This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. The ClinicalTrials.gov record identifies seven posted primary outcome measures, but does not provide formal statistical-analysis estimates, confidence intervals, or p-values for those outcomes. Accordingly, this page distinguishes the registered endpoints from statistical interpretation of how such endpoints would ordinarily be analyzed.
1. Trial at a Glance
CORAL was a randomized, parallel-group, open-label phase 3 trial evaluating medical therapy plus angioplasty and stenting in patients with renal atherosclerotic lesions. The trial enrolled 947 participants across two treatment arms.
| Feature | CORAL |
|---|---|
| Trial name | CORAL |
| Phase | Phase 3 |
| Population / conditions | Atherosclerosis; Cardiovascular Diseases; Hypertension, Renovascular; Renal Artery Obstruction |
| Design | Randomized, parallel-group, open-label |
| Primary purpose | Treatment |
| Enrollment | 947 |
| Arms | 2 |
| Start | 2004-04 |
| Primary completion | 2013-09 |
| Status | Completed |
| Lead sponsor | Baim Institute for Clinical Research |
| ClinicalTrials.gov | NCT00081731 |
2. Clinical Question
The central clinical-trial question was whether adding angioplasty plus stenting to medical therapy should be evaluated against medical therapy alone in patients with renal atherosclerotic lesions. The registry describes a randomized comparison between an optimal-medical-therapy arm and a stenting arm.
Population
Patients with renal artery stenosis represented by the registered conditions of atherosclerosis, cardiovascular diseases, renovascular hypertension, and renal artery obstruction. The registry states that patients could be enrolled with renal artery stenosis ≥60%.
Intervention
Angioplasty plus stenting using the GENESISTM Embolic Protection Stent and Angioguard Device, alongside medical therapy.
Comparator
Optimal medical therapy using Atacand/HCT and Caduet.
Primary question
How does the randomized addition of angioplasty plus stenting compare with optimal medical therapy with respect to the registered composite and individual clinical and renal endpoints?
3. Trial Design
Medical therapy
- Atacand/HCT
- Caduet
- Serious adverse events: 283/472 affected/at risk
Angioplasty plus stenting
- GENESISTM Embolic Protection Stent
- Angioguard Device
- Serious adverse events: 290/459 affected/at risk
4. Endpoints
CORAL has seven registered primary endpoints. The registry specifies that these outcomes were measured at every 3 months for the first year and annually thereafter. The composite endpoint includes only the first event per participant.
| Primary endpoint | Time frame | Registry definition / type |
|---|---|---|
| Composite Endpoint: Death From Cardiovascular or Renal Causes, Stroke, Myocardial Infarction, Hospitalization for CHF, Progressive Renal Insufficiency, or Permanent Renal Replacement Therapy | Measured at every 3 months for the first year and annually thereafter | Only the first event per participant is included in the composite. Endpoint type: Other / unclear. |
| Cardiovascular or Renal Death | Measured at every 3 months for the first year and annually thereafter | Endpoint type: Other / unclear. |
| Myocardial Infarction | Measured at every 3 months for the first year and annually thereafter | Endpoint type: Other / unclear. |
| Hospitalization for Congestive Heart Failure | Measured at every 3 months for the first year and annually thereafter | Endpoint type: Other / unclear. |
| Stroke | Measured at every 3 months for the first year and annually thereafter | Endpoint type: Other / unclear. |
| 30% Reduction of eGFR From Baseline, Persisting for Greater Than or Equal to 60 Days | Measured at every 3 months for the first year and annually thereafter | Endpoint type: Binary. |
| Need for Renal Replacement Therapy | Measured at every 3 months for the first year and annually thereafter | Endpoint type: Other / unclear. |
Why the composite endpoint is statistically important
The primary composite combines several clinically different events: cardiovascular or renal death, stroke, myocardial infarction, hospitalization for congestive heart failure, progressive renal insufficiency, and permanent renal replacement therapy. The registry specifies that only the first event per participant is included.
That construction has an important statistical consequence: the composite produces one first-event outcome per participant rather than counting every event a participant experiences. This can increase the number of participants contributing an endpoint event, but the interpretation of the composite depends on the clinical importance and frequency of its individual components.
5. Statistical Methodology
The ClinicalTrials.gov record does not provide formal statistical-analysis records for CORAL. There are no reported hazard ratios, risk ratios, odds ratios, confidence intervals, p-values, model specifications, or statistical-analysis populations in the posted results.
Time-to-event framework for the composite endpoint
The composite endpoint is naturally compatible with a time-to-first-event analysis because the registry specifies that only the first event per participant is included. In a conventional randomized analysis, each participant would contribute follow-up until the first qualifying event or an appropriate censoring time.
For a time-to-first-event endpoint, the Kaplan-Meier method can describe the event-free distribution over time, while a log-rank test can compare the randomized groups. A Cox proportional-hazards model can provide a hazard ratio comparing the groups. Those methods are described here as standard analytical approaches; the ClinicalTrials.gov record does not establish that any particular one was used for CORAL.
Here, T represents the time to the first qualifying event in a time-to-first-event analysis. Participants who have not experienced the event by the end of observed follow-up may contribute censored follow-up information.
Binary renal endpoint
The endpoint defined as a 30% reduction of eGFR from baseline persisting for greater than or equal to 60 days is classified in the ClinicalTrials.gov record as a binary endpoint. A conventional between-arm analysis could compare the proportion of participants meeting the definition in each randomized group using an appropriate risk-based or regression approach. The ClinicalTrials.gov record does not identify the formal method used or provide a treatment-effect estimate.
Individual clinical-event endpoints
Cardiovascular or renal death, myocardial infarction, hospitalization for congestive heart failure, stroke, and need for renal replacement therapy can also be analyzed as event outcomes. If time to the first event is retained, survival-analysis methods are generally appropriate. If the analysis instead focuses on whether an event occurred by a prespecified assessment point, a binary-event framework can be used. The ClinicalTrials.gov record does not specify which analytical representation was used.
6. Statistical Methods Explained
Why is randomization important in CORAL?
Randomization assigns participants to treatment groups by a process intended to prevent systematic differences in baseline characteristics from determining treatment assignment. Its statistical value is that, under appropriate conduct and assumptions, differences in outcomes between randomized groups can be attributed to the assigned intervention more directly than in an observational comparison.
Randomization does not guarantee that the groups will be numerically identical at baseline. Rather, it provides the design framework for a valid comparison and protects against systematic treatment-selection bias.
Why is a time-to-first-event analysis useful for the composite endpoint?
The registered composite is explicitly defined around the first qualifying event. A time-to-first-event analysis therefore preserves two pieces of information simultaneously: whether the participant experienced a qualifying event and when that first event occurred.
This is different from simply counting every cardiovascular or renal event. Once a participant has experienced the first qualifying component, later events do not generate additional first-composite events under the registry definition.
What would a hazard ratio mean if one were reported?
A hazard ratio compares the estimated instantaneous event rates between two groups within a time-to-event model. A hazard ratio below 1 would indicate a lower estimated event hazard in the numerator group relative to the comparator under the fitted model.
It would not mean that the same percentage of participants experienced that reduction in risk. It also would not directly provide an absolute risk difference, number needed to treat, or probability that an individual participant benefits.
A hazard ratio is a relative time-to-event measure. To understand the clinical magnitude of an effect, it is useful to pair a hazard ratio with absolute event probabilities or survival estimates at clinically meaningful time points. No such treatment-effect estimates are provided in the registry-reported CORAL statistical-analysis data.
Why does the 30% eGFR endpoint require the persistence criterion?
The registry defines the endpoint as a 30% reduction of eGFR from baseline that persists for greater than or equal to 60 days. The persistence requirement distinguishes a sustained renal-function change from a transient measurement. Statistically, this creates an endpoint with both a magnitude threshold and a duration requirement.
That definition also means the endpoint cannot be reconstructed correctly from a single eGFR measurement alone. A participant must satisfy the specified reduction and persistence conditions for the endpoint definition to be met.
Why can a composite endpoint be informative but difficult to interpret?
A composite can combine several clinically relevant events into one prespecified outcome, allowing the analysis to capture the first occurrence of any qualifying component. However, the components may differ substantially in severity, frequency, and susceptibility to treatment.
A statistically favorable composite therefore does not automatically imply that every component moved in the same direction or by the same magnitude. Component-level results are important for understanding what actually drove the composite. The registry-reported CORAL data identify the components but do not provide their statistical treatment effects.
What does a posted outcome measure tell us if no formal analysis is reported?
A posted outcome measure establishes what the registry says was measured, including its definition and time frame. It does not, by itself, establish the magnitude, precision, or statistical significance of a treatment comparison.
For that reason, a statistically responsible analysis must distinguish between an endpoint being registered or posted and a formal comparison being reported with an effect estimate, confidence interval, and p-value.
7. Planned Analysis
The registry-reported CORAL registry data contain posted outcome measures but no formal statistical-analysis entries. The appropriate statistical interpretation is therefore to describe how these endpoints would ordinarily be analyzed without attributing an unreported result to the trial.
| Endpoint family | Typical statistical approach | What would normally be reported |
|---|---|---|
| Composite first event | Time-to-first-event analysis, commonly using Kaplan-Meier estimation and a between-group time-to-event comparison | Event counts, time-to-event estimates, an effect estimate such as a hazard ratio, confidence interval, and hypothesis-test result |
| Cardiovascular or renal death | Time-to-event analysis when follow-up time is retained | Death events, time-to-event estimates, effect estimate, confidence interval, and p-value |
| Myocardial infarction | Time-to-event or binary-event analysis depending on the prespecified analysis plan | Event frequency and an appropriate between-group effect estimate with uncertainty |
| Hospitalization for congestive heart failure | Time-to-event or binary-event analysis depending on the prespecified analysis plan | Hospitalization frequency and an appropriate treatment-effect estimate |
| Stroke | Time-to-event or binary-event analysis depending on the prespecified analysis plan | Stroke frequency and an appropriate treatment-effect estimate |
| 30% reduction in eGFR persisting for ≥60 days | Binary-event analysis or a time-to-event formulation if the protocol defines time to sustained decline | Number or proportion meeting the endpoint and an appropriate effect estimate with confidence interval |
| Need for renal replacement therapy | Time-to-event or binary-event analysis depending on the prespecified analysis plan | Event frequency and an appropriate treatment-effect estimate |
8. Understanding the Composite Endpoint
The CORAL composite endpoint is unusual from a teaching perspective because it spans cardiovascular, renal, and hospitalization outcomes. The components are:
- Death from cardiovascular or renal causes.
- Stroke.
- Myocardial infarction.
- Hospitalization for congestive heart failure.
- Progressive renal insufficiency.
- Permanent renal replacement therapy.
The registry specifies that only the first event per participant is included. Thus, if a participant experiences more than one qualifying component, the composite analysis is based on the first qualifying event rather than a cumulative count of all events.
First-event interpretation
The composite asks when a participant first reaches any qualifying component, rather than how many qualifying events the participant ultimately experiences.
Component interpretation
The composite should be understood alongside its individual components because a single combined endpoint can conceal differences in the frequency or clinical character of those components.
9. Renal Endpoint: 30% eGFR Reduction
The renal-function endpoint is defined as a 30% reduction of eGFR from baseline, persisting for greater than or equal to 60 days. This is a binary endpoint in the registry classification.
All three elements are relevant to the registry definition: the reference value is baseline eGFR, the magnitude threshold is 30%, and the reduction must persist for the specified duration.
This construction is statistically important because the endpoint is not simply "eGFR decreased." It establishes a prespecified threshold and a persistence criterion. Such definitions can reduce sensitivity to short-lived fluctuations, but they also make the outcome dependent on repeated measurements and follow-up availability.
10. Safety Results
The ClinicalTrials.gov record provides serious adverse events by treatment arm as affected participants over the participants at risk.
| Safety measure | Optimal Medical Therapy | Stenting |
|---|---|---|
| Serious adverse events | 283/472 affected/at risk | 290/459 affected/at risk |
These figures should be read as the registry-reported affected/at-risk counts. They are not the same as the number of randomized participants in the overall trial, because the safety denominator reported by the registry differs between the two arms.
The appropriate statistical question for a safety comparison is not simply whether the two affected counts are numerically different. The denominators, timing of exposure, definition of serious adverse events, follow-up, and analysis population all affect the comparison. Because the ClinicalTrials.gov record does not provide a formal statistical-analysis record for serious adverse events, no inferential treatment comparison is reported here.
11. Randomization and Causal Interpretation
CORAL's randomized allocation is the central statistical feature of the design. Because treatment assignment is randomized, the primary comparison can be framed as a comparison between groups defined by assigned treatment rather than a comparison selected after observing outcomes.
This distinction matters particularly in renal artery disease, where treatment decisions can otherwise be influenced by the severity of stenosis, clinical presentation, physician judgment, and other factors associated with prognosis. Randomization is designed to break that systematic connection between prognostic factors and treatment assignment.
12. What the Registry Does Not Establish
A high-quality statistical interpretation should distinguish information that is explicitly available from information that would require additional trial documents or formal results.
| Topic | Status in the registry-reported CORAL data |
|---|---|
| Treatment-effect estimates | Not in the posted results. |
| Confidence intervals | Not reported. |
| P-values | Not reported. |
| Formal survival model | Not specified. |
| Analysis population | Not specified for the formal endpoint analyses. |
| Stratification factors | Not specified. |
| Multiplicity adjustment | Not specified. |
| Interim-analysis procedure | Not specified. |
| Missing-data / imputation strategy | Not specified. |
| Subgroup analyses | Not reported in the ClinicalTrials.gov record. |
This distinction is particularly important because a trial can have a posted outcome measure without the registry supplying enough statistical detail to reconstruct the formal inferential analysis. A responsible educational page should not fill those gaps with assumptions.
13. Important Limitations and Interpretation Issues
- Missing formal statistical analyses: The ClinicalTrials.gov record contains no statistical-analysis estimates, confidence intervals, or p-values, so this page cannot report an evidence-based numerical treatment effect for the primary endpoints.
- Open-label design: The registry specifies no masking. Lack of masking can matter most when outcome assessment or clinical management involves subjective judgment.
- Composite endpoint: The primary composite combines multiple event types with potentially different clinical importance and frequencies.
- First-event rule: Only the first event per participant is included in the composite, so subsequent qualifying events are not represented as additional composite events.
- Renal endpoint definition: The 30% eGFR reduction endpoint requires persistence for greater than or equal to 60 days, making repeated assessment and follow-up relevant to endpoint ascertainment.
- Serious adverse-event denominators: The registry-reported affected/at-risk counts differ from the overall enrollment and differ between treatment arms.
- Eligibility restriction: The registry states that patients could be enrolled with renal artery stenosis ≥60%.
- Fibromuscular dysplasia: The registry states that patients with fibromuscular dysplasia were not included.
- Enrollment selection: Some patients screened and deemed eligible were not enrolled because of physician preference, according to the registry caveat.
- Unspecified analysis details: The ClinicalTrials.gov record does not identify the formal statistical model, missing-data strategy, multiplicity procedure, or interim-analysis method.
14. Eligibility and Generalizability
The registry caveats are important when considering which patients the results can describe. Patients could be enrolled with renal artery stenosis ≥60%, while patients with fibromuscular dysplasia were not included. The registry also notes that some patients who were screened and deemed eligible were not enrolled because of physician preference.
Renal artery stenosis threshold
The registry states that patients could be enrolled with renal artery stenosis ≥60%.
Fibromuscular dysplasia
Patients with fibromuscular dysplasia were not included.
Screening to enrollment
Some screened patients deemed eligible were not enrolled because of physician preference.
Interpretive consequence
The enrolled population should not automatically be treated as representative of every patient with renal artery disease or every cause of renal artery stenosis.
15. Why This Trial Matters Statistically
CORAL is a useful teaching case because it illustrates how randomized clinical-trial statistics can become more complicated when the outcome is not a single laboratory measurement or a single disease event. The trial combines cardiovascular and renal outcomes, a first-event composite, a sustained renal-function threshold, and safety outcomes within an open-label randomized design.
| Concept | How it appears in CORAL |
|---|---|
| Randomization | Participants were randomized to two parallel treatment strategies. |
| Parallel-group design | The two arms were evaluated as separate randomized treatment groups. |
| Open-label trial | The registry specifies no masking. |
| Composite endpoint | The primary composite combines cardiovascular, renal, stroke, myocardial infarction, heart-failure hospitalization, and renal-replacement outcomes. |
| Time-to-first-event logic | Only the first event per participant is included in the composite. |
| Binary endpoint | The 30% eGFR reduction endpoint is classified as binary. |
| Repeated follow-up | Primary outcomes are measured every 3 months for the first year and annually thereafter. |
| Safety analysis | Serious adverse events are reported as affected/at-risk counts by arm. |
| Generalizability | Eligibility restrictions and enrollment decisions affect the population represented by the trial. |
| Statistical reporting | The ClinicalTrials.gov record does not provide formal effect estimates, confidence intervals, or p-values. |
16. Related Statistical Tutorials
Learn more about the methods used in this trial:
17. Related Statistical Calculators
18. Sources
- ClinicalTrials.gov: CORAL — NCT00081731.
- PubMed: PMID 24245567.
- PubMed: PMID 39402005.
- PubMed: PMID 34183258.
- PubMed: PMID 30962703.
- PubMed: PMID 27647847.
Continue through the Clinical Biostats statistical pathway
Use the trial's design and endpoints as a starting point for deeper study of randomization, composite outcomes, survival analysis, binary endpoints, and clinical-trial inference.
19. Record Summary
CORAL was a randomized phase 3, parallel-group, open-label trial with 947 enrolled participants and two treatment arms. Its seven registered primary endpoints include a first-event composite of cardiovascular or renal death, stroke, myocardial infarction, hospitalization for congestive heart failure, progressive renal insufficiency, or permanent renal replacement therapy, together with individual cardiovascular, renal, and clinical-event outcomes. The registry specifies measurement every 3 months for the first year and annually thereafter.
The ClinicalTrials.gov record supports a detailed description of the trial design and endpoint architecture, but they do not supply formal statistical-analysis estimates. Consequently, this page does not assign hazard ratios, risk ratios, confidence intervals, or p-values to CORAL outcomes. Instead, it explains the statistical framework appropriate to randomized first-event composites, individual clinical outcomes, and the binary sustained-eGFR endpoint while keeping reported trial information separate from methodological interpretation.