NCT00526474

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)

Completed Phase 3 Results posted Last updated 21 September 2018

What this trial tests

Phase 3 trial testing Vorapaxar in Atherosclerosis in 26,449 participants. Completed in 1 December 2011.

Timeline

1 September 2007

Primary endpoint
1 December 2011

1 December 2011

Quick facts

Lead sponsor	Merck Sharp & Dohme LLC
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	triple
Primary purpose	prevention
Enrollment	26,449
Start date	1 September 2007
Primary completion	1 December 2011
Estimated completion	1 December 2011

Drugs / interventions tested

• Vorapaxar (VORAPAXAR) — full drug profile →
• Placebo

Conditions studied

• Atherosclerosis — all drugs for Atherosclerosis →
• Ischemia — all drugs for Ischemia →
• Myocardial Infarction — all drugs for Myocardial Infarction →
• Cerebrovascular Accident — all drugs for Cerebrovascular Accident →

Sponsor

Merck Sharp & Dohme LLC — full company profile →

Who can join

18 and older, any sex, with Atherosclerosis or Ischemia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Kaplan-Meier Estimate of the Percentage of Participants Who Experienced Cardiovascular (CV) Death, Myocardial Infarction (MI), Stroke, or Urgent Coronary Revascularization (UCR) Within 3 Years From Randomization Primary · up to 3 years

The time (in days) from study start to the first occurrence of any of the following clinical outcomes was recorded: CV death, MI, stroke, or UCR. A Clinical Endpoints Committee (CEC) reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of

Group	Value	95% CI
Placebo	12.4
Vorapaxar	11.2

Kaplan-Meier Estimate of the Percentage of Participants Who Experienced CV Death, MI, or Stroke Within 3 Years From Randomization Secondary · up to 3 years

The time (in days) from study start to the first occurrence of any of the following clinical outcomes was recorded: CV death, MI, or stroke. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate re

Group	Value	95% CI
Placebo	10.5
Vorapaxar	9.3

Kaplan-Meier Estimate of the Percentage of Participants Who Met Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) Moderate or Severe Bleeding Criteria Within 3 Years From Randomization Secondary · up to 3 years

Adverse events were categorized as "bleeding events" if the intensity, frequency, or type of the event was other or more than would be normally expected in the given situation (eg, mild nosebleed in a person who does not normally have nosebleeds, greater bruising than expected for a given injury, greater volume of blood loss than expected for a given procedure). The investigator graded the intensity of bleeding events according to the GUSTO cooperative group criteria as follows: Mild , Moderate or Severe and the grading was adjudicated by the CEC. The Kaplan-Meier estimate reports the percenta

Group	Value	95% CI
Placebo	2.9
Vorapaxar	4.2

Kaplan-Meier Estimate of the Percentage of Participants Who Experienced Clinically Significant Bleeding Within 3 Years From Randomization Secondary · up to 3 years

Adverse events were categorized as "bleeding events" if the intensity, frequency, or type of the event was other or more than would be normally expected in the given situation (eg, mild nosebleed in a person who does not normally have nosebleeds, greater bruising than expected for a given injury, greater volume of blood loss than expected for a given procedure). The investigator graded the intensity of bleeding events according to the Thrombolysis in Myocardial Infarction (TIMI) Study Group criteria as major, minor or other. "Clinically Significant Bleeding" was defined as the composite of TIM

Group	Value	95% CI
Placebo	11.3
Vorapaxar	15.4

Kaplan-Meier Estimate of the Percentage of Participants Who Experienced Death From Any Cause, MI, Stroke, or UCR Within 3 Years From Randomization Secondary · up to 3 years

The time (in days) from study start to the occurrence of any of the following clinical outcomes was recorded: death from any cause, MI, stroke, or UCR. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who experienced death from any cause, MI, stroke, or UCR within 3 years from random

Group	Value	95% CI
Placebo	14.2
Vorapaxar	13.2

Kaplan-Meier Estimate of the Percentage of Participants Who Experienced CV Death or an MI Within 3 Years From Randomization Secondary · up to 3 years

The time (in days) from study start to the occurrence of CV death or MI. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate reports the percentage of participants who experienced CV death or MI

Group	Value	95% CI
Placebo	8.2
Vorapaxar	7.3

Kaplan-Meier Estimate of the Percentage of Participants Who Experienced CV Death, MI, Stroke, UCR, or Urgent Hospitalization for Vascular Cause of Ischemic Nature (UH-VCIN) Within 3 Years From Randomization Secondary · up to 3 years

The time (in days) from study start to the first occurrence of any of the following clinical outcomes was recorded: CV death, MI, stroke, UCR or UH-VCIN. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meie

Group	Value	95% CI
Placebo	14.7
Vorapaxar	13.1

Kaplan-Meier Estimate of the Percentage of Participants Who Died From Any Cause, or Experienced an MI, Stroke, or Any Revascularization Within 3 Years From Randomization Secondary · up to 3 years

The time (in days) from study start to death from any cause or the first occurrence of any of the following clinical outcomes was recorded: MI, stroke, or any revascularization procedure . A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). The Kaplan-Meier estimate reports the percentage of participants who died from any cause, or experienced an MI,

Group	Value	95% CI
Placebo	22.6
Vorapaxar	20.7

Kaplan-Meier Estimate of the Percentage of Participants Who Experienced CV Death, MI, Stroke, Any Revascularization, or UH-VCIN Within 3 Years From Randomization Secondary · up to 3 years

The time (in days) from study start to the first occurrence of any of the following clinical outcomes was recorded: CV death, MI, stroke, any revascularization, or UH-VCIN. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of dea

Group	Value	95% CI
Placebo	22.1
Vorapaxar	19.9

Kaplan-Meier Estimate of the Percentage of Participants Who Experienced CV Death Within 3 Years From Randomization Secondary · up to 3 years

The time (in days) from study start to CV death (if reported) was recorded. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate reports the percentage of participants who experienced CV death wit

Group	Value	95% CI
Placebo	3.0
Vorapaxar	2.7

Kaplan-Meier Estimate of the Percentage of Participants Who Experienced an MI Within 3 Years From Randomization Secondary · up to 3 years

The time (in days) from study start to the first occurrence of an MI was recorded. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate reports the percentage of participants who experienced an MI

Group	Value	95% CI
Placebo	6.1
Vorapaxar	5.2

Kaplan-Meier Estimate of the Percentage of Participants Who Experienced UCR Within 3 Years From Randomization Secondary · up to 3 years

The time (in days) from study start to the first occurrence of UCR was recorded. A CEC reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants who did not have any endpoint event until last visit or participants who were lost to follow-up and had no event were censored at the time of last available information (last study visit). If a participant had a fatal event that was not part of a specific endpoint for analysis, they were censored at the time of death. The Kaplan-Meier estimate reports the percentage of participants who experienced UCR wit

Group	Value	95% CI
Placebo	2.6
Vorapaxar	2.5

Adverse events — posted to ClinicalTrials.gov

Time frame: up to 3 years. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo

Serious: 3419/13166 (26%)

Deaths: —

Vorapaxar

Serious: 3514/13186 (27%)

Deaths: —

Serious adverse events (1476 terms)

Reaction	System	Placebo	Vorapaxar
NON-CARDIAC CHEST PAIN	General disorders	—	—
PNEUMONIA	Infections and infestations	—	—
CARDIAC FAILURE	Cardiac disorders	—	—
ATRIAL FIBRILLATION	Cardiac disorders	—	—
CARDIAC FAILURE CONGESTIVE	Cardiac disorders	—	—
OSTEOARTHRITIS	Musculoskeletal and connective tissue disorders	—	—
SYNCOPE	Nervous system disorders	—	—
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	Respiratory, thoracic and mediastinal disorders	—	—
HAEMORRHAGE INTRACRANIAL	Nervous system disorders	—	—
MELAENA	Gastrointestinal disorders	—	—
HAEMATURIA	Renal and urinary disorders	—	—
GASTROINTESTINAL HAEMORRHAGE	Gastrointestinal disorders	—	—
URINARY TRACT INFECTION	Infections and infestations	—	—
PROSTATE CANCER	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
RENAL FAILURE ACUTE	Renal and urinary disorders	—	—
RECTAL HAEMORRHAGE	Gastrointestinal disorders	—	—
ANAEMIA	Blood and lymphatic system disorders	—	—
PULMONARY EMBOLISM	Respiratory, thoracic and mediastinal disorders	—	—
INGUINAL HERNIA	Gastrointestinal disorders	—	—
CHOLELITHIASIS	Hepatobiliary disorders	—	—
CELLULITIS	Infections and infestations	—	—
MUSCULOSKELETAL CHEST PAIN	Musculoskeletal and connective tissue disorders	—	—
RENAL FAILURE	Renal and urinary disorders	—	—
POST PROCEDURAL HAEMORRHAGE	Injury, poisoning and procedural complications	—	—
VENTRICULAR TACHYCARDIA	Cardiac disorders	—	—

Other adverse events (4 terms — click to expand)

Reaction	System	Placebo	Vorapaxar
EPISTAXIS	Respiratory, thoracic and mediastinal disorders	—	—
HYPERTENSION	Vascular disorders	—	—
DIZZINESS	Nervous system disorders	—	—
CHEST PAIN	General disorders	—	—

Most-reported serious reactions: NON-CARDIAC CHEST PAIN, PNEUMONIA, CARDIAC FAILURE, ATRIAL FIBRILLATION, CARDIAC FAILURE CONGESTIVE, OSTEOARTHRITIS, SYNCOPE, CHRONIC OBSTRUCTIVE PULMONARY DISEASE.

Data from ClinicalTrials.gov NCT00526474 adverse events section.

Sponsor's own description

The study is designed to determine whether vorapaxar, when added to the existing standard of care (SOC) for preventing heart attack and stroke (eg, aspirin, clopidogrel) in participants with a known history of atherosclerosis, will yield additional benefit over the existing standard of care without vorapaxar in preventing heart attack and stroke.

The study is also designed to assess risk of bleeding with vorapaxar added to the standard of care versus the standard of care alone.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Vorapaxar in the secondary prevention of atherothrombotic events.
   Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, et al · · 2012 · cited 670× · PMID 22443427 · DOI 10.1056/nejmoa1200933
2. Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases.
   Heuberger DM, Schuepbach RA. · · 2019 · cited 274× · PMID 30976204 · DOI 10.1186/s12959-019-0194-8
3. 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.
   Scirica BM, Bonaca MP, Braunwald E, De Ferrari GM, et al · · 2012 · cited 163× · PMID 22932716 · DOI 10.1016/s0140-6736(12)61269-0
4. Platelet thrombin receptor antagonism and atherothrombosis.
   Angiolillo DJ, Capodanno D, Goto S. · · 2010 · cited 159× · PMID 19948715 · DOI 10.1093/eurheartj/ehp504
5. Atherothrombotic Risk Stratification and the Efficacy and Safety of Vorapaxar in Patients With Stable Ischemic Heart Disease and Previous Myocardial Infarction.
   Bohula EA, Bonaca MP, Braunwald E, Aylward PE, et al · · 2016 · cited 128× · PMID 27440003 · DOI 10.1161/circulationaha.115.019861
6. Acute Limb Ischemia and Outcomes With Vorapaxar in Patients With Peripheral Artery Disease: Results From the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50).
   Bonaca MP, Gutierrez JA, Creager MA, Scirica BM, et al · · 2016 · cited 126× · PMID 26826179 · DOI 10.1161/circulationaha.115.019355
7. Procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention?
   Chambers RC. · · 2008 · cited 123× · PMID 18223674 · DOI 10.1038/sj.bjp.0707603
8. Targeting PAR1: Now What?
   Flaumenhaft R, De Ceunynck K. · · 2017 · cited 73× · PMID 28558960 · DOI 10.1016/j.tips.2017.05.001