A. Bohula, Philip E Aylward, Ramón Corbalán, Marc P. Bonaca, Sabina A Murphy, Eugene Braunwald, Gaetano M De Ferrari, Basil S Lewis, Piera Angelica Merlini, Marc S Sabatine
    Abstract:

    Background —Patients with stable ischemic heart disease and prior MI vary in their risk for recurrent CV events. Atherothrombotic risk assessment may be useful to identify high-risk patients who have the greatest potential for benefit from more intensive secondary preventative therapy such as treatment with Vorapaxar. Methods —We identified independent clinical indicators of atherothrombotic risk among 8,598 stable, placebo-treated patients with a prior MI followed for 2.5 years (median) in TRA 2°P-TIMI 50. The efficacy and safety of Vorapaxar was assessed by baseline risk among patients with prior MI without prior stroke or TIA for whom there is a clinical indication for Vorapaxar. Endpoints were CV death, MI, or ischemic stroke (CVD/MI/iCVA) and GUSTO severe bleeding. Results —The 9 independent risk predictors were age, diabetes, hypertension, smoking, peripheral arterial disease, prior stroke, prior 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 CVD/MI/iCVA and the individual components (p-trend<0.001 for all). High-risk patients (≥3 risk indicators; 20% of population) had a 3.2% absolute risk reduction (ARR) in CVD/MI/iCVA with Vorapaxar and intermediate-risk (1-2; 61%) had a 2.1% ARR (p<0.001 each), translating to a number-needed-to-treat of 31 and 48. Bleeding increased across risk groups (p-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. Conclusions —Stratification of baseline atherothrombotic risk can assist with therapeutic decision-making regarding Vorapaxar use for secondary prevention after MI. Clinical Trial Registration —http://www.clinicaltrials.gov; [NCT00526474][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00526474&atom=%2Fcirculationaha%2Fearly%2F2016%2F07%2F20%2FCIRCULATIONAHA.115.019861.atom

  • Outcomes in Stable Patients With Previous Atherothrombotic Events Receiving Vorapaxar Who Experience a New Acute Coronary Event (from TRA2°P-TIMI 50).
    The American journal of cardiology, 2016
    Co-Authors: David D. Berg, Benjamin M Scirica, Ramón Corbalán, Marc P. Bonaca, Sabina A Murphy, Robert Gabor Kiss, Eugene Braunwald, Shinya Goto, Jindrich Spinar, David A Morrow
    Abstract:

    Vorapaxar is a first-in-class protease-activated receptor-1 antagonist indicated for secondary prevention in stable patients with previous myocardial infarction (MI) or peripheral artery disease and no cerebrovascular disease. Vorapaxar is not recommended for initiation in the acute phase of acute coronary syndromes (ACS) because of an unfavorable balance between bleeding and efficacy when started in that setting. The aim of this analysis was to investigate outcomes in patients who experienced a new ACS while receiving Vorapaxar for long-term secondary prevention. Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic ischemic Events-Thrombolysis In Myocardial Infarction 50 was a randomized, double-blind, placebo-controlled trial of Vorapaxar (n = 26,449). We evaluated bleeding and ischemic events during the acute care of patients with a new ACS during the trial. During a median follow-up of 30 months, 799 patients (8.9%) randomized to Vorapaxar and 913 (10.0%) to placebo had a new ACS event (p = 0.003); 87% and 86%, respectively, were on study therapy at the time of the event. In a landmark analysis through 7 days after ACS, the rates of Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding were 0.8% versus 0.8% (hazard ratio [HR] 0.99, 95% CI 0.33 to 2.94) and GUSTO moderate/severe bleeding were 2.5% versus 1.6% (HR 1.59, 95% CI 0.78 to 3.24) with Vorapaxar versus placebo. The effect of Vorapaxar on cardiovascular death, MI, or stroke (2.4% vs 4.4%; HR 0.54, 95% CI 0.31 to 0.93; p = 0.027) was consistent with the overall trial result. In conclusion, in patients who experience a new ACS event while receiving Vorapaxar for secondary prevention, continuing therapy was associated with favorable efficacy without excess severe bleeding during the period of acute ACS management.

Benjamin M Scirica - One of the best experts on this subject based on the ideXlab platform.

  • effect of Vorapaxar on cardiovascular and limb outcomes in patients with peripheral artery disease with and without coronary artery disease analysis from the tra 2 p timi 50 trial
    Vascular Medicine, 2020
    Co-Authors: Arman Qamar, Benjamin M Scirica, Marc P. Bonaca, Sabina A Murphy, David A Morrow, Mark A. Creager, Jeffrey W. Olin, Joshua A Beckman
    Abstract:

    Intensive antithrombotic therapy reduces major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with peripheral artery disease (PAD). Recent studies have suggested heterogeneity in risk and benefit in those with and without concomitant coronary artery disease (CAD) and peripheral revascularization. We evaluated the risk of MACE and MALE in patients with PAD stratified by history of concomitant CAD and prior peripheral revascularization and whether the efficacy and safety of Vorapaxar were similar in these subgroups. The TRA 2°P-TIMI 50 trial randomized 26,449 patients with prior MI, ischemic stroke, or PAD to Vorapaxar or placebo. This analysis examined the effect of Vorapaxar in a broad population of 6136 patients with PAD. Overall, Vorapaxar significantly reduced MACE (HR 0.85, 95% CI 0.73, 0.99; p = 0.034) and MALE (HR 0.70, 95% CI 0.53, 0.92; p = 0.011) in patients with PAD. The absolute risk reduction (ARR) for MACE was greater in patients with PAD and CAD versus those with PAD alone (-2.2% vs 0.1%: number needed to treat (NNT) 45 vs 1000). Conversely, the ARR for MALE was higher in those with prior lower extremity revascularization (2.5% vs 0.2%: NNT 40 vs 500). Vorapaxar increased major bleeding (HR 1.39, 95% CI 1.12, 1.71; p = 0.003). The net clinical outcome in all patients with PAD was reduced with Vorapaxar (HR 0.82, 95% CI 0.72, 0.94; p = 0.004), with benefits driven by reductions in MACE for those with CAD and by reductions in MALE for those with prior peripheral revascularization. Among patients with PAD, Vorapaxar resulted in a net clinical benefit; however, the drivers of benefit were heterogeneous, with greater reductions in MACE in those with concomitant CAD and greater reductions in MALE in those with prior lower extremity revascularization, and unclear benefit in patients with neither. These clinical characteristics may be useful in identifying the subgroups of patients with PAD most likely to benefit from potent antithrombotic therapies. ClinicalTrials.gov Identifier: NCT00526474.

  • Efficacy and safety of more potent antiplatelet therapy with Vorapaxar in patients with impaired renal function
    Journal of Thrombosis and Thrombolysis, 2019
    Co-Authors: Simon Correa, Benjamin M Scirica, Marc P. Bonaca, Sabina A Murphy, David A Morrow, Erica L. Goodrich, Michelle L. O’donoghue
    Abstract:

    Patients with renal disease are often undertreated with antiplatelet therapy due to concerns about bleeding. Vorapaxar blocks platelet activation via the PAR-1 receptor and reduces cardiovascular events in patients with stable atherosclerosis, but with increased bleeding. We examined the efficacy and safety of Vorapaxar in patients with impaired renal function. TRA2°P-TIMI 50 randomized patients with stable atherosclerosis to Vorapaxar or. We analyzed patients with eGFR assessed who qualified with a history of MI or PAD (without stroke or TIA) (n = 19,932). Cox models assessed the risk of CV events and bleeding by quartile of baseline eGFR in the placebo arm and then by randomized assignment. Net clinical outcome (NCO) was predefined as CV death, MI, stroke, or GUSTO severe bleeding. Patients with lower eGFR tended to be older, female, have hypertension, hyperlipidemia or prior PAD. In the placebo arm, baseline eGFR in the lowest quartile was associated with a 26% higher risk of CV death, MI or stroke (Q1:Q4 HR_adj 1.26, 1.03–1.55) and 73% higher risk of GUSTO moderate or severe bleeding (HR_adj 1.73, 1.12–2.65). Vorapaxar reduced the risk of MACE to a similar extent (14–26%) across quartiles of baseline eGFR (P interaction = 0.70) and increased the relative risk of GUSTO moderate or severe bleeding (P interaction = 0.54). NCO was similar across quartiles of eGFR (P interaction = 0.65). Intensification of antiplatelet therapy with Vorapaxar offers comparable net clinical benefit regardless of baseline renal function. These data support the use of more potent antiplatelet regimens in patients with renal dysfunction.

  • Peripheral Revascularization in Patients With Peripheral Artery Disease With Vorapaxar: Insights From the TRA 2°P-TIMI 50 Trial.
    JACC. Cardiovascular interventions, 2016
    Co-Authors: Marc P. Bonaca, Benjamin M Scirica, Sabina A Murphy, Eugene Braunwald, Mark A. Creager, Jeffrey W. Olin, Ian C. Gilchrist, Erica L. Goodrich, David A Morrow
    Abstract:

    Abstract Objectives The aim of this study was to determine whether the reduction in peripheral revascularization with Vorapaxar in patients with peripheral artery disease (PAD) is directionally consistent across indications, including acute limb ischemia, progressively disabling symptoms, or both. Background The protease-activated receptor–1 antagonist Vorapaxar reduces peripheral revascularization in patients with PAD. Methods The TRA 2°P–TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50) trial randomized 26,449 patients with histories of myocardial infarction, stroke, or symptomatic PAD to Vorapaxar or placebo on a background of standard therapy. A total of 5,845 patients had a known history of PAD at randomization. Peripheral revascularization procedures reported by the site were a pre-specified outcome. We explored whether the benefit of Vorapaxar was consistent across indication and type of procedure. Results Of the 5,845 patients with known PAD, a total of 934 (16%) underwent at least 1 peripheral revascularization over 2.5 years (median). More than one-half (55%) were for worsening claudication, followed by critical limb ischemia (24%), acute limb ischemia (16%), and asymptomatic severe stenosis (4%). Vorapaxar significantly reduced peripheral revascularization (19.3% for placebo, 15.4% for Vorapaxar; hazard ratio: 0.82; 95% confidence interval: 0.72 to 0.93; p = 0.003), with a consistent pattern of efficacy across indication. Conclusions Vorapaxar reduces peripheral revascularization in patients with PAD. This benefit of Vorapaxar is directionally consistent across type of procedure and indication. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2°P - TIMI 50] [P04737]; NCT00526474)

  • Outcomes in Stable Patients With Previous Atherothrombotic Events Receiving Vorapaxar Who Experience a New Acute Coronary Event (from TRA2°P-TIMI 50).
    The American journal of cardiology, 2016
    Co-Authors: David D. Berg, Benjamin M Scirica, Ramón Corbalán, Marc P. Bonaca, Sabina A Murphy, Robert Gabor Kiss, Eugene Braunwald, Shinya Goto, Jindrich Spinar, David A Morrow
    Abstract:

    Vorapaxar is a first-in-class protease-activated receptor-1 antagonist indicated for secondary prevention in stable patients with previous myocardial infarction (MI) or peripheral artery disease and no cerebrovascular disease. Vorapaxar is not recommended for initiation in the acute phase of acute coronary syndromes (ACS) because of an unfavorable balance between bleeding and efficacy when started in that setting. The aim of this analysis was to investigate outcomes in patients who experienced a new ACS while receiving Vorapaxar for long-term secondary prevention. Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic ischemic Events-Thrombolysis In Myocardial Infarction 50 was a randomized, double-blind, placebo-controlled trial of Vorapaxar (n = 26,449). We evaluated bleeding and ischemic events during the acute care of patients with a new ACS during the trial. During a median follow-up of 30 months, 799 patients (8.9%) randomized to Vorapaxar and 913 (10.0%) to placebo had a new ACS event (p = 0.003); 87% and 86%, respectively, were on study therapy at the time of the event. In a landmark analysis through 7 days after ACS, the rates of Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding were 0.8% versus 0.8% (hazard ratio [HR] 0.99, 95% CI 0.33 to 2.94) and GUSTO moderate/severe bleeding were 2.5% versus 1.6% (HR 1.59, 95% CI 0.78 to 3.24) with Vorapaxar versus placebo. The effect of Vorapaxar on cardiovascular death, MI, or stroke (2.4% vs 4.4%; HR 0.54, 95% CI 0.31 to 0.93; p = 0.027) was consistent with the overall trial result. In conclusion, in patients who experience a new ACS event while receiving Vorapaxar for secondary prevention, continuing therapy was associated with favorable efficacy without excess severe bleeding during the period of acute ACS management.

  • the efficacy and safety of Vorapaxar with and without a thienopyridine for secondary prevention in patients with prior myocardial infarction and no history of stroke or tia results from tra 2 p timi 50
    Circulation, 2015
    Co-Authors: Erin A. Bohula, Philip E Aylward, Benjamin M Scirica, Ramón Corbalán, Marc P. Bonaca, Sabina A Murphy, Harvey D White, Robert Gabor Kiss, Eugene Braunwald, David A Morrow
    Abstract:

    Background —Vorapaxar antagonizes protease-activated receptor (PAR)-1, the primary receptor for thrombin on human platelets, and reduces recurrent thrombotic events in stable patients with a prior myocardial infarction (MI). We wished to determine whether the efficacy and safety of antiplatelet therapy with Vorapaxar was modified by concurrent thienopyridine use. Methods and Results —TRA 2°P-TIMI 50 was a randomized, double-blind, placebo-controlled trial of Vorapaxar in 26,449 patients with prior atherothrombosis. This pre-specified 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 TIA 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 when compared to placebo regardless of planned thienopyridine therapy (planned thienopyridine HR 0.80, 0.70-0.91, p<0.001; no planned thienopyridine HR 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). GUSTO moderate or severe bleeding risk was increased with Vorapaxar and was not significantly altered by planned thienopyridine (planned HR 1.50, 1.18-1.89, p<0.001; no planned HR 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 prior MI, whether treated concomitantly with a thienopyridine or not. The relative risk of moderate or severe bleeding was similarly increased irrespective of thienopyridine use. Clinical Trial Registration Information —http://www.clinicaltrials.gov. Identifier: [NCT00526474][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00526474&atom=%2Fcirculationaha%2Fearly%2F2015%2F09%2F03%2FCIRCULATIONAHA.114.015042.atom

Eugene Braunwald - One of the best experts on this subject based on the ideXlab platform.

  • Peripheral Revascularization in Patients With Peripheral Artery Disease With Vorapaxar: Insights From the TRA 2°P-TIMI 50 Trial.
    JACC. Cardiovascular interventions, 2016
    Co-Authors: Marc P. Bonaca, Benjamin M Scirica, Sabina A Murphy, Eugene Braunwald, Mark A. Creager, Jeffrey W. Olin, Ian C. Gilchrist, Erica L. Goodrich, David A Morrow
    Abstract:

    Abstract Objectives The aim of this study was to determine whether the reduction in peripheral revascularization with Vorapaxar in patients with peripheral artery disease (PAD) is directionally consistent across indications, including acute limb ischemia, progressively disabling symptoms, or both. Background The protease-activated receptor–1 antagonist Vorapaxar reduces peripheral revascularization in patients with PAD. Methods The TRA 2°P–TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50) trial randomized 26,449 patients with histories of myocardial infarction, stroke, or symptomatic PAD to Vorapaxar or placebo on a background of standard therapy. A total of 5,845 patients had a known history of PAD at randomization. Peripheral revascularization procedures reported by the site were a pre-specified outcome. We explored whether the benefit of Vorapaxar was consistent across indication and type of procedure. Results Of the 5,845 patients with known PAD, a total of 934 (16%) underwent at least 1 peripheral revascularization over 2.5 years (median). More than one-half (55%) were for worsening claudication, followed by critical limb ischemia (24%), acute limb ischemia (16%), and asymptomatic severe stenosis (4%). Vorapaxar significantly reduced peripheral revascularization (19.3% for placebo, 15.4% for Vorapaxar; hazard ratio: 0.82; 95% confidence interval: 0.72 to 0.93; p = 0.003), with a consistent pattern of efficacy across indication. Conclusions Vorapaxar reduces peripheral revascularization in patients with PAD. This benefit of Vorapaxar is directionally consistent across type of procedure and indication. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2°P - TIMI 50] [P04737]; NCT00526474)

  • atherothrombotic risk stratification and the efficacy and safety of Vorapaxar in patients with stable ischemic heart disease and previous myocardial infarction
    Circulation, 2016
    Co-Authors: Erin A. Bohula, Philip E Aylward, Ramón Corbalán, Marc P. Bonaca, Sabina A Murphy, Eugene Braunwald, Gaetano M De Ferrari, Basil S Lewis, Piera Angelica Merlini, Marc S Sabatine
    Abstract:

    Background —Patients with stable ischemic heart disease and prior MI vary in their risk for recurrent CV events. Atherothrombotic risk assessment may be useful to identify high-risk patients who have the greatest potential for benefit from more intensive secondary preventative therapy such as treatment with Vorapaxar. Methods —We identified independent clinical indicators of atherothrombotic risk among 8,598 stable, placebo-treated patients with a prior MI followed for 2.5 years (median) in TRA 2°P-TIMI 50. The efficacy and safety of Vorapaxar was assessed by baseline risk among patients with prior MI without prior stroke or TIA for whom there is a clinical indication for Vorapaxar. Endpoints were CV death, MI, or ischemic stroke (CVD/MI/iCVA) and GUSTO severe bleeding. Results —The 9 independent risk predictors were age, diabetes, hypertension, smoking, peripheral arterial disease, prior stroke, prior 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 CVD/MI/iCVA and the individual components (p-trend<0.001 for all). High-risk patients (≥3 risk indicators; 20% of population) had a 3.2% absolute risk reduction (ARR) in CVD/MI/iCVA with Vorapaxar and intermediate-risk (1-2; 61%) had a 2.1% ARR (p<0.001 each), translating to a number-needed-to-treat of 31 and 48. Bleeding increased across risk groups (p-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. Conclusions —Stratification of baseline atherothrombotic risk can assist with therapeutic decision-making regarding Vorapaxar use for secondary prevention after MI. Clinical Trial Registration —http://www.clinicaltrials.gov; [NCT00526474][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00526474&atom=%2Fcirculationaha%2Fearly%2F2016%2F07%2F20%2FCIRCULATIONAHA.115.019861.atom

  • Outcomes in Stable Patients With Previous Atherothrombotic Events Receiving Vorapaxar Who Experience a New Acute Coronary Event (from TRA2°P-TIMI 50).
    The American journal of cardiology, 2016
    Co-Authors: David D. Berg, Benjamin M Scirica, Ramón Corbalán, Marc P. Bonaca, Sabina A Murphy, Robert Gabor Kiss, Eugene Braunwald, Shinya Goto, Jindrich Spinar, David A Morrow
    Abstract:

    Vorapaxar is a first-in-class protease-activated receptor-1 antagonist indicated for secondary prevention in stable patients with previous myocardial infarction (MI) or peripheral artery disease and no cerebrovascular disease. Vorapaxar is not recommended for initiation in the acute phase of acute coronary syndromes (ACS) because of an unfavorable balance between bleeding and efficacy when started in that setting. The aim of this analysis was to investigate outcomes in patients who experienced a new ACS while receiving Vorapaxar for long-term secondary prevention. Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic ischemic Events-Thrombolysis In Myocardial Infarction 50 was a randomized, double-blind, placebo-controlled trial of Vorapaxar (n = 26,449). We evaluated bleeding and ischemic events during the acute care of patients with a new ACS during the trial. During a median follow-up of 30 months, 799 patients (8.9%) randomized to Vorapaxar and 913 (10.0%) to placebo had a new ACS event (p = 0.003); 87% and 86%, respectively, were on study therapy at the time of the event. In a landmark analysis through 7 days after ACS, the rates of Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding were 0.8% versus 0.8% (hazard ratio [HR] 0.99, 95% CI 0.33 to 2.94) and GUSTO moderate/severe bleeding were 2.5% versus 1.6% (HR 1.59, 95% CI 0.78 to 3.24) with Vorapaxar versus placebo. The effect of Vorapaxar on cardiovascular death, MI, or stroke (2.4% vs 4.4%; HR 0.54, 95% CI 0.31 to 0.93; p = 0.027) was consistent with the overall trial result. In conclusion, in patients who experience a new ACS event while receiving Vorapaxar for secondary prevention, continuing therapy was associated with favorable efficacy without excess severe bleeding during the period of acute ACS management.

  • the efficacy and safety of Vorapaxar with and without a thienopyridine for secondary prevention in patients with prior myocardial infarction and no history of stroke or tia results from tra 2 p timi 50
    Circulation, 2015
    Co-Authors: Erin A. Bohula, Philip E Aylward, Benjamin M Scirica, Ramón Corbalán, Marc P. Bonaca, Sabina A Murphy, Harvey D White, Robert Gabor Kiss, Eugene Braunwald, David A Morrow
    Abstract:

    Background —Vorapaxar antagonizes protease-activated receptor (PAR)-1, the primary receptor for thrombin on human platelets, and reduces recurrent thrombotic events in stable patients with a prior myocardial infarction (MI). We wished to determine whether the efficacy and safety of antiplatelet therapy with Vorapaxar was modified by concurrent thienopyridine use. Methods and Results —TRA 2°P-TIMI 50 was a randomized, double-blind, placebo-controlled trial of Vorapaxar in 26,449 patients with prior atherothrombosis. This pre-specified 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 TIA 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 when compared to placebo regardless of planned thienopyridine therapy (planned thienopyridine HR 0.80, 0.70-0.91, p<0.001; no planned thienopyridine HR 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). GUSTO moderate or severe bleeding risk was increased with Vorapaxar and was not significantly altered by planned thienopyridine (planned HR 1.50, 1.18-1.89, p<0.001; no planned HR 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 prior MI, whether treated concomitantly with a thienopyridine or not. The relative risk of moderate or severe bleeding was similarly increased irrespective of thienopyridine use. Clinical Trial Registration Information —http://www.clinicaltrials.gov. Identifier: [NCT00526474][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00526474&atom=%2Fcirculationaha%2Fearly%2F2015%2F09%2F03%2FCIRCULATIONAHA.114.015042.atom

  • Efficacy and Safety of Vorapaxar as Approved for Clinical Use in the United States
    Journal of the American Heart Association, 2015
    Co-Authors: Giulia Magnani, Benjamin M Scirica, Marc P. Bonaca, Sabina A Murphy, Eugene Braunwald, Anthony J. Dalby, Ton Oude Ophuis, Jose C Nicolau, Keith A A Fox, Jindrich Spinar
    Abstract:

    Background Vorapaxar is a protease-activated receptor-1 antagonist approved by the U.S. Food and Drug Administration (FDA) for the reduction of thrombotic cardiovascular (CV) events in patients with a history of myocardial infarction (MI) and peripheral artery disease (PAD), without a previous stroke or transient ischemic attack (TIA). Methods and results We examined the efficacy and safety of Vorapaxar in the intended use population, considering 20,170 patients randomized in the multinational, double-blinded, placebo-controlled TRA 2°P-TIMI 50 trial. Of these, 16,897 qualified with a history of MI in the prior 2 weeks to 1 year and 3273 with PAD. At baseline 97% of the patients were treated with aspirin, 71% with a thienopyridine, and 93% a statin. At 3 years, the endpoint of CV death, MI, or stroke was significantly reduced with Vorapaxar compared with placebo (7.9% versus 9.5%, HR, 0.80; 95% CI 0.73 to 0.89; P Conclusions In patients with prior MI or PAD who have not had a previous stroke or TIA, Vorapaxar added to standard therapy is effective for long-term secondary prevention of thrombotic CV events, while increasing moderate or severe bleeding. Clinical trial registration URL: clinicaltrials.gov Unique Identifier: NCT00526474.

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