This page separates reported trial results from statistical interpretation. Numerical results are restricted to the information posted for NCT00403767 on ClinicalTrials.gov in the ClinicalTrials.gov record. Where the registry does not provide additional details, this page does not infer them from outside publications.
1. Trial at a Glance
ROCKET AF was a randomized, parallel-group, quadruple-masked phase 3 trial in cardiology. The trial compared rivaroxaban with warfarin for prevention in patients with non-valvular atrial fibrillation, with stroke and non-CNS systemic embolism forming the primary efficacy endpoint and major/non-major clinically relevant bleeding forming the primary safety endpoint.
| Feature | ROCKET AF |
|---|---|
| Trial name | ROCKET AF |
| Phase | Phase 3 |
| Status | Completed |
| Start | 2006-12 |
| Primary completion | 2010-09 |
| Population | Patients with non-valvular atrial fibrillation; registered conditions include atrial fibrillation, stroke, and embolism |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Primary purpose | Prevention |
| Enrollment | 14,269 |
| Lead sponsor | Johnson & Johnson Pharmaceutical Research & Development, L.L.C. |
| Sponsor type | Industry |
| ClinicalTrials.gov | NCT00403767 |
2. Clinical Question
The central statistical question was whether rivaroxaban was non-inferior to warfarin with respect to the time to first occurrence of stroke or non-CNS systemic embolism while on treatment. A separate superiority analysis was also posted for the same primary efficacy composite, while the primary safety analysis evaluated the time to first major or non-major clinically relevant bleeding event.
Population
Patients with non-valvular atrial fibrillation. The registry lists atrial fibrillation, stroke, and embolism among the trial conditions.
Intervention
Rivaroxaban, with matching placebo for the warfarin component used to maintain masking.
Comparator
Warfarin, with matching placebo for the rivaroxaban component used to maintain masking.
Primary question
How does rivaroxaban compare with warfarin for the time to stroke/non-CNS systemic embolism, and what is the comparative hazard of clinically relevant bleeding?
3. Trial Design
Rivaroxaban
- Rivaroxaban was the active drug intervention.
- Matching placebo for the warfarin component was used to support masking.
- Primary efficacy and safety comparisons were made against the warfarin arm.
Warfarin
- Warfarin was the active comparator intervention.
- Matching placebo for the rivaroxaban component was used to support masking.
- Primary efficacy and safety comparisons were made against the rivaroxaban arm.
4. Endpoints
ClinicalTrials.gov lists three primary endpoints. All three are time-to-event outcomes in the posted statistical analyses. The registry defines the efficacy endpoint using time from randomization to the first event while on treatment, whereas the safety endpoint uses time from the first dose to the first event while on treatment.
| Primary endpoint | Time frame | Registry definition |
|---|---|---|
| The Composite Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Non-Inferiority) | Up to 4 years | The number of patients with the first occurrence of a stroke or non-CNS systemic embolism while on treatment, defined as the time interval from the first dose to the last dose of study drug plus 2 days. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment. |
| The Composite of Event of Stroke/Non-CNS Systemic Embolism: Primary Efficacy (Superiority) | Up to 4 years | The number of patients with the first occurrence of a stroke or non-CNS systemic embolism while on treatment, defined as the time interval from the first dose to the last dose of study drug plus 2 days. The statistical analysis is based on time from randomization to the first occurrence of the event while on treatment. |
| The Composite Event of Major/Non-major Clinically Relevant Bleeding Events: Primary Safety | Up to 4 years | The number of patients with the first occurrence of a major or non-major clinically relevant bleeding event while on treatment. The statistical analysis is based on time from the first dose of study drug to the first occurrence of the event while on treatment. |
5. Analysis Populations
The registry identifies different analysis populations for the non-inferiority efficacy analysis and the other posted primary analyses. This distinction is central to interpreting the results because the non-inferiority analysis was based on the per-protocol population, whereas the superiority efficacy and primary safety analyses were based on the safety population.
| Population | Registry description / role |
|---|---|
| Per-protocol population | For the primary non-inferiority efficacy analysis, the PP population consisted of all randomized unique patients excluding those who had specific pre-defined major protocol deviations that occurred by the time of enrollment into the study. The registry text is truncated after this definition. |
| Safety population | For the superiority efficacy and primary safety analyses, the safety population consisted of all randomized unique patients who took at least 1 dose of study medication after randomization during the double-blind treatment period. The registry provides additional site-specific exclusion wording for some efficacy analyses, but the registry-reported text is truncated. |
6. Statistical Methodology
Cox proportional-hazards model
All 10 posted statistical analyses use a Cox proportional-hazards model. The effect measure is a hazard ratio. The analysis notes describe a non-stratified Cox proportional-hazards model with treatment as a covariate. The registry also identifies covariate adjustment and stratified analysis among the other concepts associated with the analyses.
For these analyses, an HR below 1 indicates a lower estimated instantaneous event hazard for rivaroxaban relative to warfarin, while an HR above 1 indicates a higher estimated instantaneous event hazard. The HR is a relative time-to-event measure, not a direct probability or absolute risk difference.
Time-to-event analysis
The endpoints are defined around the timing of a first event. This structure makes survival-analysis methods appropriate because participants can contribute different amounts of follow-up and may remain event-free through the end of their applicable observation period.
Covariate adjustment
The registry analysis notes identify treatment as a covariate in the non-stratified Cox proportional-hazards model and also identify covariate adjustment as an analysis concept. Thus, the reported HR is model-based rather than a simple ratio of two cumulative event proportions.
Stratified analysis
The registry identifies stratified analysis as an associated analysis concept. However, the ClinicalTrials.gov record does not specify the individual stratification factors or their exact implementation. No additional stratification variables are therefore inferred here.
Kaplan-Meier estimation
Kaplan-Meier estimation is a standard descriptive method for time-to-event endpoints and would normally be used to estimate event-free survival over time. However, the ClinicalTrials.gov record identifies the Cox proportional-hazards model as the posted method and do not provide a ClinicalTrials.gov statistical-analysis record specifically identifying Kaplan-Meier estimates. The registry therefore does not report Kaplan-Meier numerical results in the ClinicalTrials.gov record.
7. Non-Inferiority Framework
The primary efficacy non-inferiority analysis was based on the per-protocol population and used a non-inferiority margin of 1.46 in hazard ratio. The registry states that the alternative hypothesis was non-inferiority by this margin and that the required number of primary efficacy endpoint events was determined using a 1-sided alpha of 0.025.
Prespecified non-inferiority margin
Non-inferiority margin for the primary efficacy analysis
Analysis population: per-protocol · 1-sided alpha: 0.025
The logic of a hazard-ratio non-inferiority analysis is different from simply asking whether a conventional two-sided confidence interval includes 1. The relevant question is whether the observed treatment effect is sufficiently far from the unfavorable boundary that the prespecified non-inferiority criterion is met.
Here, the registry specifies an unfavorable hazard-ratio boundary of 1.46. The reported estimate of 0.79 is below that boundary. The formal conclusion should be tied to the prespecified one-sided testing framework rather than to an isolated comparison with HR = 1.
8. Primary Results
Primary Efficacy — Non-Inferiority
The primary non-inferiority analysis compared rivaroxaban with warfarin for the first occurrence of stroke or non-CNS systemic embolism while on treatment, with a time frame of up to 4 years. The analysis used the per-protocol population and a Cox proportional-hazards model.
Stroke / non-CNS systemic embolism
95% CI: 0.66–0.96 · P < 0.001
Rivaroxaban vs warfarin · per-protocol population · non-inferiority analysis
What the estimate means: the reported HR of 0.79 means that, under the fitted Cox model, the estimated instantaneous hazard of the first on-treatment stroke/non-CNS systemic embolism event was 0.79 times that in the warfarin group. Expressed as a simple relative interpretation, this corresponds to an estimated hazard that was 21% lower for rivaroxaban under the model.
What it does not mean: it does not mean that 21% of patients avoided an event, that each individual patient's risk fell by exactly 21%, or that the cumulative event probability was 21% lower.
Confidence interval: the 95% CI of 0.66–0.96 describes uncertainty around the estimated hazard ratio under the analysis framework. It does not describe the range of individual treatment effects.
P-value: P < 0.001 describes evidence against the relevant null hypothesis in the posted analysis; it does not measure the size or clinical importance of the treatment effect.
Non-inferiority caution: the key comparison is with the prespecified non-inferiority margin of 1.46, not simply with HR = 1. The registry specifies a one-sided alpha of 0.025 for this non-inferiority framework.
Population and censoring: the analysis was based on the per-protocol population and on-treatment event definitions. Consequently, the result should be interpreted within that analysis framework rather than as a generic statement about every randomized patient regardless of protocol deviations or treatment exposure.
Proportional-hazards assumption: the Cox model expresses the treatment comparison through a hazard ratio. The ClinicalTrials.gov record does not report a diagnostic assessment of proportional hazards, so the assumption cannot be evaluated from this record alone.
Primary Efficacy — Superiority
The same composite of stroke/non-CNS systemic embolism was also analyzed under a superiority hypothesis. The posted analysis used the safety population and a Cox proportional-hazards model with treatment as a covariate.
Stroke / non-CNS systemic embolism
95% CI: 0.65–0.95 · P = 0.015
Rivaroxaban vs warfarin · safety population · superiority analysis
What the estimate means: the HR of 0.79 represents an estimated instantaneous event hazard approximately 0.79 times that of warfarin in the posted superiority analysis. In relative terms, that corresponds to an estimated hazard 21% lower for rivaroxaban under the model.
What it does not mean: the HR is not a 21% absolute reduction in the number of patients with events, and it does not indicate that every patient experiences the same proportional change.
Confidence interval: the 95% CI of 0.65–0.95 quantifies uncertainty around the HR estimate. Its width reflects statistical precision; it does not provide a range of outcomes that individual patients can be expected to experience.
P-value: P = 0.015 is evidence from the specified superiority test against its null hypothesis. A p-value is not an effect-size measure and should not be used as a substitute for the HR or its confidence interval.
Population matters: this analysis used the safety population, rather than the per-protocol population used for the primary non-inferiority analysis. The two primary efficacy estimates therefore arise from different analysis populations and should be labeled accordingly.
Model caution: the result comes from a Cox proportional-hazards model. The ClinicalTrials.gov record does not report a formal assessment of the proportional-hazards assumption.
Primary Safety
The primary safety endpoint was the first occurrence of a major or non-major clinically relevant bleeding event while on treatment, assessed over up to 4 years. The posted analysis used the safety population and a Cox proportional-hazards model.
Major / non-major clinically relevant bleeding
95% CI: 0.96–1.11 · P = 0.442
Rivaroxaban vs warfarin · safety population · superiority analysis
What the estimate means: an HR of 1.03 indicates that the estimated instantaneous hazard of the first major or non-major clinically relevant bleeding event was approximately 1.03 times that in the warfarin group under the posted Cox model.
What it does not mean: it does not establish that the two treatments have identical bleeding risks. It also does not translate into a 3% absolute increase or decrease in the proportion of patients experiencing bleeding.
Confidence interval: the 95% CI of 0.96–1.11 describes uncertainty around the HR. It includes HR = 1, so the estimate is compatible with modestly lower or modestly higher instantaneous hazard within this interval.
P-value: P = 0.442 is not a measure of the magnitude of the observed HR. A nonsignificant p-value should not be interpreted as proof that the treatment effects are identical.
Safety interpretation: this was a superiority analysis of a composite safety endpoint. The registry separately reports serious adverse events by arm, but those serious-adverse-event figures should not be substituted for the primary bleeding endpoint.
Model and exposure caution: the analysis was based on the safety population and on-treatment timing. The Cox proportional-hazards assumption is also relevant here, and the ClinicalTrials.gov record does not provide a formal diagnostic assessment.
9. Primary Results Side by Side
| Endpoint | Population | HR | 95% CI | P-value | Hypothesis |
|---|---|---|---|---|---|
| Stroke/non-CNS systemic embolism | Per-protocol | 0.79 | 0.66–0.96 | <0.001 | Non-inferiority |
| Stroke/non-CNS systemic embolism | Safety | 0.79 | 0.65–0.95 | 0.015 | Superiority |
| Major/non-major clinically relevant bleeding | Safety | 1.03 | 0.96–1.11 | 0.442 | Superiority |
The two efficacy analyses produce the same point estimate, 0.79, but different confidence intervals and p-values because they represent distinct analyses with different populations and hypothesis frameworks. The safety endpoint has a point estimate close to 1 and a confidence interval spanning both sides of 1.
10. Secondary Endpoint Results
The registry posts seven secondary time-to-event analyses in addition to the three primary analyses. Each used a Cox proportional-hazards model, compared rivaroxaban with warfarin, and was analyzed under a superiority hypothesis.
| Secondary endpoint | HR | 95% CI | P-value |
|---|---|---|---|
| Stroke/non-CNS systemic embolism/vascular death | 0.86 | 0.74–0.99 | 0.034 |
| Stroke/non-CNS systemic embolism/myocardial infarction/vascular death | 0.85 | 0.74–0.96 | 0.010 |
| Stroke | 0.85 | 0.70–1.03 | 0.092 |
| Non-CNS systemic embolism | 0.23 | 0.09–0.61 | 0.003 |
| Myocardial infarction | 0.81 | 0.63–1.06 | 0.121 |
| Vascular death | 0.89 | 0.73–1.10 | 0.289 |
| All-cause mortality | 0.85 | 0.70–1.02 | 0.073 |
These results are all relative hazard estimates rather than absolute event probabilities. For example, the reported HR of 0.23 for non-CNS systemic embolism indicates a substantially lower estimated instantaneous hazard under the Cox model, but the ClinicalTrials.gov record does not include the underlying event counts or cumulative incidence needed to translate that estimate into absolute risk.
11. Reading the Secondary Hazard Ratios
HR 0.86
For the composite of stroke/non-CNS systemic embolism/vascular death, the estimated instantaneous hazard was 0.86 times the warfarin-group hazard under the posted model.
HR 0.85
For the broader stroke/non-CNS systemic embolism/myocardial infarction/vascular death composite, the estimated hazard ratio was 0.85.
HR 0.23
For non-CNS systemic embolism alone, the estimated hazard ratio was 0.23, with a 95% CI of 0.09–0.61.
HR 0.85
For all-cause mortality, the estimated hazard ratio was 0.85, with a 95% CI of 0.70–1.02.
The variation among estimates illustrates why a trial should not be summarized using a single hazard ratio. Each endpoint defines a different event process. Composite endpoints also combine multiple clinical events, so their interpretation depends on which components contribute events and how those components relate to the clinical question.
12. Safety: Serious Adverse Events
The ClinicalTrials.gov record reports serious adverse events by treatment arm as affected patients divided by patients at risk.
| Arm | Affected / at risk | Registry measure |
|---|---|---|
| Rivaroxaban | 2649 / 7111 | Serious adverse events |
| Warfarin | 2720 / 7125 | Serious adverse events |
The serious-adverse-event figures are descriptive affected/at-risk counts. They are not the same endpoint as the primary composite of major/non-major clinically relevant bleeding events, and the ClinicalTrials.gov record does not provide a statistical-analysis record for the serious-adverse-event measure itself.
13. Statistical Methods Explained
Why was a Cox proportional-hazards model used?
The primary and secondary endpoints are time-to-event outcomes. A Cox model is designed to compare event hazards while accounting for the timing of events and censoring rather than reducing follow-up to a single yes/no outcome at a fixed time. The registry explicitly identifies the Cox proportional-hazards model as the method used for all 10 posted statistical analyses.
What does an HR of 0.79 mean?
An HR of 0.79 means that the fitted model estimates the instantaneous event hazard in the rivaroxaban group at 79% of the corresponding hazard in the warfarin group. A simple relative interpretation is a 21% lower estimated hazard. It is not equivalent to saying that 21% fewer patients experienced the event.
Why is the non-inferiority margin 1.46 rather than 1?
Superiority asks whether the treatment effect differs from the null value of HR = 1 in the favorable direction. Non-inferiority asks a different question: whether the experimental treatment is not worse than the comparator by more than a prespecified clinically acceptable amount. The registry specifies that amount as an HR margin of 1.46.
Why was the per-protocol population important for non-inferiority?
The registry states that the primary non-inferiority analysis used the per-protocol population. This is important because protocol deviations can make an experimental treatment and comparator appear more similar, potentially making it easier to conclude non-inferiority. The ClinicalTrials.gov record does not provide the complete protocol-deviation definition, so the analysis should be described using the registry's stated population rather than reconstructing additional criteria.
Why are there two analyses of the same efficacy endpoint?
The registry explicitly distinguishes a primary efficacy non-inferiority analysis from a primary efficacy superiority analysis. The first uses the per-protocol population and a non-inferiority hypothesis; the second uses the safety population and a superiority hypothesis. Because the hypotheses and populations differ, the two results answer related but non-identical statistical questions.
What does a 95% confidence interval tell us?
A 95% confidence interval communicates statistical uncertainty around the estimated hazard ratio under the specified analysis framework. A narrower interval generally indicates greater precision than a wider interval, but the interval does not describe individual patients' possible treatment responses. For the primary non-inferiority result, the interval is also not the sole criterion because the registry specifies a one-sided non-inferiority framework with a prespecified margin.
Why doesn't the p-value measure treatment effect size?
A p-value is a measure of compatibility between the observed data and a specified null hypothesis under the statistical test. It depends on both the observed effect and the amount of information in the analysis. The hazard ratio describes the estimated relative effect, while its confidence interval describes uncertainty around that estimate. These quantities should be considered together.
14. Confidence Intervals and Precision
The three primary analyses illustrate why a point estimate should never be interpreted without its confidence interval.
| Endpoint | Estimate | 95% CI | Precision interpretation |
|---|---|---|---|
| Primary efficacy, non-inferiority | 0.79 | 0.66–0.96 | The interval spans a range of plausible model-based hazard ratios below 1 and remains below the non-inferiority margin of 1.46. |
| Primary efficacy, superiority | 0.79 | 0.65–0.95 | The interval is relatively concentrated around the point estimate and remains below 1. |
| Primary safety | 1.03 | 0.96–1.11 | The interval is centered close to 1 and includes both values below and above 1. |
The intervals should be interpreted in the context of their respective hypotheses and analysis populations. In particular, the primary efficacy non-inferiority interval should not be treated as though it were a conventional superiority confidence interval answering the same question.
15. P-values and Hypothesis Types
| Analysis | Hypothesis type | P-value | What the test addresses |
|---|---|---|---|
| Primary efficacy | Non-inferiority or equivalence | <0.001 | Whether the treatment meets the prespecified non-inferiority framework |
| Primary efficacy | Superiority | 0.015 | Whether the treatment shows superiority under the posted analysis |
| Primary safety | Superiority | 0.442 | Whether the bleeding hazard differs under the posted superiority analysis |
The numerical p-values are not directly comparable as though they were measuring the same hypothesis. The first is attached to a non-inferiority framework with a specified margin and one-sided alpha; the latter two are superiority analyses.
16. Censoring and On-Treatment Definitions
Time-to-event analysis depends not only on whether an event occurs, but also on how follow-up is defined. The registry provides explicit on-treatment definitions for the primary endpoints.
Efficacy timing
The efficacy definition considers events from the first dose through the last dose of study drug plus 2 days, while the statistical analysis uses time from randomization to the first occurrence while on treatment.
Safety timing
The safety endpoint is based on time from the first dose of study drug to the first occurrence of the bleeding event while on treatment.
This distinction matters because the statistical clock and the treatment-exposure definition are not simply interchangeable concepts. A Cox model can use time from randomization while the event itself is classified according to the registry's on-treatment definition.
17. Stratification and Covariate Adjustment
The registry identifies both covariate adjustment and stratified analysis among the concepts associated with the posted analyses. The specific analysis notes describe a (non-stratified) Cox Proportional Hazards model with treatment as covariate.
The ClinicalTrials.gov record does not specify the exact covariates or strata used beyond the treatment covariate description. A detailed reconstruction of the model matrix or stratum definitions would therefore go beyond the available registry information.
18. Interim Analysis and Multiplicity
The ClinicalTrials.gov record identifies non-inferiority and superiority hypothesis types and provide the one-sided alpha of 0.025 used for the non-inferiority design. They do not provide a documented interim-analysis schedule, alpha-spending function, stopping boundary, or multiplicity-adjustment procedure.
| Design topic | What the ClinicalTrials.gov record supports |
|---|---|
| Non-inferiority margin | 1.46 in hazard ratio |
| Non-inferiority alpha | 1-sided alpha of 0.025 |
| Superiority testing | Posted for the primary efficacy endpoint and primary safety endpoint |
| Multiplicity adjustment | Not specified in the ClinicalTrials.gov record |
| Interim-analysis plan | Not specified in the ClinicalTrials.gov record |
| Bayesian methods | Not reported in the statistical analyses posted on ClinicalTrials.gov |
19. Randomization and Blinding
ROCKET AF used randomized allocation, a parallel design, and quadruple masking. These design features address different sources of bias and support the interpretability of the treatment comparison.
Randomization
Randomized allocation helps create treatment groups whose differences can be interpreted through the assigned treatment rather than through investigator selection.
Parallel design
The two randomized groups were evaluated as parallel treatment arms rather than as sequential exposures within the same patients.
Quadruple masking
The registry identifies the study as quadruple-masked and lists matching placebos for both treatment components.
Prevention objective
The registry identifies prevention as the primary purpose, with stroke and embolism-related time-to-event outcomes forming the central efficacy framework.
20. Secondary Endpoint Interpretation
The secondary analyses show a range of hazard-ratio estimates. Reading them correctly requires keeping the event definition, confidence interval, and hypothesis test together.
| Endpoint | Statistical reading |
|---|---|
| Stroke/non-CNS systemic embolism/vascular death | HR 0.86 indicates a lower estimated event hazard under the Cox model; 95% CI 0.74–0.99 and P = 0.034 are the posted uncertainty and superiority-test results. |
| Stroke/non-CNS systemic embolism/myocardial infarction/vascular death | HR 0.85 indicates a lower estimated event hazard; 95% CI 0.74–0.96 and P = 0.010 are the posted results. |
| Stroke | HR 0.85 indicates a lower point estimate of hazard, but the 95% CI of 0.70–1.03 crosses 1 and the posted P-value is 0.092. |
| Non-CNS systemic embolism | HR 0.23 is substantially below 1, with a 95% CI of 0.09–0.61 and P = 0.003. |
| Myocardial infarction | HR 0.81 is below 1, but the 95% CI of 0.63–1.06 crosses 1 and P = 0.121. |
| Vascular death | HR 0.89 is below 1, with a 95% CI of 0.73–1.10 and P = 0.289. |
| All-cause mortality | HR 0.85 is below 1, with a 95% CI of 0.70–1.02 and P = 0.073. |
A useful statistical distinction is between direction and evidence. An HR below 1 gives the direction of the point estimate, but the confidence interval and hypothesis test determine how precisely and strongly that estimate differs from the relevant null under the specified analysis.
21. Why the Composite Endpoint Matters
The primary efficacy endpoint combines stroke and non-CNS systemic embolism. Composite endpoints can increase the number of observed events and thereby provide a broader measure of treatment effect, but the components are clinically distinct events and should also be examined individually when component analyses are available.
ROCKET AF provides component analyses for stroke and non-CNS systemic embolism. The posted HR for stroke is 0.85, whereas the HR for non-CNS systemic embolism is 0.23. These estimates demonstrate why the composite HR should not be interpreted as though every component had the same treatment effect.
22. All-Cause Mortality as a Secondary Endpoint
All-cause mortality was analyzed as a secondary time-to-event endpoint using a Cox proportional-hazards model in the safety population.
All-cause mortality
95% CI: 0.70–1.02 · P = 0.073
Rivaroxaban vs warfarin · superiority analysis
The point estimate is below 1, indicating a lower estimated mortality hazard under the fitted model. However, the 95% CI extends from 0.70 to 1.02, and the posted p-value is 0.073. The registry data therefore support reporting the estimate, interval, and p-value together rather than reducing the result to a binary label.
23. What the Hazard Ratio Does — and Does Not — Mean
A reported HR of 0.79 means that, under the fitted Cox model, the estimated instantaneous rate of the specified event in the rivaroxaban group was approximately 79% of the corresponding rate in the warfarin group. A simple relative interpretation is a 21% lower estimated hazard.
It does not mean that 21% fewer patients experienced the event, that each patient had exactly a 21% reduction in risk, or that the absolute difference between treatment groups was 21 percentage points.
The 95% CI describes uncertainty around the estimated hazard ratio. For the primary non-inferiority analysis, the interval is 0.66–0.96. For the superiority analysis of the same endpoint, it is 0.65–0.95. The intervals are not ranges of individual patient outcomes.
The p-value quantifies evidence under a specified null hypothesis and testing framework. It does not tell us whether an effect is large, small, clinically important, or unimportant. Those questions require the hazard ratio, confidence interval, endpoint definition, and clinical context to be considered together.
24. Clinical Interpretation vs Statistical Interpretation
Statistical interpretation
The primary efficacy endpoint had an HR of 0.79 in the posted non-inferiority analysis and an HR of 0.79 in the posted superiority analysis. The primary safety endpoint had an HR of 1.03. Each estimate has its own confidence interval, p-value, hypothesis type, and analysis population.
Clinical interpretation
The statistical record describes comparative hazards for stroke/non-CNS systemic embolism and clinically relevant bleeding, along with secondary cardiovascular and mortality endpoints. The ClinicalTrials.gov record does not provide enough absolute event information to translate every HR into an absolute treatment benefit or harm.
25. Important Limitations and Interpretation Issues
- Analysis-population differences: the primary non-inferiority efficacy analysis used the per-protocol population, whereas the superiority efficacy and primary safety analyses used the safety population.
- Incomplete PP definition: the registry text truncates the detailed definition of major protocol deviations used to construct the per-protocol population.
- Incomplete safety-population detail: the registry-reported efficacy-analysis text includes a truncated site-specific GCP-violation description, so this page does not reconstruct additional exclusions.
- On-treatment framework: the primary endpoints use specific on-treatment definitions, so the results should not be interpreted as simple all-follow-up randomized-group event rates.
- Hazard-ratio assumptions: the Cox proportional-hazards model relies on a proportional-hazards framework. The ClinicalTrials.gov record does not report a formal assessment of that assumption.
- Absolute risk information: the statistical analyses posted on ClinicalTrials.gov provide hazard ratios and confidence intervals but not the underlying event counts or cumulative event probabilities for the primary and secondary analyses.
- Multiplicity: the ClinicalTrials.gov record does not specify a multiplicity-adjustment procedure for the secondary superiority analyses.
- Interim analysis: the ClinicalTrials.gov record does not provide an interim-analysis schedule, stopping boundary, or alpha-spending procedure.
- Missing data: the ClinicalTrials.gov record does not report a specific missing-data or imputation strategy.
- Subgroup information: the ClinicalTrials.gov record does not provide subgroup estimates, forest plots, or interaction tests.
- Bayesian analysis: no Bayesian methods are reported in the statistical analyses posted on ClinicalTrials.gov.
- Long-term details: the ClinicalTrials.gov record provides results through time frames of up to 4 years but does not provide median survival times, Kaplan-Meier estimates, or long-term follow-up summaries.
26. Why This Trial Matters Statistically
ROCKET AF is a useful teaching case because it combines randomized treatment allocation, quadruple masking, a non-inferiority framework, superiority testing, time-to-event endpoints, Cox proportional-hazards modeling, different analysis populations, and component analyses of a composite endpoint.
| Concept | How it appears in ROCKET AF |
|---|---|
| Randomization | Randomized parallel-group phase 3 design |
| Blinding | Quadruple masking with matching placebos |
| Time-to-event endpoints | Primary and secondary outcomes analyze time to first event |
| Hazard ratio | Primary and secondary treatment effects are expressed as HRs |
| Cox model | Posted statistical method for all 10 analyses |
| Non-inferiority | Primary efficacy analysis with HR margin 1.46 |
| One-sided alpha | 1-sided alpha of 0.025 for the non-inferiority design |
| Per-protocol analysis | Used for the primary non-inferiority efficacy analysis |
| Safety population | Used for the primary superiority efficacy and safety analyses |
| Composite endpoint | Stroke/non-CNS systemic embolism is the primary efficacy composite |
| Component analysis | Stroke and non-CNS systemic embolism are separately analyzed |
| Secondary endpoints | Vascular death, myocardial infarction, and all-cause mortality are also analyzed |
| Serious adverse events | Reported descriptively by treatment arm |
27. A Statistical Walkthrough of the Primary Efficacy Result
The primary non-inferiority result can be understood as a sequence of statistical decisions rather than as a single number.
Define the unfavorable boundary
The registry specifies a non-inferiority margin of 1.46 in hazard ratio and a one-sided alpha of 0.025.
Use the per-protocol population
The posted primary non-inferiority analysis is based on the per-protocol population.
Fit the Cox proportional-hazards model
Treatment is included as a covariate in the reported non-stratified Cox proportional-hazards model.
Obtain the hazard ratio
The estimated HR is 0.79, with a 95% CI of 0.66–0.96.
Evaluate non-inferiority
The posted p-value is <0.001. The interpretation is made against the prespecified non-inferiority framework rather than treating HR = 1 as the sole decision boundary.
28. What the Registry Does Not Report Here
The ClinicalTrials.gov record is rich enough to reconstruct the main statistical architecture and all 10 posted statistical analyses, but they do not provide several details that would be necessary for a fuller reconstruction of the original statistical analysis plan.
| Topic | Available in the ClinicalTrials.gov record? |
|---|---|
| Primary HR estimates | Yes |
| 95% confidence intervals | Yes |
| P-values | Yes |
| Analysis populations | Yes, with some definitions truncated |
| Non-inferiority margin | Yes: 1.46 |
| One-sided alpha | Yes: 0.025 |
| Kaplan-Meier numerical estimates | No |
| Median survival/event times | No |
| Event counts by arm for primary endpoints | No |
| Baseline characteristics | No |
| Subgroup estimates | No |
| Interaction tests | No |
| Detailed missing-data strategy | No |
| Detailed interim-analysis plan | No |
| Multiplicity-adjustment procedure | No |
| Bayesian methods | No |
These omissions are important because they define the boundary between what can be independently reconstructed from the registry and what would require additional protocol, statistical analysis plan, or underlying patient-level information.
29. Related Tutorials
Learn more about the methods used in this trial:
30. Related Statistical Calculators
31. Sources
- ClinicalTrials.gov: ROCKET AF — NCT00403767.
- PubMed: PMID 40163217.
- PubMed: PMID 31376090.
- PubMed: PMID 30371223.
- PubMed: PMID 30219887.
- PubMed: PMID 29898836.
Continue through the Clinical Biostats statistical pathway
Use the trial's endpoints and methods as a practical route into survival analysis, hazard ratios, confidence intervals, and non-inferiority trial design.
32. Record Summary
ROCKET AF provides a detailed example of how a randomized clinical trial can use a time-to-event framework to address both non-inferiority and superiority questions. The primary efficacy endpoint was analyzed first under a non-inferiority framework using a per-protocol population, a hazard-ratio margin of 1.46, and a one-sided alpha of 0.025. The posted estimate was HR 0.79 with a 95% CI of 0.66–0.96 and P < 0.001.
The same efficacy composite was subsequently analyzed for superiority in the safety population, producing HR 0.79 with a 95% CI of 0.65–0.95 and P = 0.015. The primary safety endpoint, major/non-major clinically relevant bleeding, produced HR 1.03 with a 95% CI of 0.96–1.11 and P = 0.442. Seven secondary time-to-event analyses provide additional hazard-ratio estimates for composite and individual cardiovascular outcomes.