This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. The numerical results presented here are restricted to the VESALIUS-CV ClinicalTrials.gov record.
1. Trial at a Glance
VESALIUS-CV was a randomized, quadruple-masked, parallel-group phase 3 trial evaluating evolocumab versus placebo in patients at high cardiovascular risk without prior myocardial infarction or stroke and with coronary heart disease. The registry reports 12301 enrolled participants and two primary time-to-event endpoints.
| Feature | VESALIUS-CV |
|---|---|
| Trial name | VESALIUS-CV |
| Phase | Phase 3 |
| Condition | Coronary Heart Disease (CHD) |
| Population | Patients at high cardiovascular risk without prior myocardial infarction or stroke |
| Design | Randomized, parallel, quadruple-masked |
| Allocation | Randomized |
| Primary purpose | Treatment |
| Enrollment | 12301 |
| Interventions | Evolocumab; placebo |
| Primary endpoints | Two binary registry endpoints analyzed as time-to-event outcomes |
| Results | Posted on ClinicalTrials.gov |
| ClinicalTrials.gov | NCT03872401 |
2. Clinical Question
The trial addresses whether evolocumab changes the time to first occurrence of major cardiovascular events in patients at high cardiovascular risk without prior myocardial infarction or stroke who were receiving optimized lipid lowering therapy.
Population
Patients at high cardiovascular risk without prior myocardial infarction or stroke and with coronary heart disease.
Intervention
Evolocumab 140 mg Q2W.
Comparator
Placebo Q2W.
Primary question
Does evolocumab reduce the hazard of experiencing the prespecified first cardiovascular event compared with placebo?
3. Trial Design
Placebo Q2W
- Placebo administered every two weeks.
- Comparator group for the randomized efficacy analyses.
Evolocumab 140 mg Q2W
- Evolocumab 140 mg administered every two weeks.
- Intervention group for the randomized efficacy analyses.
4. Endpoints
The registry lists two primary endpoints. Although the registered endpoint wording is expressed as the number of participants who experienced an event, the posted statistical analyses treat these outcomes as time-to-event endpoints using a log-rank test and a hazard ratio.
| Primary endpoint | Registered time frame | Statistical treatment |
|---|---|---|
| Number of Participants Who Experienced Coronary Heart Disease (CHD) Death, Myocardial Infarction (MI), or Ischemic Stroke, Whichever Occurred First | From enrollment to last confirmed survival status date; median (min, max) time on trial was 55.2 (0.0, 72.7) months | Time-to-event; stratified log-rank test; hazard ratio from a stratified Cox model |
| Number of Participants Who Experienced CHD Death, MI, Ischemic Stroke, or Any Ischemia-driven Arterial Revascularization, Whichever Occurred First | From enrollment to last confirmed survival status date; median (min, max) time on trial was 55.2 (0.0, 72.7) months | Time-to-event; stratified log-rank test; hazard ratio from a stratified Cox model |
Endpoint adjudication
The registry states that all deaths and individual components were adjudicated by an independent external clinical events committee (CEC), using standardized definitions. This is important because composite cardiovascular endpoints depend on consistent classification of each component event.
5. Statistical Methodology
Full analysis set
The primary efficacy analyses used the full analysis set (FAS), which included all randomized participants. Participants were analyzed according to their randomized treatment assignment. This preserves the treatment comparison created by randomization rather than redefining treatment groups according to what participants subsequently received.
Time-to-event analysis
The registry identifies the primary and posted secondary analyses as time-to-event analyses. The analysis therefore considers not only whether an event occurred, but also when the first qualifying event occurred during follow-up.
Participants who do not experience the event during observable follow-up can contribute information until their last confirmed survival status date. This is one reason survival-analysis methods are appropriate for long follow-up with incomplete event observation.
Stratified log-rank test
The primary analyses used a 2-sided log-rank test stratified by randomization factors collected via interactive voice and web response systems (IVRS/IWRS). Stratification allows the treatment comparison to account for the randomization strata rather than treating the entire randomized population as an unstratified sample.
Stratified Cox model
The hazard ratio was based on a Cox model stratified by the randomization stratification factors collected via IVRS/IWRS. The Cox model provides a relative measure of the instantaneous event rate between randomized treatment groups while accounting for the specified stratification structure.
A hazard ratio compares estimated instantaneous event rates under the fitted survival model. It is not the same quantity as a relative risk, an absolute risk reduction, or the proportion of participants who benefit.
Superiority hypothesis
Both primary analyses were identified as superiority analyses. The posted tests were two-sided, so the statistical question was whether the treatment groups differed in either direction under the prespecified survival-analysis framework, with the observed estimates indicating the direction of the difference.
6. Primary Results
Primary Endpoint 1: CHD Death, MI, or Ischemic Stroke
The first primary endpoint counted the first occurrence of CHD death, myocardial infarction, or ischemic stroke. The posted analysis used the FAS, a stratified two-sided log-rank test, and a stratified Cox model.
Hazard ratio for the first primary endpoint
95% CI: 0.65–0.86 · P < 0.001
Comparison: Placebo Q2W vs Evolocumab 140 mg Q2W
| Feature | Reported result |
|---|---|
| Endpoint | CHD death, MI, or ischemic stroke, whichever occurred first |
| Analysis population | FAS; all randomized participants analyzed according to randomized treatment assignment |
| Method | 2-sided stratified log-rank test |
| Effect measure | Hazard ratio |
| Hazard ratio | 0.75 |
| 95% confidence interval | 0.65–0.86 |
| P-value | < 0.001 |
| Hypothesis | Superiority |
The reported HR of 0.75 means that, under the stratified Cox model, the estimated instantaneous rate of experiencing the first qualifying event was approximately 25% lower with evolocumab than with placebo. The 25% figure is the direct relative interpretation of 1 − 0.75; it is not an absolute reduction in the probability of an event.
The estimate does not mean that exactly 25% fewer participants experienced an event, nor does it mean that every participant had a 25% reduction in individual risk. A hazard ratio is a relative time-to-event measure.
The 95% CI of 0.65–0.86 describes uncertainty around the estimated hazard ratio under the analysis framework. It does not give a range in which individual treatment effects must fall. The interval is entirely below 1, consistent with the direction of the reported superiority analysis.
The P < 0.001 result addresses evidence against the null hypothesis in the reported statistical test. It does not measure the magnitude of the treatment effect; the hazard ratio and its confidence interval provide the effect estimate and its statistical precision.
Because the result is based on a Cox model, interpretation of a single HR also depends on the model's proportional-hazards framework. The ClinicalTrials.gov record does not report a separate assessment of that assumption, so the HR should be understood as the reported model-based summary rather than as a claim that hazards were constant or proportional at every time point.
Primary Endpoint 2: CHD Death, MI, Ischemic Stroke, or Ischemia-driven Revascularization
The second primary endpoint broadened the composite to include any ischemia-driven arterial revascularization as an additional component, with the first qualifying event determining the endpoint time.
Hazard ratio for the second primary endpoint
95% CI: 0.73–0.89 · P < 0.001
Comparison: Placebo Q2W vs Evolocumab 140 mg Q2W
| Feature | Reported result |
|---|---|
| Endpoint | CHD death, MI, ischemic stroke, or any ischemia-driven arterial revascularization, whichever occurred first |
| Analysis population | FAS; all randomized participants analyzed according to randomized treatment assignment |
| Method | 2-sided stratified log-rank test |
| Effect measure | Hazard ratio |
| Hazard ratio | 0.81 |
| 95% confidence interval | 0.73–0.89 |
| P-value | < 0.001 |
| Hypothesis | Superiority |
The reported HR of 0.81 corresponds to an estimated 19% lower instantaneous rate of the composite event in the evolocumab group relative to placebo under the fitted Cox model. As with the first endpoint, this is a relative hazard interpretation, not a statement that 19% of participants avoided an event.
The 95% CI of 0.73–0.89 quantifies uncertainty around the estimated HR. It remains below 1 throughout the interval, while the width of the interval indicates that the estimate is not an exact measure of the underlying treatment effect.
The P < 0.001 value indicates strong evidence against the null hypothesis under the reported two-sided log-rank test. It should not be read as a 0.1% probability that the treatment effect is real, nor as a measure of clinical magnitude.
The broader composite includes arterial revascularization. Composite endpoints should therefore be interpreted as the endpoint as defined, rather than assuming that the hazard ratio applies identically to every individual component.
7. Secondary Endpoint Results
The registry also posts ten secondary statistical analyses. They use the same general analytical framework: the FAS, randomized treatment assignment, a two-sided stratified log-rank test, and a stratified Cox model for the hazard ratio.
| Secondary endpoint | HR | 95% CI | P-value |
|---|---|---|---|
| MI, ischemic stroke, or any ischemia-driven arterial revascularization | 0.79 | 0.72–0.88 | < 0.001 |
| CHD death, MI, or any ischemia-driven arterial revascularization | 0.79 | 0.72–0.88 | < 0.001 |
| Cardiovascular death, MI, or ischemic stroke | 0.73 | 0.64–0.84 | < 0.001 |
| CHD death or MI | 0.73 | 0.62–0.87 | < 0.001 |
| MI | 0.64 | 0.52–0.79 | < 0.001 |
| Any ischemia-driven arterial revascularization | 0.79 | 0.70–0.88 | < 0.001 |
| CHD death | 0.89 | 0.68–1.16 | = 0.39 |
| Cardiovascular death | 0.79 | 0.64–0.98 | = 0.031 |
| Death due to any cause | 0.80 | 0.70–0.91 | < 0.001 |
| Ischemic stroke | 0.79 | 0.62–1.01 | = 0.062 |
How the secondary estimates should be read
The secondary estimates are not interchangeable. Each hazard ratio applies to a different endpoint definition, so the numerical value must always be interpreted together with the event definition and follow-up period.
For example, the HR of 0.64 for MI represents the reported relative hazard for myocardial infarction specifically, whereas the HR of 0.80 for death due to any cause represents a different time-to-event outcome. A smaller HR does not automatically mean that the endpoint is more clinically important or that the underlying absolute difference is larger.
8. Individual Secondary Outcomes in More Detail
Myocardial infarction
MI hazard ratio
95% CI: 0.52–0.79 · P < 0.001
The MI analysis has an estimated hazard ratio of 0.64. In relative terms, this corresponds to an estimated 36% lower instantaneous hazard of myocardial infarction in the evolocumab group under the reported model. The confidence interval, 0.52–0.79, represents the statistical uncertainty around that estimate.
Cardiovascular death
Cardiovascular-death hazard ratio
95% CI: 0.64–0.98 · P = 0.031
The reported HR of 0.79 corresponds to an estimated 21% lower instantaneous hazard of cardiovascular death in the evolocumab group under the fitted model. The 95% CI extends from 0.64 to 0.98, showing greater uncertainty than some of the composite endpoint estimates.
CHD death
CHD-death hazard ratio
95% CI: 0.68–1.16 · P = 0.39
The estimated HR of 0.89 is below 1, but the 95% CI of 0.68–1.16 includes 1. The reported P-value is 0.39. This illustrates why an estimated HR below 1 should not automatically be described as statistically demonstrated evidence of a treatment effect: the confidence interval and hypothesis test must be considered together.
Ischemic stroke
Ischemic-stroke hazard ratio
95% CI: 0.62–1.01 · P = 0.062
The estimated HR of 0.79 corresponds to a 21% lower estimated instantaneous hazard under the fitted model, but the 95% CI of 0.62–1.01 includes 1 and the reported P-value is 0.062. The appropriate statistical description is therefore the reported estimate together with its uncertainty and P-value, rather than converting the point estimate into a definitive conclusion about the endpoint.
9. Time-to-Event Statistics Explained
Why use time-to-event analysis for these endpoints?
Each primary endpoint is defined by the first occurrence of one of several cardiovascular events and is followed from enrollment to the last confirmed survival status date. Participants can therefore have different lengths of observable follow-up. Time-to-event methods are designed for precisely this structure because they incorporate both event timing and censored follow-up.
The Kaplan-Meier estimator updates the estimated event-free survival whenever an event occurs while retaining information from participants who remain under observation without experiencing the event.
Why does the analysis use the first event?
The primary endpoints specify that the qualifying event occurring whichever occurred first determines the endpoint. This converts several possible clinical events into a single time-to-first-event outcome. Once the first qualifying event occurs, that participant has experienced the endpoint regardless of whether additional qualifying events occur later.
Why is the Cox model used with the log-rank test?
The log-rank test provides a statistical comparison of the time-to-event distributions between randomized groups. The Cox model supplies a hazard ratio that summarizes the relative event rate between groups. In VESALIUS-CV, both are stratified according to the randomization factors collected through IVRS/IWRS.
10. Statistical Methods Explained
What does a hazard ratio of 0.75 mean?
An HR of 0.75 means that the estimated instantaneous rate of the endpoint is 0.75 times the corresponding rate in the comparator group under the fitted Cox model. Equivalently, 1 − 0.75 = 0.25, so the model-based relative hazard is estimated to be 25% lower. This is not the same as saying that 25% of participants avoided the event.
Why is the confidence interval important?
The point estimate alone does not communicate statistical precision. The 95% CI of 0.65–0.86 for the first primary endpoint describes the uncertainty surrounding the estimated HR. A relatively narrow interval provides more precision than a very wide interval, although precision should always be considered alongside the clinical context and endpoint definition.
Why does the P-value not measure effect size?
A P-value measures the evidence against a specified null hypothesis under the statistical test. It depends on both the magnitude of the observed difference and the amount of information in the analysis. Consequently, a very small P-value can occur with a modest effect when the sample contains substantial information, while a larger P-value can occur for an effect estimate with considerable uncertainty.
Why was a stratified log-rank test used?
The registry states that the log-rank test was stratified by randomization factors collected via IVRS/IWRS. Stratification preserves the structure used when assigning participants to treatment groups and allows the comparison of event-time distributions within the specified strata rather than ignoring those factors.
What does the Cox model add?
The stratified Cox model converts the treatment comparison into a hazard-ratio estimate with a confidence interval. The model is particularly useful because it expresses the relative event rate on a common scale while retaining the time-to-event structure and the prespecified stratification.
Why can a composite endpoint differ from one of its components?
A composite endpoint combines several possible first events. Its hazard ratio reflects the combined endpoint as defined. A treatment can therefore have one hazard ratio for a composite of CHD death, MI, and ischemic stroke and a different hazard ratio for MI alone. The component and composite analyses answer different questions.
What does a confidence interval crossing 1 mean for a hazard ratio?
For a hazard ratio, 1 represents equal estimated hazard between groups. A confidence interval that includes 1 indicates that equality remains within the interval of values compatible with the statistical uncertainty at that confidence level. In VESALIUS-CV, the CHD-death interval of 0.68–1.16 and ischemic-stroke interval of 0.62–1.01 illustrate this distinction.
11. Follow-up and Trial Timing
Trial start
The registry lists June 11, 2019 as the study start date.
Primary completion
The registry lists July 25, 2025 as the primary completion date.
Registry status
The ClinicalTrials.gov record identifies the trial as completed and reports statistical results for 12 outcome measures.
The endpoint time frame is from enrollment to the last confirmed survival status date. The registry reports a median time on trial of 55.2 months, with a minimum of 0.0 months and a maximum of 72.7 months.
12. Safety Results
The ClinicalTrials.gov record reports serious adverse events by randomized treatment arm using affected participants divided by participants at risk.
| Safety measure | Placebo Q2W | Evolocumab 140 mg Q2W |
|---|---|---|
| Serious adverse events, affected / at risk | 1772 / 6122 | 1726 / 6125 |
The serious-adverse-event figures should be read as affected participants divided by participants at risk, exactly as reported in the ClinicalTrials.gov record. They are not the same statistical quantity as the time-to-event efficacy hazard ratios and should not be compared by simply subtracting the two affected-participant counts.
13. Randomization and Stratified Analysis
Randomization is the central design feature supporting the treatment comparison. Once participants are randomized, the treatment groups can be compared without requiring the statistical analysis to explain every baseline characteristic individually. The registry-reported primary analyses retain that randomized assignment through the FAS.
The survival analyses additionally use the randomization stratification factors collected through IVRS/IWRS. The purpose of stratification is not to change the treatment groups but to incorporate the design's stratification structure into the analysis.
Randomization
Creates the basis for comparing treatment groups under the randomized design.
FAS analysis
Includes all randomized participants and analyzes them according to randomized treatment assignment.
Stratified log-rank
Compares time-to-event outcomes while accounting for the randomization stratification factors.
Stratified Cox model
Provides the hazard ratio and confidence interval using the same stratification structure.
14. Understanding the Two Primary Endpoints Together
The two primary endpoints are related but not identical. The first includes CHD death, MI, or ischemic stroke. The second adds any ischemia-driven arterial revascularization to those events.
| Primary endpoint | HR | 95% CI | P-value |
|---|---|---|---|
| CHD death, MI, or ischemic stroke | 0.75 | 0.65–0.86 | < 0.001 |
| CHD death, MI, ischemic stroke, or any ischemia-driven arterial revascularization | 0.81 | 0.73–0.89 | < 0.001 |
The HRs are not expected to be identical because the endpoints contain different event definitions. Adding revascularization creates a broader composite and changes the population's observed time-to-first-event distribution.
Both reported estimates are below 1 and both have two-sided P-values below 0.001. The statistical interpretation should nevertheless remain endpoint-specific: the first result concerns the narrower composite, while the second concerns the broader composite.
15. What the Hazard Ratio Does — and Does Not — Mean
An HR of 0.75 means the estimated instantaneous hazard under the model is 0.75 times the comparator hazard. This corresponds to a 25% lower estimated hazard relative to the comparator.
The hazard ratio does not tell us how many percentage points the cumulative probability of an event changed. Absolute risk requires the underlying event probabilities or survival estimates at a specified time point.
An HR does not mean that a particular percentage of individual participants benefited. Treatment effects vary across individuals, while the HR is a population-level model-based summary.
The 95% confidence interval describes statistical uncertainty around the estimated HR. For the first primary endpoint, 0.65–0.86 indicates that the point estimate of 0.75 should not be treated as exact.
The P-value addresses the hypothesis test under the reported statistical framework. It does not quantify the magnitude of the observed treatment effect and should be interpreted alongside the HR and confidence interval.
16. Limitations
- Registry-level reporting: the analysis presented here is limited to the statistical information from the ClinicalTrials.gov record. The ClinicalTrials.gov record does not include detailed baseline tables, subgroup estimates, Kaplan-Meier coordinates, or individual participant data.
- Composite endpoints: each primary endpoint combines multiple clinical events. The reported HR applies to the composite as defined and should not automatically be assigned to every component.
- Hazard-ratio assumptions: the Cox HR is a model-based summary. The ClinicalTrials.gov record does not report a separate assessment of the proportional-hazards assumption.
- Multiplicity: the ClinicalTrials.gov record does not specify a complete multiplicity-adjustment hierarchy for the posted secondary analyses. Their P-values should therefore not automatically be interpreted as individually multiplicity-controlled confirmatory tests.
- Analysis population: primary efficacy results use the FAS and randomized assignment. Safety summaries use reported arm-specific affected/at-risk counts, so efficacy and safety should not be treated as if they necessarily used an identical denominator.
- Follow-up censoring: time-to-event analyses necessarily account for participants whose event status is not observed indefinitely. The ClinicalTrials.gov record does not provide individual censoring patterns.
- Limited event-component detail: the ClinicalTrials.gov record provides formal estimates for the listed endpoints but do not provide component-level event counts for the primary composites.
- External exclusions: 44 participants enrolled in the trial were excluded from all efficacy and safety analysis because of site-wide serious breaches and good clinical practice (GCP) violations.
17. Why This Trial Matters Statistically
VESALIUS-CV is a useful teaching case because it illustrates how a large randomized cardiovascular trial can combine binary registry endpoint labels with formal time-to-event methodology. The statistical story is not contained in the event definition alone: the analysis depends on follow-up time, censoring, stratification, the log-rank comparison, and the Cox hazard-ratio model.
| Concept | How it appears in VESALIUS-CV |
|---|---|
| Randomization | Randomized parallel-group phase 3 design |
| Blinding | Quadruple masking |
| FAS analysis | All randomized participants analyzed according to randomized treatment assignment |
| Time-to-event endpoints | Primary and secondary cardiovascular outcomes analyzed according to time from enrollment to event or censoring |
| Log-rank test | Two-sided comparison stratified by IVRS/IWRS randomization factors |
| Hazard ratio | Primary effect measure for treatment comparisons |
| Stratified Cox model | Used to obtain the reported hazard ratios and confidence intervals |
| Confidence intervals | Quantify uncertainty around the reported HR estimates |
| Composite endpoints | Primary outcomes combine several cardiovascular event types |
| Multiplicity | Multiple primary and secondary analyses require careful interpretation of P-values |
| Safety analysis | Serious adverse events reported as affected participants over participants at risk by arm |
18. Related Tutorials
Learn more about the methods used in this trial:
19. Related Calculators
20. Sources
- ClinicalTrials.gov: NCT03872401 — VESALIUS-CV.
- PubMed: PMID 42670293.
- PubMed: PMID 42663360.
- PubMed: PMID 42183757.
- PubMed: PMID 42153665.
- PubMed: PMID 41903215.
Continue through the Clinical Biostats statistical pathway
Explore the underlying survival-analysis concepts and statistical tools used to understand randomized time-to-event trials.
21. Record Summary
VESALIUS-CV provides a detailed example of randomized time-to-event analysis in a large cardiovascular trial. The ClinicalTrials.gov record uses the full analysis set, randomized treatment assignment, two-sided stratified log-rank testing, and stratified Cox models to estimate hazard ratios with 95% confidence intervals. Both primary endpoints produced reported HRs below 1 with P-values below 0.001, while the secondary analyses illustrate why endpoint definition, confidence intervals, and multiplicity considerations matter when interpreting a large set of cardiovascular outcomes.
The most useful statistical reading of the record combines the hazard ratio, confidence interval, P-value, endpoint definition, analysis population, follow-up structure, and stratification strategy. The reported serious-adverse-event counts provide a separate safety perspective and should not be treated as another form of the efficacy hazard-ratio analysis.