This page separates reported trial results from statistical interpretation. Trial-specific numerical results and design facts on this page are taken from the ClinicalTrials.gov record. The registry reports two primary time-to-event analyses and six additional posted statistical analyses.
1. Trial at a Glance
CIRT was a randomized, parallel-group, triple-masked, phase 3 trial comparing methotrexate with placebo in participants with cardiovascular disease. The trial enrolled 4786 participants and had two registered primary endpoints, both analyzed as time-to-event outcomes.
| Feature | CIRT |
|---|---|
| Brief title | Cardiovascular Inflammation Reduction Trial |
| Phase | Phase 3 |
| Status | COMPLETED |
| Therapeutic area | Cardiovascular |
| Condition | Cardiovascular Disease |
| Allocation | RANDOMIZED |
| Design model | PARALLEL |
| Masking | TRIPLE |
| Primary purpose | TREATMENT |
| Enrollment | 4786 |
| Lead sponsor | Brigham and Women's Hospital |
| Start | 2013-04 |
| Primary completion | 2019-04-15 |
| Registered primary endpoints | 2 |
| Outcome measures posted | 13 |
| Statistical analyses posted | 8 |
2. Clinical Question
The primary statistical question was whether assignment to methotrexate, compared with placebo, changed the time to occurrence of major cardiovascular events in participants with cardiovascular disease. The registry specified two primary time-to-event endpoints and a superiority hypothesis for each.
Population
Participants enrolled in the phase 3 trial with the registry condition of cardiovascular disease.
Intervention
Methotrexate.
Comparator
Placebo.
Primary question
Does methotrexate change the hazard of the prespecified cardiovascular time-to-event outcomes compared with placebo?
3. Trial Design
Methotrexate
- Randomized study intervention.
- Included in the primary and secondary time-to-event comparisons.
- Serious adverse events: 569 affected participants among 2391 at risk.
Placebo
- Randomized comparator.
- Included in the primary and secondary time-to-event comparisons.
- Serious adverse events: 549 affected participants among 2395 at risk.
4. Primary Endpoints
The two registered primary endpoints were both defined around the first occurrence of clinically important cardiovascular events. Both were analyzed from randomization to the trial end, April 2, 2018, with a maximum follow-up of 5 years.
| Primary endpoint | Registered definition | Time frame |
|---|---|---|
| Number of Subjects With Major Adverse Cardiovascular Events | The first occurrence of Major Adverse Cardiovascular Event, defined as the occurrence of one or more of the following: Cardiovascular Death, Non-Fatal Myocardial Infarction or Non-Fatal Stroke. | From randomization to trial end (April 2, 2018) up to a maximum of 5 years |
| Number of Subjects With Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina That Led to Urgent Coronary Revascularization | The first occurrence of Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina that led to Urgent Coronary Revascularization. | From randomization to trial end (April 2, 2018) - up to a maximum of 5 years |
5. Statistical Methodology
Time-to-event analysis
Both primary endpoints were treated as time-to-event outcomes. The relevant quantity is not simply whether an event occurred, but when the first qualifying event occurred during follow-up. Participants who did not experience the endpoint before the end of their available follow-up contribute information until their censoring time.
This distinction is important because two randomized groups can have similar proportions of observed events at one point in time while having different event timing. Survival-analysis methods use the ordering and timing of events rather than reducing the entire follow-up period to a single binary outcome.
Log-rank test
The registry reports a log-rank test for both primary endpoints. The log-rank procedure compares the observed pattern of events between randomized groups over follow-up, accounting for the changing number of participants at risk.
The log-rank test evaluates whether the observed event experience differs systematically between the treatment groups under the specified survival-analysis framework. Its P-value addresses evidence against the null hypothesis; it is not a measure of how large or clinically important an effect is.
Hazard ratio
The effect measure reported for the primary analyses was a Cox proportional-hazard estimate. A hazard ratio compares the estimated instantaneous event rate between groups within the fitted model.
An HR below 1 indicates a lower estimated hazard in the methotrexate group; an HR above 1 indicates a higher estimated hazard. The HR is not an absolute risk difference and does not state the probability that an individual participant will experience an event.
Stratified analysis
The primary analyses were stratified according to type of qualifying event, time of qualifying event, and risk status. The registry specifies risk status using diabetes or metabolic syndrome alone for the first primary endpoint and metabolic syndrome alone or diabetes at enrollment for the second primary endpoint.
Stratification allows the comparison to account for prespecified categories that can affect the event process. Rather than assuming that all participants contribute to a single completely homogeneous risk set, the analysis compares treatment experience within the relevant strata and combines the resulting information according to the statistical model.
Analysis population
The primary MACE analysis used all randomized subjects. The second primary analysis used all randomized participants. This is consistent with an analysis anchored to randomized assignment rather than restricting the efficacy comparison to participants who completed a particular amount of treatment.
6. Primary Results: Major Adverse Cardiovascular Events
The first primary endpoint was the first occurrence of a Major Adverse Cardiovascular Event, defined in the registry as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. The posted analysis compared methotrexate with placebo using a stratified log-rank test and a Cox proportional-hazard estimate.
Hazard ratio for Major Adverse Cardiovascular Events
95% CI: 0.82–1.25 · P = 0.91
Analysis population: all randomized subjects · Two-sided 95% confidence interval
| Endpoint | Method | Effect measure | Estimate | 95% CI | P-value |
|---|---|---|---|---|---|
| Major Adverse Cardiovascular Events | Stratified log-rank test | Cox proportional hazard | 1.01 | 0.82–1.25 | 0.91 |
The estimated hazard ratio of 1.01 is very close to 1.00. Within the fitted Cox model, this corresponds to an estimated instantaneous event rate that is approximately the same in the methotrexate and placebo groups.
The estimate does not mean that the two groups had exactly identical event risks for every participant or at every point in time. A hazard ratio is a model-based relative measure of event rates over the analyzed follow-up.
The 95% confidence interval of 0.82–1.25 shows the statistical uncertainty around the estimate. It spans values below and above 1.00, so the interval is compatible with a lower hazard, little difference, or a higher hazard under the statistical model and sampling framework.
The P = 0.91 value addresses the strength of evidence against the specified null hypothesis; it does not measure effect size, clinical importance, or the probability that the treatment has no effect. The size and location of the hazard-ratio estimate and its confidence interval are needed to understand the magnitude and precision of the comparison.
The analysis notes also state that confidence intervals were not adjusted for multiplicity. Therefore, the reported interval should be interpreted in the context of the broader set of analyses rather than as an independently multiplicity-adjusted interval.
7. Primary Results: Major Adverse Cardiovascular Event or Urgent Coronary Revascularization
The second primary endpoint expanded the event definition to the first occurrence of a Major Adverse Cardiovascular Event or hospitalization for unstable angina that led to urgent coronary revascularization.
Hazard ratio for the second primary endpoint
95% CI: 0.79–1.16 · P = 0.67
Analysis population: all randomized participants · Two-sided 95% confidence interval
| Endpoint | Method | Effect measure | Estimate | 95% CI | P-value |
|---|---|---|---|---|---|
| Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina That Led to Urgent Coronary Revascularization | Stratified log-rank test | Cox proportional hazard | 0.96 | 0.79–1.16 | 0.67 |
The hazard ratio of 0.96 corresponds to an estimated hazard approximately 4% lower in the methotrexate group than in the placebo group under the fitted model. That small relative difference is an estimate, not a statement that each participant had exactly 4% lower risk.
The 95% confidence interval of 0.79–1.16 includes 1.00. It therefore encompasses both a lower estimated hazard and a higher estimated hazard, illustrating the uncertainty around the point estimate.
The P = 0.67 value is evidence against the null hypothesis at the level represented by that test, but it should not be interpreted as a 67% probability that the treatment works or does not work. P-values do not quantify the magnitude of an effect.
As with the first primary endpoint, the analysis was stratified and the confidence interval was not adjusted for multiplicity. The registry specifically cautions that inferences drawn from these intervals may not be reproducible.
8. Secondary Time-to-Event Results
The registry also posts formal analyses for four secondary endpoints. Each used all randomized participants, compared methotrexate with placebo, and used a log-rank test with a Cox proportional-hazard effect measure. The analyses incorporated stratification and the registry notes that confidence intervals were not adjusted for multiplicity.
| Secondary endpoint | HR | 95% CI | P-value | Time frame |
|---|---|---|---|---|
| All-cause mortality | 1.16 | 0.87–1.56 | 0.32 | From randomization to trial end (April 2, 2018) up to a maximum of 5 years |
| Major Adverse Cardiovascular Event or Any Coronary Revascularization | 0.95 | 0.81–1.12 | 0.57 | From randomization to trial end (April 2, 2018) - up to a maximum of 5 years |
| Hospitalization for Congestive Heart Failure | 0.89 | 0.60–1.31 | 0.54 | From randomization to trial end (April 2, 2018) up to a maximum of 5 years |
| Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality | 0.98 | 0.84–1.14 | 0.80 | From randomization to trial end (April 2, 2018) up to a maximum of 5 years |
How these secondary estimates should be read
The secondary estimates range from 0.89 to 1.16. Some point estimates are below 1 and one is above 1, but the confidence intervals posted on ClinicalTrials.gov for these analyses all include 1.00. These estimates therefore do not provide a simple basis for treating any one secondary endpoint as an isolated definitive treatment-effect finding.
There is an additional statistical issue: the registry explicitly states that the confidence intervals were not adjusted for multiplicity. When multiple endpoints are examined, the probability of obtaining an apparently unusual result somewhere among the collection of analyses can increase. Consequently, nominal confidence intervals and P-values from individual secondary analyses should be interpreted as part of the overall analysis set rather than as though each were a standalone confirmatory test.
9. Additional Pre-Specified Analyses
Two additional pre-specified time-to-event analyses were posted in the registry. The first compares methotrexate for hospitalization for unstable angina that led to unplanned coronary revascularization; the registry's analysis record lists the compared group as Methotrexate. The second evaluates coronary revascularization and explicitly compares methotrexate with placebo.
| Endpoint | Groups compared | HR | 95% CI | P-value |
|---|---|---|---|---|
| Hospitalization for Unstable Angina That Led to Unplanned Coronary Revascularization | Methotrexate | 0.81 | 0.53–1.22 | 0.31 |
| Coronary Revascularization | Methotrexate vs Placebo | 0.92 | 0.75–1.12 | 0.38 |
Both analyses used a log-rank test and Cox proportional-hazard effect measure. Both used two-sided 95% confidence intervals, and both included the registry's stratification and multiplicity caveat. The point estimate of 0.81 for hospitalization for unstable angina that led to unplanned coronary revascularization is compatible with a lower hazard, but its confidence interval of 0.53–1.22 also includes values above 1.00.
10. Statistical Methods Explained
Why was a log-rank test used?
All eight posted statistical analyses use time-to-event methods. A log-rank test is designed for comparing survival or event-time distributions between groups while accounting for the timing of events and censoring. That makes it more informative for these endpoints than simply comparing the proportion of participants who eventually experienced an event.
What does a hazard ratio of 1.01 mean?
An HR of 1.01 means the fitted model estimates the instantaneous event hazard in the methotrexate group to be about 1.01 times that in the placebo group. Because 1.01 is very close to 1, the estimated relative difference is small. It does not mean that the cumulative risks are exactly equal at every time point.
Why does the confidence interval matter?
The point estimate is only one estimate from the observed trial data. The 95% confidence interval describes statistical uncertainty around that estimate under the model and sampling framework. For the first primary endpoint, 0.82–1.25 is considerably wider than the single value 1.01 and includes both sides of the null value 1.00.
Why doesn't the P-value measure the size of the treatment effect?
A P-value evaluates how compatible the observed data are with a specified null hypothesis under the statistical model. It depends on both the estimated effect and the amount of information in the analysis. It therefore cannot be used as a substitute for the hazard ratio or its confidence interval.
Why was stratification used?
The registry states that the analyses were stratified according to type of qualifying event, time of qualifying event, and risk status. Stratification permits the analysis to account for these specified categories when comparing event times, rather than treating all risk sets as if they were identical.
What does the proportional-hazards assumption contribute?
The Cox proportional-hazards framework expresses treatment effect through a hazard ratio. The interpretation of a single HR is most straightforward when the relative hazards are reasonably represented by a proportional-hazards relationship over time. The registry supplies the Cox hazard-ratio estimates, but the ClinicalTrials.gov record does not provide a diagnostic assessment of proportional hazards. Therefore, this page does not infer that the assumption was verified.
Why is multiplicity important here?
The registry reports two primary endpoints plus multiple secondary and additional pre-specified analyses. It also explicitly states that the reported confidence intervals were not adjusted for multiplicity. That means a reader should distinguish the prespecified analysis framework from an interpretation in which every posted endpoint is treated as an independent confirmatory test.
11. Confidence Intervals, Null Values, and Effect Size
| Estimate | 95% CI | P-value | What the numbers describe |
|---|---|---|---|
| Primary MACE HR 1.01 | 0.82–1.25 | 0.91 | Point estimate close to 1, with uncertainty spanning lower and higher hazards |
| Primary expanded endpoint HR 0.96 | 0.79–1.16 | 0.67 | Small estimated relative difference, with uncertainty spanning 1 |
| All-cause mortality HR 1.16 | 0.87–1.56 | 0.32 | Point estimate above 1, with substantial uncertainty around the direction and magnitude |
| MACE or any coronary revascularization HR 0.95 | 0.81–1.12 | 0.57 | Point estimate slightly below 1, with interval including 1 |
| Hospitalization for congestive heart failure HR 0.89 | 0.60–1.31 | 0.54 | Point estimate below 1, with a relatively wide interval |
| Expanded cardiovascular composite HR 0.98 | 0.84–1.14 | 0.80 | Point estimate close to 1, with interval spanning both sides |
A useful discipline in reading these results is to separate three quantities. The hazard ratio describes the estimated relative effect. The confidence interval describes uncertainty around that estimate. The P-value addresses compatibility with a null hypothesis. None of the three alone describes absolute event probability or an individual's treatment response.
For a hazard ratio, 1.00 is the null value. Values below 1 indicate a lower estimated hazard in the treatment group, while values above 1 indicate a higher estimated hazard. Whether the estimate is precise enough to support a particular conclusion depends on the confidence interval, the prespecified analysis plan, multiplicity, censoring, and the assumptions underlying the survival model.
12. Multiplicity and the Broader Analysis Set
CIRT's registry record contains 13 posted outcome measures and 8 posted statistical analyses. The two primary analyses were accompanied by several secondary and additional pre-specified analyses.
Multiple endpoints
Testing or estimating several outcomes creates a broader inferential context than evaluating a single endpoint in isolation.
Unadjusted intervals
The registry states that confidence intervals were not adjusted for multiplicity and cautions that inferences from them may not be reproducible.
Nominal P-values
A P-value reported for an individual endpoint should not automatically be interpreted as if it came from a separate confirmatory testing family.
Interpretation hierarchy
Primary endpoints, secondary endpoints, and other pre-specified analyses should remain distinguishable when summarizing the evidence.
This distinction is especially important for clinical-trial pages because a table of many P-values can visually imply that every row carries the same evidentiary status. The CIRT registry data do not support treating the eight posted analyses as eight equivalent confirmatory tests.
13. Early Termination and Futility
The registry reports that CIRT was terminated early because the pre-specified boundary for futility was crossed for both the original and the final primary endpoints. It also reports a lack of evidence of a reduction in hsCRP level with methotrexate treatment.
What the futility statement means statistically
A futility boundary is a prespecified decision rule concerning whether continued trial follow-up is sufficiently promising under the trial's design assumptions.
Futility monitoring is different from declaring that a treatment has been proven ineffective. The statistical meaning depends on the prespecified monitoring rule, the information available at the interim assessment, and the assumptions used to define the boundary. The ClinicalTrials.gov record identifies the reason for early termination but do not provide the numerical futility boundary, interim information fraction, or interim estimate. Those quantities therefore are not reproduced here.
14. Safety Results
The ClinicalTrials.gov record reports serious adverse events by randomized arm as affected participants divided by participants at risk.
| Safety measure | Methotrexate | Placebo |
|---|---|---|
| Serious adverse events | 569 / 2391 | 549 / 2395 |
The registry supplies these counts as the serious-adverse-event measure. They should not be converted here into an independently calculated percentage because the page's data rules require reported numerical values to be preserved exactly and the ClinicalTrials.gov recordset does not provide an explicit percentage. The at-risk denominators also differ slightly between the two arms.
15. Reading the Primary Results Together
The two primary hazard-ratio estimates are 1.01 for Major Adverse Cardiovascular Events and 0.96 for Major Adverse Cardiovascular Event or hospitalization for unstable angina that led to urgent coronary revascularization. The corresponding 95% confidence intervals are 0.82–1.25 and 0.79–1.16, respectively.
Both estimates are close to the null value of 1.00, and both confidence intervals include 1.00. The corresponding P-values are 0.91 and 0.67. These numbers describe the results of the posted superiority analyses; they do not by themselves establish that every possible cardiovascular outcome is unaffected, nor do they quantify the probability that methotrexate has no biological effect.
The registry's early-termination statement provides an important design context. Because the trial crossed a pre-specified futility boundary for both primary endpoints, the observed results should be understood within a trial that stopped early rather than as if it had necessarily continued to its originally intended endpoint of follow-up.
The central statistical lesson is that point estimates, uncertainty, hypothesis tests, and trial-monitoring decisions are different pieces of evidence. The HR tells us the direction and relative magnitude estimated by the model. The CI describes uncertainty. The P-value quantifies evidence relative to a null hypothesis. The futility decision reflects a prespecified interim-monitoring rule. None should be substituted for another.
16. Limitations
- Early termination: the registry states that the trial was terminated early after crossing a pre-specified futility boundary for both the original and final primary endpoints.
- Multiplicity: confidence intervals were not adjusted for multiplicity, and the registry cautions that inferences drawn from them may not be reproducible.
- Multiple analyses: the record contains 13 posted outcome measures and 8 statistical analyses, so individual secondary results should be interpreted within the broader analysis set.
- Proportional-hazards framework: the posted effect measures are Cox proportional-hazard estimates. The ClinicalTrials.gov record does not report a diagnostic assessment of the proportional-hazards assumption.
- Censoring: time-to-event methods rely on censoring mechanisms and follow-up information. The ClinicalTrials.gov recordset does not provide enough participant-level information to independently evaluate censoring assumptions.
- Limited event detail: the ClinicalTrials.gov record reports hazard ratios, confidence intervals, and P-values but do not provide the underlying event counts for the primary efficacy endpoints.
- Limited interim detail: the registry identifies futility as a reason for early termination but does not provide the numerical futility boundary or interim information fraction in the ClinicalTrials.gov record.
- Safety detail: the ClinicalTrials.gov recordset provides serious adverse events by arm but does not provide a more extensive safety table for this analysis.
- No individual-level reconstruction: the available summary statistics are insufficient to reconstruct Kaplan-Meier curves or independently reproduce the Cox estimates from participant-level data.
17. Why This Trial Matters Statistically
CIRT is a useful teaching case because its registry record connects randomized treatment assignment with multiple time-to-event outcomes and illustrates how statistical interpretation changes when a trial has several endpoints, stratified survival analyses, multiplicity considerations, and early stopping for futility.
| Concept | How it appears in CIRT |
|---|---|
| Randomization | The trial used randomized allocation to methotrexate or placebo. |
| Parallel design | The registry identifies a parallel-group design model. |
| Triple masking | The registry identifies the trial as triple-masked. |
| Time-to-event endpoints | Both primary endpoints and the posted secondary analyses were analyzed as time-to-event outcomes. |
| Log-rank test | Each posted statistical analysis used a log-rank comparison. |
| Hazard ratio | Cox proportional-hazard estimates were used as the effect measure. |
| Stratified analysis | Analyses were stratified according to event type, event timing, and risk status. |
| Confidence intervals | Primary analyses reported two-sided 95% confidence intervals. |
| Multiplicity | The registry explicitly states that confidence intervals were not adjusted for multiplicity. |
| Superiority testing | The posted analyses identify superiority as the hypothesis type. |
| Futility monitoring | Early termination occurred after crossing a pre-specified futility boundary for both primary endpoints. |
| Safety analysis | Serious adverse events are reported by randomized arm as affected participants among those at risk. |
18. Statistical Interpretation: What the Hazard Ratios Do — and Do Not — Mean
The MACE HR of 1.01 indicates an estimated instantaneous event hazard approximately 1% higher in the methotrexate group than in the placebo group under the fitted Cox model. This is a relative model-based estimate; it does not mean that 1% more participants experienced MACE.
The second primary HR of 0.96 indicates an estimated instantaneous event hazard approximately 4% lower in the methotrexate group than in the placebo group under the fitted model. It does not mean that the cumulative probability of the composite endpoint was exactly 4% lower.
The first primary 95% CI, 0.82–1.25, and the second primary 95% CI, 0.79–1.16, quantify uncertainty around the corresponding point estimates. Both include the null value of 1.00, so the intervals encompass both lower and higher hazards.
The primary P-values, 0.91 and 0.67, are hypothesis-test quantities. They should not be interpreted as effect sizes or as probabilities that the null hypothesis is true. The hazard ratio and confidence interval provide the essential information about estimated magnitude and precision.
19. Analysis Population, Censoring, and Model Interpretation
The primary MACE analysis used all randomized subjects, and the second primary analysis used all randomized participants. This preserves the randomized comparison as the basis for efficacy inference.
For a time-to-event analysis, participants can contribute information even when they do not experience the endpoint during the observed follow-up. Their follow-up may end through administrative study termination or another censoring mechanism. The statistical model uses their available event-free time rather than simply discarding them.
The Cox proportional-hazard model then summarizes the treatment contrast through a hazard ratio. A single HR is convenient and widely interpretable, but it is not a complete description of two survival distributions. If the relative hazard changes substantially over time, the meaning of one summary HR can become less straightforward.
20. Early Stopping: A Statistical Perspective
Early stopping for futility is fundamentally a decision rule, not an effect-size metric. A trial can be stopped because the accumulating information crosses a boundary indicating that continuing is unlikely to provide the prespecified level of evidence or benefit under the design assumptions.
What is known
The registry states that a pre-specified futility boundary was crossed for both the original and final primary endpoints.
What is not reported
The ClinicalTrials.gov record do not give the numerical futility boundary, interim hazard-ratio estimate, or information fraction at the stopping decision.
Why it matters
Stopping changes the amount and timing of information available for the final analysis and should therefore remain part of the statistical interpretation.
What it does not mean
A futility decision should not automatically be restated as proof of no treatment effect across every possible endpoint or population.
21. Registry Results Summary
| Endpoint role | Endpoint | HR | 95% CI | P-value |
|---|---|---|---|---|
| Primary | Major Adverse Cardiovascular Events | 1.01 | 0.82–1.25 | 0.91 |
| Primary | Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina That Led to Urgent Coronary Revascularization | 0.96 | 0.79–1.16 | 0.67 |
| Secondary | All-cause Mortality | 1.16 | 0.87–1.56 | 0.32 |
| Secondary | Major Adverse Cardiovascular Event or Any Coronary Revascularization | 0.95 | 0.81–1.12 | 0.57 |
| Secondary | Hospitalization for Congestive Heart Failure | 0.89 | 0.60–1.31 | 0.54 |
| Secondary | Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality | 0.98 | 0.84–1.14 | 0.80 |
| Other pre-specified | Hospitalization for Unstable Angina That Led to Unplanned Coronary Revascularization | 0.81 | 0.53–1.22 | 0.31 |
| Other pre-specified | Coronary Revascularization | 0.92 | 0.75–1.12 | 0.38 |
All eight analyses used a log-rank test and a Cox proportional-hazard effect measure. The analyses were stratified according to the event and risk-status factors specified in the registry analysis notes. The confidence intervals were two-sided 95% intervals and were not adjusted for multiplicity.
22. Clinical Interpretation vs Statistical Interpretation
Statistical interpretation
The two primary Cox hazard-ratio estimates were 1.01 and 0.96, with two-sided 95% confidence intervals of 0.82–1.25 and 0.79–1.16. Both intervals include the null value of 1.00, and the corresponding P-values were 0.91 and 0.67.
Clinical interpretation
The ClinicalTrials.gov record does not provide absolute event rates, median event times, or participant-level outcome trajectories for the primary endpoints. Accordingly, this page does not infer an absolute magnitude of clinical benefit or harm from the hazard ratios alone.
The appropriate interpretation is therefore deliberately narrower than a simple statement based on a P-value. The trial provides estimated relative effects for the prespecified time-to-event endpoints, together with uncertainty intervals and a documented early-termination decision. Those pieces should be considered together.
23. Related Tutorials
Learn more about the methods used in this trial:
24. Related Statistical Calculators
25. Sources
- ClinicalTrials.gov: CIRT — NCT01594333.
- PubMed record: PMID 39657237 — PubMed.
- PubMed record: PMID 38663834 — PubMed.
- PubMed record: PMID 35671649 — PubMed.
- PubMed record: PMID 35606100 — PubMed.
- PubMed record: PMID 34551998 — PubMed.
Continue through the Clinical Biostats library
Explore tutorials and statistical calculators that explain the survival-analysis methods, confidence intervals, hypothesis testing, and clinical-trial concepts used in CIRT.
26. Record Summary
CIRT is a phase 3 randomized, parallel, triple-masked trial comparing methotrexate with placebo in cardiovascular disease. Its two primary endpoints were time-to-event composites, and both were analyzed using stratified log-rank tests with Cox proportional-hazard estimates. The primary MACE analysis produced an HR of 1.01 (95% CI 0.82–1.25; P = 0.91), while the primary analysis of MACE or hospitalization for unstable angina leading to urgent coronary revascularization produced an HR of 0.96 (95% CI 0.79–1.16; P = 0.67).
The posted secondary and additional pre-specified analyses likewise use survival-analysis methods, with hazard-ratio estimates ranging from 0.81 to 1.16 across the endpoints posted on ClinicalTrials.gov. Their confidence intervals were not adjusted for multiplicity. The registry also states that the trial was terminated early after crossing a pre-specified futility boundary for both the original and final primary endpoints and because of the lack of evidence of a reduction in hsCRP level with methotrexate treatment.