Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial

doi:10.1016/S0140-6736(12)61269-0

The Lancet

Volume 380, Issue 9850, 13–19 October 2012, Pages 1317-1324

https://doi.org/10.1016/S0140-6736(12)61269-0 Get rights and content

Summary

Background

Vorapaxar inhibits platelet activation by antagonising thrombin-mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial.

Methods

In TRA 2°P-TIMI 50—a randomised, placebo-controlled, parallel trial—we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2·5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2°P-TIMI 50 is registered at ClinicalTrials.gov (NCT00526474).

Findings

17 779 of 26 449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 to placebo). Median follow-up was 2·5 years (IQR 2·0–2·9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in the placebo group (3-year Kaplan-Meier estimates 8·1% vs 9·7%, HR 0·80, 95% CI 0·72–0·89; p<0·0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 [3·4%, 3-year Kaplan-Meier estimate] vs 151/8849 [2·1%, 3-year Kaplan-Meier estimate], HR 1·61, 95% CI 1·31–1·97; p<0·0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0·6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0·4%, 3-year Kaplan-Meier estimate) with placebo (p=0·076). Other serious adverse events were equally distributed between groups.

Interpretation

For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding.

Funding

Merck.

Introduction

Despite treatments for secondary prevention, patients with a history of myocardial infarction are at substantial risk of recurrent thrombotic events.¹ Platelets have a central role in coronary thrombosis and are an important target for drug treatment. Inhibition of platelets with P2Y12 inhibitors added to aspirin for up to a year after myocardial infarction reduces recurrent thrombotic events but increases bleeding.2, 3, 4 However, the benefit of treatment with antiplatelet therapy in addition to aspirin for long-term secondary prevention has not been established.⁵

Protease-activated receptor 1 is the main receptor for thrombin on human platelets. We reported⁶ the efficacy and safety of vorapaxar—a potent and selective antagonist of protease-activated receptor 1—for a broad group of patients with a history of atherothrombosis in the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial (NCT00526474). For 26 449 patients with a history of myocardial infarction, ischaemic stroke, or peripheral arterial disease, vorapaxar reduced the risk of cardiovascular death, myocardial infarction, or stoke by 13% (p<0·001) and increased the risk of moderate or severe bleeding by 66% (p<0·001). On the basis of studies suggesting different benefits of long-term antiplatelet therapy for patients with myocardial infarction⁷ compared with patients with stroke and peripheral arterial disease;8, 9, 10 we planned an analysis of the subgroup with myocardial infarction. Here we report the efficacy and safety of vorapaxar in addition to standard therapy for secondary prevention of thrombotic events for patients with a previous myocardial infarction. We also report results of a post-hoc test of criteria developed in a previous clinical trial for identification of patients who have the best potential of net clinical benefit with potent antiplatelet treatment.3, 11

Section snippets

Patients

TRA 2°P-TIMI 50 was a multinational, double-blind, randomised, placebo-controlled trial.6, 12 Between September, 2007, and November, 2009, patients with a history of atherothrombosis were assigned to treatment. Patients were enrolled on the basis of myocardial infarction if they had had a spontaneous myocardial infarction within the previous 2 weeks to 12 months. Patients were ineligible if they had a revascularisation procedure that was planned but not yet done, a history of bleeding

Results

17 779 of 26 449 patients (67% of the total trial population) qualified on the basis of previous myocardial infarction and were assigned to receive either vorapaxar or placebo (figure 1). Table 1 shows baseline characteristics. The qualifying previous myocardial infarction was ST elevation in 9248 (52%) patients, non-ST elevation in 7375 (41%), and of unknown type in 1156 (7%) patients. 15 278 (86%) patients had a history of any coronary revascularisation, of whom 12 636 (83%) had had

Discussion

In contrast to treatment of patients with an acute coronary syndrome, a benefit of antiplatelet therapy additional to aspirin for secondary prevention of thrombotic events has not previously been established in stable patients with a history of myocardial infarction (panel).⁵ On the basis of randomised trials,2, 3, 4 current treatment guidelines recommend that treatment with aspirin and P2Y12 inhibitors continues for 1 year after an acute coronary syndrome.15, 16, 17, 18 The benefit of

References (22)

DL Bhatt et al.
Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial
J Am Coll Cardiol
(2007)
HC Diener et al.
Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial
Lancet
(2004)
SD Wiviott et al.
Efficacy and safety of intensive antiplatelet therapy with prasugrel from TRITON-TIMI 38 in a core clinical cohort defined by worldwide regulatory agencies
Am J Cardiol
(2011)
CP Cannon et al.
American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. A report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee)
J Am Coll Cardiol
(2001)
RS Wright et al.
2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons
J Am Coll Cardiol
(2011)
EM Antman et al.
Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis
J Am Coll Cardiol
(2008)
PG Steg et al.
One-year cardiovascular event rates in outpatients with atherothrombosis
JAMA
(2007)
S Yusuf et al.
Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation
N Engl J Med
(2001)
SD Wiviott et al.
Prasugrel versus clopidogrel in patients with acute coronary syndromes
N Engl J Med
(2007)
L Wallentin et al.
Ticagrelor versus clopidogrel in patients with acute coronary syndromes
N Engl J Med
(2009)

DL Bhatt et al.

Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events

N Engl J Med

(2006)

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Acute Coronary Syndrome (ACS) is a term that describes pathologies related to myocardial ischemia, and is comprised of unstable angina, non-ST elevation myocardial infarction, and ST elevation myocardial infarction. Urgent management of ACS is typically necessary to prevent future morbidity and mortality. Current medical recommendations of ACS management involve use of dual antiplatelet therapy, typically with aspirin and clopidogrel. However, newer therapies are being designed and researched to improve outcomes for patients with ACS. Vorapaxar is a novel antiplatelet therapy that inhibits thrombin-mediated platelet aggregation to prevent recurrence of ischemic events. It has been Food and Drug Administration approved for reduction of thrombotic cardiovascular events in patients with a history of MI or peripheral arterial disease with concomitant use of clopidogrel and/or aspirin, based upon the findings of the TRA 2°P–TIMI 50 trial. However, Vorapaxar was also found to have a significantly increased risk of bleeding, which must be considered when administering this drug. Based upon further subgroup analysis of both the TRA 2°P–TIMI 50 trial and TRACER trial, Vorapaxar was found to be potentially beneficial in patients with peripheral artery disease, coronary artery bypass grafting, and ischemic stroke. There are current trials in progress that are further evaluating the use of Vorapaxar in those conditions, and future research and trials are necessary to fully determine the utility of this drug.
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Neutrophils extensively infiltrate maternal blood vessels in preeclampsia. This could explain why multiple organs are affected in this enigmatic disorder. Lipid peroxides produced by the placenta are probably the first factors that activate neutrophils as they circulate through the intervillous space, but then a second factor specific to pregnancy comes into play, protease-activated receptor 1. The only time neutrophils express protease-activated receptor 1 is during pregnancy. This means that neutrophils can be activated by a mechanism specific to pregnancy, that is, by proteases. Two proteases that are elevated in preeclampsia and activate protease-activated receptor 1 are matrix metalloproteinase-1 and neutrophil elastase. There is an 8-fold increase in vascular protease-activated receptor 1 expression in women with preeclampsia, and protease-activated receptor 1 is also expressed on the placenta, a pregnancy-specific tissue.
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ArticlesVorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients

Results

Discussion

J Am Coll Cardiol

Lancet

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

One-year cardiovascular event rates in outpatients with atherothrombosis

JAMA

Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation

N Engl J Med

Prasugrel versus clopidogrel in patients with acute coronary syndromes

N Engl J Med

Ticagrelor versus clopidogrel in patients with acute coronary syndromes

N Engl J Med

Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events

N Engl J Med

Articles
Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial