This page separates reported trial results from statistical interpretation. Numerical results are restricted to the ClinicalTrials.gov trial data posted on ClinicalTrials.gov for NCT00439777. The registry provides the official trial record.
1. Trial at a Glance
EINSTEIN-PE was a randomized, parallel, open-label phase 3 treatment trial with 4833 enrolled participants. It compared rivaroxaban with enoxaparin overlapping with and followed by VKA for pulmonary embolism, using a prespecified non-inferiority framework for the primary endpoint.
| Feature | EINSTEIN-PE |
|---|---|
| Trial name | EINSTEIN-PE |
| Brief title | Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism - The EINSTEIN PE Study |
| Phase | Phase 3 |
| Status | Completed |
| Condition | Pulmonary Embolism |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None |
| Primary purpose | Treatment |
| Enrollment | 4833 |
| Lead sponsor | Bayer |
| Study start | 2007-03 |
| Primary completion | 2011-09 |
2. Clinical Question
The statistical question was whether rivaroxaban was at least as effective as enoxaparin overlapping with and followed by VKA with respect to the registered primary endpoint: symptomatic recurrent venous thromboembolism until the intended end of study treatment.
Population
Participants enrolled in a phase 3 study of patients with pulmonary embolism. The ClinicalTrials.gov record identifies the condition as pulmonary embolism and the brief title as acute symptomatic pulmonary embolism.
Intervention
Rivaroxaban, identified in the registry as Rivaroxaban (Xarelto, BAY59-7939).
Comparator
Enoxaparin overlapping with and followed by VKA.
Primary question
Can the rivaroxaban regimen demonstrate non-inferiority to the comparator for symptomatic recurrent VTE?
3. Trial Design
Rivaroxaban
- Rivaroxaban (Xarelto, BAY59-7939)
- Compared directly with the enoxaparin/VKA strategy
- Study treatment period: 3, 6, or 12 months
Enoxaparin/VKA
- Enoxaparin overlapping with and followed by VKA
- Comparator treatment strategy
- Study treatment period: 3, 6, or 12 months
4. Endpoints
| Endpoint | Registry definition | Time frame | Analysis type |
|---|---|---|---|
| Primary | Percentage of Participants With Symptomatic Recurrent Venous Thromboembolism [VTE] (i.e. the Composite of Recurrent Deep Vein Thrombosis [DVT] or Fatal or Non-fatal Pulmonary Embolism [PE]) Until the Intended End of Study Treatment | 3-, 6-, or 12-month study treatment period | Time-to-event; Cox proportional-hazards model |
| Secondary | Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment | 3-, 6-, or 12-month study treatment period | Time-to-event; Cox proportional-hazards model |
| Secondary | Percentage of Participants With an Event for Net Clinical Benefit 1 Until the Intended End of Study Treatment | 3-, 6-, or 12-month study treatment period | Time-to-event; Cox proportional-hazards model |
| Secondary | Percentage of Participants With Recurrent PE Until the Intended End of Study Treatment | 3-, 6- or 12-month study treatment period | Time-to-event; Cox proportional-hazards model |
| Secondary | Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment | 3-, 6- or 12-month study treatment period | Time-to-event; Cox proportional-hazards model |
| Secondary safety | Percentage of Participants With Clinically Relevant Bleeding, Treatment-emergent (Time Window: Until 2 Days After Last Dose) | 3-, 6- or 12-month study treatment period | Time-to-event; Cox proportional-hazards model |
Central event adjudication
The primary endpoint events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. The registry definition identifies compression ultrasound and venography for DVT assessment; spiral CT scanning, pulmonary angiography, ventilation/perfusion lung scanning, and lung scintigraphy for PE assessment; and autopsy for fatal PE, together with assessment of unexplained death.
This is statistically important because a composite time-to-event endpoint is only as reliable as its event definitions and ascertainment. Central adjudication that is blinded to treatment assignment can reduce the opportunity for treatment knowledge to influence event classification.
5. Analysis Populations
| Population | Definition / role |
|---|---|
| Intention-to-treat | All randomized participants with valid informed consent. Participants were analyzed according to the treatment assigned at randomization. This was the efficacy analysis population for the reported primary and secondary efficacy analyses. |
| Valid-for-safety | All participants randomized with valid informed consent who received at least one dose of anticoagulant study treatment after randomization. The clinically relevant bleeding analysis used this safety population. |
The distinction is fundamental. The ITT population preserves the randomized treatment comparison for efficacy, whereas the safety analysis requires actual exposure to study treatment. The two populations therefore answer related but different questions.
6. Statistical Methodology
Cox proportional-hazards model
The registry reports Cox proportional-hazards regression as the method for the primary endpoint and each posted secondary statistical analysis. The model estimates a relative hazard between the randomized treatment groups while allowing each participant to contribute follow-up until an event or censoring.
The hazard ratio is obtained from the fitted coefficient as exp(β). In this trial, the reported effect measure was the hazard ratio comparing rivaroxaban with enoxaparin/VKA.
Stratification and covariate adjustment
The reported Cox analyses were stratified by intended treatment duration and adjusted for the presence of active malignancy at baseline. This means the model was not simply an unadjusted comparison of two event curves. It incorporated prespecified design or prognostic information identified in the registry analysis notes.
Intention-to-treat analysis
The ITT population consisted of all randomized participants with valid informed consent, analyzed according to their assigned treatment. This approach maintains the treatment comparison created by randomization and avoids redefining treatment groups according to subsequent treatment behavior.
Hazard ratio
An HR above 1 indicates a higher estimated hazard in the rivaroxaban group relative to the comparator; an HR below 1 indicates a lower estimated hazard. The HR is a relative time-to-event measure and is not itself an absolute event probability.
Confidence interval
The registry reports two-sided 95% confidence intervals for the hazard ratios. The confidence interval quantifies statistical uncertainty around the estimated relative hazard under the fitted model. It does not describe the range of effects that individual participants experienced.
7. Non-Inferiority Design
The primary analysis was explicitly framed as a non-inferiority comparison. The ClinicalTrials.gov record states that, assuming equal efficacy, a total of 88 events would provide 90% power to demonstrate that rivaroxaban was at least as effective as the comparator, using a relative non-inferiority upper confidence-limit margin for the hazard ratio of 2.0 with two-sided alpha=0.05.
Prespecified non-inferiority criterion
Primary HR: 1.12 · 95% CI: 0.75–1.68
The reported upper confidence limit of 1.68 is below the prespecified relative non-inferiority margin of 2.0.
Why the margin matters
Non-inferiority is not established merely because a conventional superiority test fails to reject the null hypothesis. The treatment effect must be sufficiently compatible with the prespecified non-inferiority boundary.
What 2.0 means
The margin permits the upper confidence limit of the hazard ratio to reach, but not equal or exceed, 2.0 under the registry-reported analysis rule. It represents the largest relative hazard compatible with the prespecified non-inferiority criterion.
8. Primary Result: Symptomatic Recurrent VTE
The primary endpoint was symptomatic recurrent venous thromboembolism, defined as the composite of recurrent DVT or fatal or non-fatal PE, until the intended end of study treatment. The analysis used the ITT population and a Cox proportional-hazards model.
Hazard ratio for symptomatic recurrent VTE
95% CI: 0.75–1.68 · P = 0.0026
Non-inferiority margin: upper HR confidence-limit boundary of 2.0
| Primary analysis component | Reported value |
|---|---|
| Analysis population | Intention-to-treat |
| Comparison | Rivaroxaban vs Enoxaparin/VKA |
| Method | Cox proportional-hazards model |
| Effect measure | Hazard ratio |
| Estimate | 1.12 |
| 95% CI | 0.75–1.68 |
| Test | Two-sided |
| P-value | 0.0026 |
| Hypothesis type | Non-inferiority or equivalence |
| Non-inferiority upper margin | 2.0 |
The estimated hazard ratio of 1.12 means that the fitted model estimated the instantaneous hazard of symptomatic recurrent VTE to be 12% higher with rivaroxaban than with enoxaparin/VKA. That is a relative model-based estimate, not a statement that 12% more participants experienced VTE.
The estimate does not mean that rivaroxaban produced a 12% higher absolute risk. It also does not mean that every participant had the same relative hazard.
The 95% CI of 0.75–1.68 describes uncertainty around the estimated hazard ratio. Importantly for this non-inferiority analysis, its upper limit of 1.68 is below the prespecified upper margin of 2.0. Thus, under the registry's stated decision rule, the confidence interval is compatible with the non-inferiority criterion.
The reported P = 0.0026 should not be read as an effect-size measure. A p-value describes evidence against a specified statistical hypothesis under the testing framework; it does not say that the treatment effect is 0.26% or that there is a 99.74% probability that the treatment is effective. Here, the registry identifies the hypothesis type as non-inferiority or equivalence, so the p-value should be interpreted within that framework rather than as a conventional superiority claim.
Because this is a Cox analysis, interpretation also depends on the model's proportional-hazards assumption. The ClinicalTrials.gov record does not provide a diagnostic assessment of that assumption, so the single HR should be understood as the model's summary relative effect rather than a complete description of how hazards behaved at every point in follow-up.
9. Secondary Efficacy Results
Composite of recurrent DVT, non-fatal PE, and all-cause mortality
Hazard ratio
95% CI: 0.86–1.56 · P = 0.33
Superiority hypothesis
The HR of 1.16 corresponds to an estimated 16% higher instantaneous hazard for the composite in the rivaroxaban group relative to enoxaparin/VKA. The 95% CI of 0.86–1.56 spans 1.0, indicating uncertainty that includes both a lower and a higher hazard relative to the comparator.
The P = 0.33 does not measure the size of the observed effect. It is evidence from the superiority testing framework reported for this endpoint. It should not be converted into a probability that one treatment is better or worse.
Net Clinical Benefit 1
Hazard ratio
95% CI: 0.63–1.14 · P = 0.275
Superiority hypothesis
The estimated HR of 0.85 is below 1.0, corresponding to an estimated 15% lower instantaneous hazard for the reported net clinical benefit endpoint with rivaroxaban. The 95% CI of 0.63–1.14 includes 1.0, so the estimate remains compatible with both a lower and a higher hazard under the model.
The P = 0.275 is not an effect-size statistic and should not be interpreted as the probability that the treatments are equivalent. The endpoint was analyzed under a superiority hypothesis rather than the primary non-inferiority framework.
Recurrent pulmonary embolism
Hazard ratio
95% CI: 0.70–1.93 · P = 0.55
Superiority hypothesis
The HR of 1.16 is an estimated 16% higher instantaneous hazard of recurrent PE with rivaroxaban relative to the comparator. The relatively broad 95% CI of 0.70–1.93 includes 1.0 and spans a substantial range of possible relative effects.
The P = 0.55 does not imply that there is no difference. It indicates that the reported superiority analysis did not provide strong statistical evidence for a difference under its specified testing framework. The confidence interval is particularly important for understanding the remaining uncertainty.
Recurrent deep vein thrombosis
Hazard ratio
95% CI: 0.49–1.79 · P = 0.85
Superiority hypothesis
The HR of 0.94 is close to 1.0, corresponding to an estimated 6% lower instantaneous hazard of recurrent DVT with rivaroxaban. The point estimate alone, however, should not be treated as evidence of equivalence.
The 95% CI of 0.49–1.79 is wide and includes both substantially lower and substantially higher hazards. The P = 0.85 is a superiority-test result and does not measure the clinical magnitude of the effect.
10. Safety Result: Clinically Relevant Bleeding
Clinically relevant bleeding was a secondary safety endpoint. The registry specifies a treatment-emergent time window extending until 2 days after the last dose. The analysis used the valid-for-safety population and a Cox proportional-hazards model.
Hazard ratio for clinically relevant bleeding
95% CI: 0.76–1.07 · P = 0.23
Superiority hypothesis
| Safety analysis component | Reported value |
|---|---|
| Analysis population | Valid-for-safety population |
| Time window | Until 2 days after last dose |
| Method | Cox proportional-hazards model |
| Effect measure | Hazard ratio |
| Estimate | 0.90 |
| 95% CI | 0.76–1.07 |
| P-value | 0.23 |
The HR of 0.90 corresponds to an estimated 10% lower instantaneous hazard of clinically relevant bleeding with rivaroxaban relative to enoxaparin/VKA. The 95% CI of 0.76–1.07 includes 1.0, so the data summarized by this model remain compatible with both a modestly lower and a modestly higher hazard.
The P = 0.23 is a superiority-test result and is not a measure of bleeding-risk magnitude. It should not be described as proof that the two strategies have identical bleeding risk.
Serious adverse events by arm
| Arm | Affected / at risk |
|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | 504/2412 |
| Enoxaparin/VKA | 495/2405 |
These serious adverse-event counts are reported separately from the Cox analysis of clinically relevant bleeding. The ClinicalTrials.gov record does not provide a formal statistical comparison for the serious-adverse-event counts, so they should not be converted into an unreported p-value or hazard ratio.
11. The Primary Non-Inferiority Result in Context
The primary result illustrates an important distinction between a point estimate, a confidence interval, and a non-inferiority margin.
| Quantity | Value | Statistical meaning |
|---|---|---|
| Hazard ratio | 1.12 | Estimated relative hazard for rivaroxaban versus enoxaparin/VKA |
| Lower 95% CI | 0.75 | Lower boundary of uncertainty interval |
| Upper 95% CI | 1.68 | Upper boundary relevant to the non-inferiority decision |
| NI margin | 2.0 | Prespecified upper relative-hazard boundary |
| P-value | 0.0026 | Reported p-value under the non-inferiority/equivalence hypothesis framework |
The entire reported 95% confidence interval lies below the prespecified upper non-inferiority margin. This is the central statistical feature of the primary result.
The point estimate itself is not the decision rule. Even though the HR is above 1.0, the upper confidence limit remains below 2.0. That distinction is precisely why non-inferiority trials require a prespecified margin and an interval-based interpretation.
12. Stratification and Covariate Adjustment
The posted Cox analyses were stratified by intended treatment duration and adjusted for the presence of active malignancy at baseline. The same approach appears in the primary and reported secondary efficacy and safety analyses.
Stratification
Stratification allows the baseline analysis to account for intended treatment-duration strata rather than treating all participants as if they belonged to one homogeneous duration group.
Adjustment
Active malignancy at baseline was included as an adjustment variable. This can improve control for prognostic imbalance and precision when the variable is relevant to the event process.
Adjustment does not replace randomization. Randomization establishes the treatment comparison, while covariate adjustment modifies the statistical model used to estimate that comparison. A properly specified adjusted model can therefore preserve the randomized comparison while accounting for prespecified covariates.
13. Intention-to-Treat and Censoring
The ITT definition posted on ClinicalTrials.gov for the efficacy analyses includes all randomized participants with valid informed consent, analyzed according to assigned treatment. For time-to-event analysis, participants contribute information until an observed event or an appropriate censoring point.
The Cox model uses the timing of events and the available follow-up rather than reducing the entire trial to a simple event/no-event proportion.
The registry's primary endpoint is labeled as a percentage endpoint, but the formal statistical analysis posted for it is explicitly classified as time-to-event. This distinction matters because two participants with the same eventual event status can contribute different amounts of information if their follow-up durations differ.
14. Why the Hazard Ratio Is Not a Risk Ratio
A hazard ratio and a risk ratio answer different questions.
| Measure | Question addressed |
|---|---|
| Hazard ratio | How do the modeled instantaneous event rates compare over follow-up? |
| Risk / proportion | What proportion of participants experience an event over a specified period? |
| Absolute risk difference | How much does the event probability differ between groups? |
Because the registry-reported EINSTEIN-PE statistical analyses report hazard ratios rather than arm-specific event probabilities for the primary result, the hazard ratios should not be translated into absolute risk differences. A statement such as “HR 0.90 means 10% fewer bleeding events” would be statistically incorrect if interpreted as an absolute reduction in the percentage of participants with bleeding.
15. Statistical Methods Explained
Why was a Cox proportional-hazards model used?
The primary and posted secondary endpoints are analyzed as time-to-event outcomes. A Cox model is designed for this setting because it uses both event occurrence and event timing while accommodating censoring. The reported effect measure is a hazard ratio, which summarizes the modeled relative event hazard.
Why is the non-inferiority margin more important than whether the HR is above 1?
Non-inferiority does not require the point estimate to be below 1.0. The question is whether the uncertainty around the treatment effect excludes effects worse than the prespecified acceptable margin. Here, the reported upper 95% CI is 1.68, while the stated non-inferiority margin is 2.0.
What does an HR of 1.12 mean?
It means the fitted Cox model estimates the instantaneous hazard for symptomatic recurrent VTE to be 1.12 times that of the comparator, or approximately 12% higher. It does not mean that 12% of participants had recurrent VTE, nor does it mean that the absolute event probability was 12% higher.
Why does the confidence interval matter?
The point estimate is only one estimate from the data. The 95% CI of 0.75–1.68 shows the statistical uncertainty around it. In a non-inferiority analysis, the upper boundary is especially important because the prespecified margin is an upper limit.
Why does the p-value not measure effect size?
A p-value summarizes evidence under a specified hypothesis and testing procedure. It does not quantify the magnitude of the treatment effect. The magnitude is described by the HR, while its uncertainty is described by the confidence interval.
Why distinguish ITT from the safety population?
The efficacy analysis preserves randomized assignment through ITT, while the safety analysis is based on participants who actually received at least one dose after randomization. The former is centered on the treatment assignment; the latter is centered on treatment exposure.
Why were analyses stratified by intended treatment duration?
The Cox analyses were reported as stratified by intended treatment duration. Stratification allows the baseline hazard structure to differ across those duration strata while estimating the treatment comparison within the model's overall framework.
16. What the Primary Result Does — and Does Not — Mean
The primary Cox model estimated an HR of 1.12 for symptomatic recurrent VTE, with a two-sided 95% CI of 0.75–1.68. The registry specifies an upper non-inferiority margin of 2.0, and the reported upper confidence limit is below that margin.
It does not mean that rivaroxaban has exactly the same efficacy as enoxaparin/VKA. It does not mean that every patient has a 12% higher hazard. It does not provide an absolute risk difference. It also does not establish superiority on the basis of the primary p-value.
The primary non-inferiority conclusion depends on the relationship between the confidence interval and the prespecified margin. Looking only at the HR of 1.12 would omit the key feature of the trial's hypothesis-testing framework.
17. Secondary Results as a Statistical Profile
| Endpoint | HR | 95% CI | P-value | Hypothesis |
|---|---|---|---|---|
| Symptomatic recurrent VTE | 1.12 | 0.75–1.68 | 0.0026 | Non-inferiority or equivalence |
| Recurrent DVT + non-fatal PE + all-cause mortality | 1.16 | 0.86–1.56 | 0.33 | Superiority |
| Net Clinical Benefit 1 | 0.85 | 0.63–1.14 | 0.275 | Superiority |
| Recurrent PE | 1.16 | 0.70–1.93 | 0.55 | Superiority |
| Recurrent DVT | 0.94 | 0.49–1.79 | 0.85 | Superiority |
| Clinically relevant bleeding | 0.90 | 0.76–1.07 | 0.23 | Superiority |
This table illustrates why statistical interpretation should not be reduced to identifying which p-values are below a threshold. The primary endpoint has a non-inferiority hypothesis and a margin-based decision rule, whereas the listed secondary analyses use superiority hypotheses. Their confidence intervals also vary considerably in width, reflecting different levels of statistical precision.
18. Non-Inferiority vs Superiority: Two Different Questions
Non-inferiority
The primary question asks whether the treatment is not unacceptably worse than the comparator, according to a prespecified margin. Here the stated upper HR margin is 2.0.
Superiority
The secondary analyses listed in the registry are framed as superiority comparisons. Their p-values therefore address evidence for a difference rather than the primary non-inferiority question.
A failure to demonstrate superiority is not the same statistical statement as demonstration of non-inferiority. Conversely, a treatment can satisfy a non-inferiority criterion without having a point estimate below 1.0. The hypothesis being tested determines how the confidence interval and p-value should be interpreted.
19. Interim Analysis, Multiplicity, Crossover, and Bayesian Methods
The ClinicalTrials.gov record provides explicit information about the primary non-inferiority design, including the event target, power, alpha level, and margin. They do not provide a stated interim-analysis procedure, multiplicity-adjustment strategy beyond the reported primary framework, or a Bayesian method.
| Design topic | What the ClinicalTrials.gov record supports |
|---|---|
| Non-inferiority margin | Relative upper hazard-ratio margin of 2.0 |
| Power | 90% power assuming equal efficacy and a total of 88 events |
| Alpha | Two-sided alpha=0.05 |
| Interim analysis | Not specified in the ClinicalTrials.gov record |
| Multiplicity | Not specified in the ClinicalTrials.gov record |
| Crossover | Not specified in the ClinicalTrials.gov record |
| Missing-data/imputation method | Not specified in the ClinicalTrials.gov record |
| Bayesian methods | Not reported in the statistical analyses posted on ClinicalTrials.gov |
20. Safety and Efficacy Are Different Statistical Questions
The trial reports both recurrent-thromboembolism outcomes and clinically relevant bleeding. These outcomes describe different components of treatment experience and should not be collapsed into a single informal “benefit-risk” number unless a prespecified composite or net-benefit endpoint is being analyzed.
Efficacy
The primary endpoint concerns symptomatic recurrent VTE, a composite of recurrent DVT or fatal or non-fatal PE.
Safety
Clinically relevant bleeding was a separate treatment-emergent secondary endpoint with follow-up extending until 2 days after the last dose.
Net clinical benefit
A separate secondary endpoint, Net Clinical Benefit 1, was analyzed using a Cox model and had an HR of 0.85 with a 95% CI of 0.63–1.14.
Serious adverse events
The registry data report 504/2412 affected/at risk in the rivaroxaban arm and 495/2405 in the enoxaparin/VKA arm.
21. Important Limitations and Interpretation Issues
- Non-inferiority depends on the margin: the primary interpretation is conditional on the prespecified upper hazard-ratio margin of 2.0. The margin is a design choice, not an empirical estimate from the final result.
- Primary endpoint classification: the registry labels the registered primary endpoint as binary, while the posted formal analysis classifies it as time-to-event and uses a Cox model. The statistical analysis should therefore be understood according to the posted analysis method.
- Hazard-ratio interpretation: a single HR compresses a time-to-event comparison into one relative measure and does not describe absolute risks or the entire event trajectory.
- Proportional-hazards assumption: Cox interpretation relies on the model framework. The ClinicalTrials.gov record does not report diagnostics for proportional hazards.
- Confidence-interval width: several secondary endpoints have broad intervals, particularly recurrent PE and recurrent DVT. Point estimates should therefore be interpreted together with their uncertainty intervals.
- Secondary hypotheses: the registry-reported secondary analyses are identified as superiority analyses. Their results should not be substituted for the primary non-inferiority question.
- Safety population: the clinically relevant bleeding analysis uses the valid-for-safety population rather than the ITT definition used for efficacy.
- Unreported design details: the ClinicalTrials.gov record does not specify interim monitoring, crossover, missing-data methods, multiplicity procedures, or Bayesian analyses. These cannot be reconstructed reliably from the posted results alone.
- Serious adverse-event counts: the reported affected/at-risk counts do not have a formal comparison statistic in the ClinicalTrials.gov record and therefore should not be treated as if they did.
22. Why This Trial Matters Statistically
EINSTEIN-PE is a useful teaching case because it shows how a randomized clinical trial can be structured around non-inferiority rather than superiority, while still using the same core time-to-event tools familiar from superiority trials.
| Concept | How it appears in EINSTEIN-PE |
|---|---|
| Randomization | Randomized parallel-group phase 3 design |
| Intention-to-treat | Primary and secondary efficacy analyses use the ITT population |
| Time-to-event endpoint | Primary and posted secondary analyses are classified as time-to-event |
| Cox model | Used for the primary and posted secondary analyses |
| Hazard ratio | Primary and secondary effect measure |
| Confidence interval | Two-sided 95% intervals accompany the reported hazard ratios |
| Non-inferiority | Primary hypothesis with an upper HR margin of 2.0 |
| Stratification | Analyses stratified by intended treatment duration |
| Covariate adjustment | Active malignancy at baseline included in the model |
| Safety analysis | Clinically relevant bleeding analyzed in the valid-for-safety population |
| Central adjudication | Primary events adjudicated by a central independent committee blinded to treatment |
The primary result is particularly instructive because the HR of 1.12 is above 1.0, yet the upper confidence limit of 1.68 remains below the prespecified non-inferiority margin of 2.0. That is the core lesson: non-inferiority is an interval-and-margin problem, not simply a question of whether the point estimate is below or above 1.
23. Statistical Concepts in This Trial
Learn more about the methods used in this trial:
24. Related Statistical Calculators
Explore calculators that correspond to the statistical pathway used in this trial:
25. Sources
- ClinicalTrials.gov: NCT00439777 — EINSTEIN-PE.
- PubMed record: PMID 22449293.
- PubMed record: PMID 23829521.
- PubMed record: PMID 24053656.
- PubMed record: PMID 24341332.
- PubMed record: PMID 24432872.
Continue through the Clinical Biostats statistical pathway
Move from this trial's non-inferiority and survival-analysis framework to tutorials and statistical calculators covering the underlying methods.
26. Record Summary
EINSTEIN-PE provides a clear example of how statistical interpretation changes when the primary objective is non-inferiority. The trial randomized 4833 participants in a parallel phase 3 design and evaluated symptomatic recurrent VTE using a Cox proportional-hazards model in the ITT population. The primary HR was 1.12, with a two-sided 95% CI of 0.75–1.68. Because the registry specifies an upper non-inferiority margin of 2.0, the upper confidence limit is the key quantity for the primary margin-based interpretation.
The secondary analyses demonstrate the same Cox framework applied to recurrent DVT, recurrent PE, a composite including all-cause mortality, Net Clinical Benefit 1, and clinically relevant bleeding. Their reported hazard ratios range from 0.85 to 1.16, with confidence intervals that should be read alongside the estimates rather than replaced by p-values alone. The safety analysis additionally reports serious adverse events of 504/2412 for rivaroxaban and 495/2405 for enoxaparin/VKA.