This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record.
1. Trial at a Glance
TRA 2P-TIMI 50 was a randomized, parallel-group, triple-masked, phase 3 prevention trial comparing vorapaxar with placebo in participants with atherosclerosis and related cardiovascular conditions. The registry reports a primary time-to-event endpoint analyzed with a Cox proportional-hazards model.
| Feature | TRA 2P-TIMI 50 |
|---|---|
| Trial name | TRA 2P-TIMI 50 |
| NCT identifier | NCT00526474 |
| Brief title | 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) |
| Phase | 3 |
| Status | COMPLETED |
| Therapeutic area | Cardiovascular |
| Conditions | Atherosclerosis; Ischemia; Myocardial Infarction; Cerebrovascular Accident; Peripheral Arterial Disease |
| Allocation | RANDOMIZED |
| Design model | PARALLEL |
| Masking | TRIPLE |
| Primary purpose | PREVENTION |
| Enrollment | 26449.0 |
| Interventions | Vorapaxar; Placebo |
| Registered primary endpoints | 1 |
| Outcome measures posted | 32 |
| Statistical analyses posted | 32 |
2. Clinical Question
The primary statistical question was whether vorapaxar was superior to placebo for the time to first occurrence of cardiovascular death, myocardial infarction, stroke, or urgent coronary revascularization within 3 years from randomization.
Population
Participants enrolled in a phase 3 prevention trial involving atherosclerosis, ischemia, myocardial infarction, cerebrovascular accident, and peripheral arterial disease.
Intervention
Vorapaxar.
Comparator
Placebo.
Primary question
Does vorapaxar reduce the hazard of the registered composite cardiovascular endpoint relative to placebo?
3. Trial Design
Participants were randomly assigned to one of two treatment arms.
The two intervention groups were followed as parallel randomized groups.
The registry identifies the study as triple-masked.
The registered primary purpose was prevention.
Study timeline
Study start
The registry lists 2007-09-01 as the study start date.
Primary completion
The registry lists 2011-12-01 as the primary completion date.
COMPLETED
The study is listed as completed, with results posted.
4. Endpoints
Primary endpoint
| Endpoint | Definition / analysis |
|---|---|
| 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 |
Time frame: up to 3 years. The time in days from study start to the first occurrence of CV death, MI, stroke, or UCR was recorded. A Clinical Endpoints Committee reviewed and adjudicated each suspected efficacy endpoint event while blinded to treatment. Participants without an endpoint event until last visit, or participants lost to follow-up without an event, were handled as time-to-event observations. |
Secondary endpoints
The registry contains 15 secondary statistical analyses. All use time-to-event methodology and compare placebo with vorapaxar unless otherwise noted.
| Secondary endpoint | Population | HR (95% CI) | P-value |
|---|---|---|---|
| CV death, MI, or stroke within 3 years | ITT | 0.87 (0.80–0.94) | <0.001 |
| GUSTO moderate or severe bleeding within 3 years | As Treated | 1.51 (1.31–1.74) | <0.001 |
| Clinically significant bleeding within 3 years | As Treated | 1.41 (1.31–1.51) | <0.001 |
| Death from any cause, MI, stroke, or UCR within 3 years | ITT | 0.91 (0.85–0.98) | 0.009 |
| CV death or MI within 3 years | ITT | 0.86 (0.78–0.94) | 0.002 |
| CV death, MI, stroke, UCR, or UH-VCIN within 3 years | ITT | 0.87 (0.81–0.93) | <0.001 |
| Death from any cause, MI, stroke, or any revascularization within 3 years | ITT | 0.91 (0.86–0.96) | 0.001 |
| CV death within 3 years | ITT | 0.89 (0.76–1.04) | 0.151 |
| MI within 3 years | ITT | 0.83 (0.74–0.93) | 0.001 |
| UCR within 3 years | ITT | 0.88 (0.75–1.03) | 0.108 |
| Stroke within 3 years | ITT | 0.97 (0.83–1.14) | 0.733 |
| Death from any cause within 3 years | ITT | 0.95 (0.85–1.07) | 0.411 |
| UH-VCIN within 3 years | ITT | 0.83 (0.74–0.93) | 0.001 |
| Any revascularization within 3 years | ITT | 0.89 (0.83–0.95) | <0.001 |
| All secondary endpoint estimates | Cox proportional-hazards regression with covariates for treatment and stratification factors, unless otherwise specified by the registry population definition. | ||
5. Statistical Methodology
Kaplan-Meier estimation
The primary endpoint is explicitly described as a Kaplan-Meier estimate of the percentage of participants experiencing the event within 3 years. This is appropriate for a time-to-event endpoint because it uses information from participants who have experienced the event as well as participants whose follow-up ends before an event is observed.
Here, di represents the number of events at event time ti, and ni represents the number at risk immediately before that time.
Cox proportional-hazards regression
The registry reports Cox proportional-hazards regression for the primary endpoint and the secondary and post-hoc time-to-event analyses. The corresponding effect measure is a hazard ratio.
For a treatment indicator, the hazard ratio is represented by exp(β). A hazard ratio below 1 corresponds to a lower estimated hazard in the vorapaxar group relative to placebo under the fitted model.
Covariate adjustment and stratification
The registry analysis notes state that the hazard ratio was calculated with covariates for treatment and stratification factors. The registry also identifies covariate adjustment and stratified analysis as concepts in the primary analysis.
Intention-to-treat analysis
The primary endpoint was analyzed in the ITT population, defined by the registry as all participants randomly assigned to a treatment arm. This preserves treatment assignment as the basis of the primary comparison rather than redefining groups according to treatment exposure after randomization.
Superiority hypothesis
The primary analysis is explicitly classified as a superiority hypothesis. The reported confidence interval is two-sided at the 95% level, and the P-value is reported as 0.001.
6. Primary Result
Primary cardiovascular composite endpoint
95% CI 0.82–0.95 · P = 0.001
ITT population · Cox proportional-hazards regression · Superiority
| Element | Reported result |
|---|---|
| Endpoint | CV death, MI, stroke, or UCR within 3 years from randomization |
| Comparison | Placebo vs vorapaxar |
| Analysis population | Intent to Treat (ITT) |
| Method | Cox Proportional Hazards Regression |
| Effect measure | Hazard ratio |
| Estimate | 0.88 |
| 95% CI | 0.82–0.95 |
| P-value | 0.001 |
| Hypothesis | Superiority |
The reported hazard ratio of 0.88 means that, under the fitted Cox model, the estimated instantaneous hazard of the primary composite endpoint was 0.88 times that in the placebo group. Equivalently, 1 − 0.88 = 0.12, so the model-based relative hazard is approximately 12% lower with vorapaxar than with placebo.
The hazard ratio does not mean that exactly 12% of participants avoided an event, nor does it represent a 12-percentage-point difference in event probability. It is a relative time-to-event measure that incorporates the timing of events and censoring.
The 95% confidence interval of 0.82 to 0.95 describes statistical uncertainty around the estimated hazard ratio. Because the interval is entirely below 1, the reported interval is consistent with a lower hazard under the fitted model.
The P-value of 0.001 addresses evidence against the null hypothesis specified for the statistical test. It does not measure the magnitude of the treatment effect, the probability that vorapaxar is effective, or the probability that the null hypothesis is true.
The interpretation also depends on the proportional-hazards framework underlying the Cox model. A single hazard ratio is most straightforward to interpret when the relative hazards are reasonably represented by a common ratio over follow-up. The registry result alone does not provide a separate diagnostic assessment of that assumption.
7. Secondary Results
The registry reports 15 secondary time-to-event analyses. They provide a more detailed decomposition of the cardiovascular outcomes and also include two bleeding endpoints.
| Endpoint | HR | 95% CI | P-value | Population |
|---|---|---|---|---|
| CV death, MI, or stroke | 0.87 | 0.80–0.94 | <0.001 | ITT |
| GUSTO moderate or severe bleeding | 1.51 | 1.31–1.74 | <0.001 | As Treated |
| Clinically significant bleeding | 1.41 | 1.31–1.51 | <0.001 | As Treated |
| Death, MI, stroke, or UCR | 0.91 | 0.85–0.98 | 0.009 | ITT |
| CV death or MI | 0.86 | 0.78–0.94 | 0.002 | ITT |
| CV death, MI, stroke, UCR, or UH-VCIN | 0.87 | 0.81–0.93 | <0.001 | ITT |
| Death, MI, stroke, or any revascularization | 0.91 | 0.86–0.96 | 0.001 | ITT |
| CV death | 0.89 | 0.76–1.04 | 0.151 | ITT |
| MI | 0.83 | 0.74–0.93 | 0.001 | ITT |
| UCR | 0.88 | 0.75–1.03 | 0.108 | ITT |
| Stroke | 0.97 | 0.83–1.14 | 0.733 | ITT |
| Death from any cause | 0.95 | 0.85–1.07 | 0.411 | ITT |
| UH-VCIN | 0.83 | 0.74–0.93 | 0.001 | ITT |
| Any revascularization | 0.89 | 0.83–0.95 | <0.001 | ITT |
The secondary results show why composite endpoints should be examined component by component. Several cardiovascular composites have hazard ratios below 1, while individual endpoints such as CV death, UCR, stroke, and death from any cause have confidence intervals that include 1. The individual components therefore do not all reproduce the same statistical pattern as the primary composite.
The bleeding endpoints point in the opposite direction: the reported hazard ratios are 1.51 for GUSTO moderate or severe bleeding and 1.41 for clinically significant bleeding. A hazard ratio above 1 indicates a higher estimated hazard in the vorapaxar group relative to placebo for these endpoints.
These secondary P-values should not automatically be interpreted as though every endpoint represented an independent confirmatory hypothesis with a separate type I error budget. The ClinicalTrials.gov record identifies the analyses as superiority analyses but do not provide a multiplicity-adjustment framework for this set of secondary comparisons.
8. Safety
The registry supplies serious adverse-event counts by treatment arm:
| Arm | Serious adverse events affected / at risk |
|---|---|
| Placebo | 3419 / 13166 |
| Vorapaxar | 3514 / 13186 |
The registry also includes bleeding as a secondary time-to-event outcome. GUSTO moderate or severe bleeding had a hazard ratio of 1.51 (95% CI 1.31–1.74; P <0.001), while clinically significant bleeding had a hazard ratio of 1.41 (95% CI 1.31–1.51; P <0.001), both in the As Treated population.
9. Post-Hoc Analyses
The registry reports 16 post-hoc statistical analyses. These analyses include an intended label population consisting of all enrolled participants with coronary arterial disease (CAD) or peripheral arterial disease (PAD) and no history of stroke or transient ischemic attack (TIA), as well as an intended label safety population with the same CAD/PAD and no-stroke/TIA criteria who received at least 1 dose of study drug.
| Post-hoc endpoint | Population | HR | 95% CI | P-value |
|---|---|---|---|---|
| CV death, MI, stroke, or UCR | Intended Label Population | 0.83 | 0.76–0.90 | <0.001 |
| CV death, MI, or stroke | Intended Label Population | 0.80 | 0.73–0.89 | <0.001 |
| GUSTO moderate or severe bleeding | Intended Label Safety Population | 1.45 | 1.23–1.71 | <0.001 |
| Clinically significant bleeding | Intended Label Safety Population | 1.42 | 1.31–1.54 | <0.001 |
| Death, MI, stroke, or UCR | Intended Label Population | 0.86 | 0.79–0.93 | <0.001 |
| CV death or MI | Intended Label Population | 0.83 | 0.75–0.93 | <0.001 |
| CV death, MI, stroke, UCR, or UH-VCIN | Intended Label Population | 0.83 | 0.77–0.90 | <0.001 |
| Death, MI, stroke, or any revascularization | Intended Label Population | 0.89 | 0.83–0.95 | <0.001 |
| CV death, intended label population | Intended Label Population | 0.86 | 0.71–1.03 | 0.108 |
| MI | Intended Label Population | 0.82 | 0.73–0.93 | 0.002 |
| UCR | Intended Label Population | 0.88 | 0.74–1.04 | 0.127 |
| Stroke | Intended Label Population | 0.67 | 0.52–0.87 | 0.002 |
| Death from any cause | Intended Label Population | 0.92 | 0.80–1.06 | 0.249 |
| UH-VCIN | Intended Label Population | 0.86 | 0.76–0.98 | 0.019 |
| Any revascularization | Intended Label Population | 0.89 | 0.83–0.96 | 0.003 |
All post-hoc analyses use Cox proportional-hazards regression with treatment and stratification-factor covariates or the corresponding registry-described covariate adjustment. The endpoint time frame is up to 3 years for each analysis.
10. Important Registry Caveat: Stroke
The registry contains an important study-level caveat: prior to completion of the study, based on a communication from the Data and Safety Monitoring Board, all participants who had experienced a stroke either before or during the study had study drug discontinued.
11. Statistical Methods Explained
Why was a Cox proportional-hazards model used?
The endpoints in this registry record are time-to-event outcomes. A Cox model is designed to compare event hazards between groups while incorporating the timing of events and censoring. The TRA 2P-TIMI 50 registry analyses explicitly report Cox proportional-hazards regression.
What does a hazard ratio of 0.88 mean?
A hazard ratio of 0.88 means the estimated instantaneous hazard in the vorapaxar group is 0.88 times the corresponding hazard in the placebo group under the fitted model. It does not mean that 12% fewer participants necessarily experienced the endpoint.
Why is the Kaplan-Meier method paired with the Cox model?
They answer related but different questions. Kaplan-Meier estimation describes the event-free survival pattern over time, whereas the Cox model provides a relative hazard measure comparing treatment groups. Using both provides complementary information about the time-to-event distribution.
Why does the analysis population matter?
The primary endpoint uses the ITT population, preserving randomized assignment. The bleeding endpoints use the As Treated population, consisting of participants who received at least 1 dose. These populations answer different questions and should not be conflated.
What does the 95% confidence interval tell us?
The 95% confidence interval quantifies uncertainty around the estimated hazard ratio under the statistical model and sampling framework. A narrow interval indicates greater precision than a wider interval, but the interval is not a range containing the individual treatment effects experienced by patients.
Why does a P-value not measure effect size?
A P-value measures the compatibility of the observed data with a specified null hypothesis under the statistical testing framework. It depends on both the estimated effect and the amount of information in the data. Effect size is described by the hazard ratio and its confidence interval, not by the P-value alone.
What should be considered when interpreting many secondary and post-hoc P-values?
Multiple statistical tests create opportunities for apparently small P-values to occur by chance even when individual null hypotheses are true. The ClinicalTrials.gov record identifies the hypothesis type as superiority but do not specify a complete multiplicity-adjustment strategy for all secondary and post-hoc analyses. These results should therefore be interpreted in the context of the primary endpoint and the overall analysis plan.
12. Interpreting the Primary Hazard Ratio
The primary HR of 0.88 corresponds to an estimated hazard approximately 12% lower in the vorapaxar group relative to placebo, because 1 − 0.88 = 0.12.
The 95% CI of 0.82–0.95 indicates that the reported estimate is accompanied by uncertainty, while the entire interval remains below 1.
The HR is not an absolute risk reduction, a number needed to treat, a probability of individual benefit, or a statement that all patients experience the same relative reduction in event hazard.
The HR is generated by a Cox proportional-hazards model. Its interpretation therefore depends on the model framework, including the proportional-hazards assumption and the handling of censoring.
13. Comparing Efficacy and Bleeding Endpoints
| Endpoint class | Hazard ratio | 95% CI | Interpretive direction |
|---|---|---|---|
| Primary CV death / MI / stroke / UCR | 0.88 | 0.82–0.95 | HR below 1 favors lower event hazard with vorapaxar |
| CV death / MI / stroke | 0.87 | 0.80–0.94 | HR below 1 |
| MI | 0.83 | 0.74–0.93 | HR below 1 |
| Stroke | 0.97 | 0.83–1.14 | CI includes 1 |
| Death from any cause | 0.95 | 0.85–1.07 | CI includes 1 |
| GUSTO moderate or severe bleeding | 1.51 | 1.31–1.74 | HR above 1 |
| Clinically significant bleeding | 1.41 | 1.31–1.51 | HR above 1 |
This table illustrates an important feature of clinical-trial interpretation: different endpoints can move in different directions. A statistical analysis should therefore preserve the endpoint definitions rather than collapsing efficacy and safety into a single undifferentiated conclusion.
14. Why This Trial Matters Statistically
TRA 2P-TIMI 50 is a useful teaching case because the registry combines randomized treatment assignment with a large set of time-to-event outcomes, covariate-adjusted Cox models, stratified analyses, ITT efficacy analyses, As Treated safety analyses, and post-hoc population definitions.
| Concept | How it appears in TRA 2P-TIMI 50 |
|---|---|
| Randomization | Participants were randomly assigned to vorapaxar or placebo. |
| Triple masking | The registry classifies the study as triple-masked. |
| Parallel design | The registry classifies the design model as PARALLEL. |
| Kaplan-Meier estimation | The primary and secondary endpoint definitions are expressed as Kaplan-Meier estimates. |
| Cox proportional-hazards model | The registry reports Cox proportional-hazards regression for the statistical analyses. |
| Hazard ratio | The primary and other time-to-event analyses use hazard ratios as the effect measure. |
| Confidence intervals | The primary and posted analyses include two-sided 95% confidence intervals. |
| ITT analysis | The primary endpoint is analyzed in the ITT population. |
| As Treated analysis | The two bleeding secondary endpoints use the As Treated population. |
| Covariate adjustment | The registry analysis notes describe adjustment for treatment and stratification factors. |
| Stratified analysis | Stratified analysis is identified as an analysis concept in the registry. |
| Superiority testing | The primary and posted analyses are classified under a superiority hypothesis. |
| Post-hoc analysis | Sixteen post-hoc time-to-event analyses are posted. |
| Safety analysis | Serious adverse events are reported by treatment arm, alongside time-to-event bleeding analyses. |
15. Limitations
- Composite endpoint interpretation: the primary endpoint combines CV death, MI, stroke, and UCR. A statistically significant composite does not imply that every component has the same magnitude or direction of effect.
- Component endpoints differ: the ClinicalTrials.gov record shows different estimates for CV death, MI, stroke, and UCR. Individual components therefore require their own interpretation.
- Bleeding is a distinct endpoint: the reported bleeding hazard ratios are above 1, illustrating why efficacy and safety outcomes should be evaluated separately.
- ITT versus As Treated: the primary efficacy endpoint and bleeding endpoints use different analysis populations.
- Post-hoc analyses: post-hoc results are not equivalent to a prespecified primary endpoint and should be interpreted accordingly.
- Multiplicity: the ClinicalTrials.gov record does not specify a complete multiplicity-adjustment strategy for all secondary and post-hoc comparisons.
- Proportional hazards: the Cox hazard ratio is model-based and relies on the proportional-hazards framework. The ClinicalTrials.gov record does not provide a separate diagnostic assessment of that assumption.
- Stroke-related treatment discontinuation: the registry notes that all participants who experienced stroke before or during the study had study drug discontinued following communication from the Data and Safety Monitoring Board.
- Serious adverse events: affected/at-risk counts should not be interpreted as time-to-event rates because the registry also provides separate Cox analyses for bleeding outcomes.
16. A Statistical Reading of the Complete Results
The primary result is a Cox-model hazard ratio of 0.88 with a two-sided 95% CI of 0.82–0.95 and P = 0.001 for the composite of CV death, MI, stroke, or UCR within 3 years. The corresponding analysis is based on the ITT population and adjusts for treatment and stratification factors.
The secondary cardiovascular endpoints generally report hazard ratios below 1, including 0.87 for CV death, MI, or stroke; 0.86 for CV death or MI; 0.83 for MI; 0.83 for UH-VCIN; and 0.89 for any revascularization. At the same time, some individual outcomes have confidence intervals that include 1, including CV death, UCR, stroke, and death from any cause.
The bleeding analyses provide an important counterpoint. GUSTO moderate or severe bleeding has an HR of 1.51 and clinically significant bleeding has an HR of 1.41, both with P <0.001. Thus, the registry contains efficacy and safety endpoints with different estimated hazard directions.
The post-hoc analyses narrow the population for several cardiovascular endpoints to participants with CAD or PAD and no history of stroke or TIA. Within those analyses, the registry reports HRs of 0.83 for the primary composite, 0.80 for CV death, MI, or stroke, and 0.67 for stroke, among other results. Because these analyses are post-hoc, their statistical role should remain distinct from that of the prespecified primary analysis.
17. Related Tutorials
Learn more about the methods used in this trial:
18. Related Calculators
19. Sources
- ClinicalTrials.gov: TRA 2P-TIMI 50 — NCT00526474.
- PubMed: PMID 35224730.
- PubMed: PMID 33884889.
- PubMed: PMID 32000630.
- PubMed: PMID 31642690.
- PubMed: PMID 27765312.
Continue through the Clinical Biostats statistical pathway
Use the trial's methods as a starting point for deeper study of survival analysis, hazard ratios, randomized clinical-trial design, and statistical inference.
20. Record Summary
TRA 2P-TIMI 50 provides a detailed example of time-to-event analysis in a large randomized cardiovascular prevention trial. The registry reports a primary composite endpoint analyzed with a covariate-adjusted Cox proportional-hazards model in the ITT population, with a hazard ratio of 0.88, a two-sided 95% confidence interval of 0.82–0.95, and P = 0.001.
The broader registry results illustrate several important statistical principles: composite endpoints must be interpreted alongside their components; efficacy and safety can show different hazard directions; ITT and As Treated populations answer different questions; confidence intervals provide information about precision that P-values do not; and post-hoc analyses should remain clearly separated from prespecified primary analyses.