This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. The numerical trial facts on this page are restricted to the ClinicalTrials.gov record. The registry reports that results were posted, but the ClinicalTrials.gov record does not contain formal statistical-analysis estimates, confidence intervals, or p-values.
1. Trial at a Glance
FIRE AND ICE was a randomized, parallel-group clinical trial comparing two pulmonary-vein isolation procedures in patients with symptomatic paroxysmal atrial fibrillation. The trial enrolled 769 participants and compared cryoballoon ablation with radiofrequency ablation.
| Feature | FIRE AND ICE |
|---|---|
| Trial name | FIRE AND ICE |
| ClinicalTrials.gov identifier | NCT01490814 |
| Condition | Symptomatic Paroxysmal Atrial Fibrillation (PAF) |
| Therapeutic area | Cardiology |
| Status | COMPLETED |
| Start | 2011-12 |
| Primary completion | 2016-01 |
| Allocation | RANDOMIZED |
| Design model | PARALLEL |
| Masking | NONE |
| Primary purpose | TREATMENT |
| Enrollment | 769 |
| Intervention | Electrical isolation of the pulmonary veins (procedure) |
| Comparator intervention | Electrical isolation of pulmonary veins (procedure) |
| Primary endpoints | 2 |
| Outcome measures posted | 8 |
| Lead sponsor | Medtronic Cardiac Ablation Solutions |
| Sponsor type | INDUSTRY |
2. Clinical Question
The central question was whether two pulmonary-vein isolation procedures produced different outcomes in patients with symptomatic paroxysmal atrial fibrillation. The ClinicalTrials.gov record identifies the two procedures as cryoballoon ablation and radiofrequency ablation in the reported safety-by-arm data.
Population
Patients with symptomatic Paroxysmal Atrial Fibrillation (PAF).
Intervention
Electrical isolation of the pulmonary veins using the procedure identified in the posted safety data as Cryoballoon Ablation.
Comparator
Electrical isolation of the pulmonary veins using the procedure identified in the posted safety data as Radiofrequency Ablation.
Primary question
How do the two randomized ablation procedures compare with respect to recurrence-related efficacy and the registered composite primary safety event?
3. Trial Design
Cryoballoon Ablation
- Electrical isolation of the pulmonary veins.
- Procedure identified in the posted safety data as Cryoballoon Ablation.
Radiofrequency Ablation
- Electrical isolation of the pulmonary veins.
- Procedure identified in the posted safety data as Radiofrequency Ablation.
The randomized parallel structure is important statistically because treatment assignment is made before the outcome comparison. In principle, randomization creates the framework for comparing outcomes between the two procedure groups while reducing systematic differences in measured and unmeasured baseline characteristics. The ClinicalTrials.gov record does not provide the allocation ratio, arm-specific enrollment numbers, stratification factors, or a detailed randomization procedure, so those features are not inferred here.
4. Endpoints
The registry lists two primary endpoints. Both have a time frame of 33 months.
| Endpoint | Registry definition | Time frame |
|---|---|---|
| Primary efficacy endpoint | Number of Subjects With Recurrence of Atrial Arrhythmias or Prescription of Anti-arrhythmic Drug or Re-ablation After a Blanking Period of Three Months After the Initial Ablation Procedure | 33 months |
| Primary safety endpoint | Number of Subjects With a Primary Safety Event. A Primary Safety Event Includes a Composite of Death (Including Cardiovascular Death), All-cause Stroke/Transient Ischemic Attack (TIA) and Serious Adverse Events of Special Interest. | 33 months |
Why the three-month blanking period matters
The efficacy endpoint explicitly excludes the first three months after the initial ablation procedure by applying a blanking period. Statistically, this defines when recurrence events begin to count toward the primary efficacy endpoint. That distinction is important because the endpoint is not simply "any atrial arrhythmia at any time after ablation"; it is the registry-defined recurrence, medication, or re-ablation outcome after the specified three-month period.
The efficacy endpoint is composite in a practical sense
The registered efficacy endpoint can be triggered by more than one type of event: recurrence of atrial arrhythmias, prescription of an anti-arrhythmic drug, or re-ablation. These components may have different clinical meanings. A statistical comparison of the composite therefore answers whether the overall protocol-defined endpoint occurred, not whether every component necessarily changed by the same amount.
The safety endpoint is explicitly composite
The safety endpoint combines death, all-cause stroke/TIA, and serious adverse events of special interest. A composite endpoint can increase the number of observed events and therefore provide a broader measure of safety, but interpretation requires attention to the individual components. A treatment comparison on the composite does not automatically establish that each component has the same treatment effect.
5. Planned Analysis
Primary efficacy endpoint
The registry defines the efficacy outcome as the number of subjects with recurrence of atrial arrhythmias or prescription of an anti-arrhythmic drug or re-ablation after a three-month blanking period, assessed over 33 months. For an endpoint recorded as time until the first occurrence of a qualifying event, a time-to-event analysis would ordinarily be appropriate. Kaplan-Meier methods could describe event-free survival over time, while a log-rank test and a Cox proportional-hazards model could be used for a randomized comparison if those methods were prespecified in the statistical analysis plan.
A hazard ratio is a relative time-to-event measure. It does not directly report the percentage of patients who experienced the endpoint, nor does it replace absolute event probabilities at clinically meaningful time points.
The ClinicalTrials.gov record does not state that a Cox model, Kaplan-Meier estimator, or log-rank test was actually used for this endpoint. These methods are therefore described here as the standard analytical framework for this type of endpoint, not as a claim about an unprovided analysis.
Primary safety endpoint
The primary safety outcome is a composite of death, all-cause stroke/TIA, and serious adverse events of special interest over 33 months. If analyzed as a time-to-first-event endpoint, the same general survival-analysis framework could be appropriate. If the registry instead summarizes whether each subject experienced the composite by the analysis time, a two-group comparison of cumulative proportions could be used. The ClinicalTrials.gov record does not specify which formal approach was used.
The distinction matters because a simple proportion comparison and a time-to-event comparison answer related but different questions. A proportion asks how many subjects experienced the event by a defined point, whereas a time-to-event analysis also uses information about when the event occurred and can account for censoring.
6. Statistical Methodology
Randomization
Randomization is the central design feature identified in the registry. Because treatment assignment is randomized, the primary comparison can be framed around the difference between the two assigned procedures rather than around observational associations between treatment choice and outcome.
The strength of the randomized design comes from the assignment mechanism. The numerical treatment effect still requires the observed endpoint data and the prespecified analysis method, neither of which is reported here in formal statistical-analysis form.
Time-to-event analysis
The primary efficacy endpoint has a 33-month follow-up window and a three-month blanking period, features that make time-to-event analysis particularly relevant if the registry endpoint was analyzed according to the time of first qualifying event. Such analyses distinguish participants who experience an event from participants who remain event-free through their last observation.
Kaplan-Meier estimation
For a time-to-event endpoint, the Kaplan-Meier estimator describes the probability of remaining event-free as follow-up progresses. Censoring allows participants who do not experience the endpoint during their available observation period to contribute information up to the point at which their outcome is no longer observed.
Here, di is the number of events at time ti and ni is the number at risk immediately before that time.
Cox proportional-hazards model
If a Cox model is used, its hazard ratio summarizes the relative instantaneous event rate between the randomized procedure groups under the fitted model. The proportional-hazards assumption is important: a single hazard ratio is most straightforward to interpret when the relative hazards are reasonably stable over the relevant follow-up period.
Composite endpoints
Both registered primary endpoints contain multiple clinically distinct pathways to an endpoint event. Composite outcomes should therefore be examined at two levels: the overall composite and its component events. A difference in the composite can be driven disproportionately by one component, particularly when components differ greatly in frequency or clinical importance.
7. Statistical Methods Explained
Why does randomization matter?
Randomization assigns participants to the competing procedures using a predefined assignment process rather than allowing treatment choice to be determined by clinical characteristics. This helps establish comparability between groups and supports causal interpretation of the randomized treatment comparison, subject to adherence, missingness, crossover or other post-randomization issues that may arise.
Why is there a three-month blanking period?
The registry definition explicitly places the primary efficacy assessment after a three-month blanking period following the initial ablation procedure. This means the primary endpoint is designed around the post-blanking period rather than counting every early recurrence. The blanking period is therefore part of the endpoint definition, not simply a statistical adjustment added after the results are observed.
Why might Kaplan-Meier methods be useful?
If the primary efficacy endpoint is evaluated as time to first qualifying event, participants can have different lengths of observable follow-up or remain event-free at the end of observation. Kaplan-Meier estimation uses the timing of events and accommodates right censoring, making it more informative than a simple event percentage when follow-up is not identical for everyone.
What would a hazard ratio mean here?
A hazard ratio below 1 would indicate a lower estimated instantaneous rate of the endpoint in the numerator group under the fitted Cox model; a hazard ratio above 1 would indicate a higher estimated rate. It would not mean that the same percentage of patients had a proportional reduction in their personal probability of recurrence or that the treatment changed the risk by a fixed amount for every patient.
Why should the composite safety endpoint be unpacked?
The registered primary safety endpoint combines death, all-cause stroke/TIA, and serious adverse events of special interest. Those events can differ substantially in frequency and clinical meaning. A single composite estimate can therefore conceal which component is contributing most to an observed difference. Component-level reporting is essential for interpretation.
Why does a confidence interval matter?
A confidence interval quantifies statistical uncertainty around an estimated treatment effect under the specified statistical framework. A narrow interval indicates greater precision than a wide interval, all else equal. It does not describe the range of outcomes that individual patients will experience and does not by itself establish clinical importance.
8. Reported Safety
The ClinicalTrials.gov record provides serious adverse events by randomized procedure arm. These are reported as affected participants over the corresponding at-risk populations.
| Safety measure | Cryoballoon Ablation | Radiofrequency Ablation |
|---|---|---|
| Serious adverse events | 129/374 | 158/376 |
The counts show that serious adverse events were reported in both procedure groups. Because the ClinicalTrials.gov record provides counts and denominators but no formal statistical analysis, this page does not attach a p-value, confidence interval, relative risk, odds ratio, or hazard ratio to the difference.
9. Interpreting the Safety Endpoint Correctly
The serious-adverse-event counts are not themselves the same thing as the registered primary safety endpoint. The registered endpoint is specifically a composite of death, all-cause stroke/TIA, and serious adverse events of special interest. The ClinicalTrials.gov record separately identify "Serious AEs by Arm" and do not provide the event counts for every component of the registered composite.
What the registry-reported counts tell us
They report affected and at-risk counts for serious adverse events in each procedure group.
What they do not tell us
They do not provide a formal statistical comparison of the registered primary safety composite.
Why components matter
The registered composite contains death, stroke/TIA, and serious adverse events of special interest, which are not interchangeable outcomes.
Why denominators matter
The reported safety denominators differ from the total enrollment and should not be replaced with 769 without supporting data.
10. Primary Endpoint Interpretation
The registered efficacy endpoint asks whether a participant experienced atrial-arrhythmia recurrence, received an anti-arrhythmic prescription, or underwent re-ablation after the three-month blanking period. This is a broad endpoint that captures several clinically relevant forms of post-ablation treatment failure or management escalation.
The ClinicalTrials.gov record does not provide the number of efficacy events in each arm, a hazard ratio, a confidence interval, or a p-value. Therefore, no numerical claim about the relative efficacy of cryoballoon versus radiofrequency ablation can be made from the registry-reported statistical-analysis field.
If a formal time-to-event analysis was prespecified, the most informative result would ordinarily combine an estimated effect measure with its confidence interval and an absolute event-free estimate at a clinically meaningful time point.
11. Primary Safety Endpoint Interpretation
The registered primary safety endpoint is a composite containing death, all-cause stroke/TIA, and serious adverse events of special interest. A formal comparison would need to preserve that exact endpoint definition.
The ClinicalTrials.gov record provides serious-adverse-event counts of 129/374 for Cryoballoon Ablation and 158/376 for Radiofrequency Ablation, but they do not provide the corresponding counts for every component of the registered composite or a formal comparison estimate.
These counts therefore should not be presented as though they were the complete primary safety endpoint. A confidence interval, when available, would describe uncertainty around the corresponding treatment-effect estimate; a p-value would address the specified statistical hypothesis and would not measure the magnitude or clinical importance of the effect.
12. Limitations
- Incomplete statistical-analysis detail: the ClinicalTrials.gov record states that results are posted but contain no formal statistical analyses. Exact treatment-effect estimates, confidence intervals, and p-values are therefore unavailable in the ClinicalTrials.gov record.
- Incomplete efficacy results: the ClinicalTrials.gov record does not provide event counts or treatment-effect estimates for the registered primary efficacy endpoint.
- Composite safety endpoint: the registered primary safety outcome combines several different event types, but the ClinicalTrials.gov record does not provide component-level results for the full composite.
- Safety denominators: the reported serious-adverse-event denominators are 374 and 376, while total enrollment is 769. The ClinicalTrials.gov record does not explain the denominator difference.
- No subgroup results: the ClinicalTrials.gov record contains no subgroup estimates. No subgroup conclusions should therefore be inferred.
- No formal multiplicity information: the ClinicalTrials.gov record does not describe multiplicity adjustment, endpoint hierarchy, alpha allocation, or a familywise type I error strategy.
- No interim-analysis information: the ClinicalTrials.gov record does not state whether an interim efficacy or safety analysis was performed or specify any stopping boundary.
- No missing-data strategy: the ClinicalTrials.gov record does not identify an imputation method, censoring rules beyond the three-month efficacy blanking period, or other missing-data procedures.
- No stratification factors: the ClinicalTrials.gov record identifies randomization but does not provide stratification variables or strata-specific analysis methods.
- No Bayesian analysis information: the ClinicalTrials.gov record contains no Bayesian model, prior distribution, posterior estimate, or Bayesian decision rule.
13. Why This Trial Matters Statistically
FIRE AND ICE is a useful statistical teaching case because the clinical question is naturally framed as a randomized comparison of two procedures rather than as a treatment-versus-placebo question. That changes the interpretation of both the design and the endpoint analysis.
| Concept | How it appears in FIRE AND ICE |
|---|---|
| Randomization | The trial uses RANDOMIZED allocation. |
| Parallel design | The two procedure groups are studied in a PARALLEL design. |
| Time-to-event analysis | The primary efficacy endpoint is defined after a three-month blanking period and followed through 33 months, making time-to-event methods a natural analytical framework if prespecified. |
| Composite endpoint | The primary safety endpoint combines death, stroke/TIA, and serious adverse events of special interest. |
| Endpoint definition | The efficacy endpoint combines recurrence, anti-arrhythmic prescription, and re-ablation. |
| Censoring | A time-to-event analysis would need explicit rules for participants who remain event-free or have incomplete observation. |
| Effect estimation | A formal comparison would ordinarily pair an effect estimate with its confidence interval and, where prespecified, a hypothesis-test result. |
| Safety denominators | Serious adverse events are reported using arm-specific at-risk denominators of 374 and 376. |
14. A Deeper Statistical Reading of the Trial Design
Randomization is not the same as statistical analysis
The registry establishes that the trial was randomized, but randomization alone does not specify how the endpoint was analyzed. A rigorous statistical report still needs the estimand, analysis population, endpoint definition, censoring rules, treatment-effect measure, confidence interval method, and hypothesis-testing procedure. The ClinicalTrials.gov record does not provide those details.
The endpoint definition determines the estimand
Because the primary efficacy endpoint includes recurrence, anti-arrhythmic drug prescription, and re-ablation, the treatment effect concerns the protocol-defined composite experience rather than recurrence alone. This distinction is especially important when comparing procedures: a participant can reach the endpoint through different pathways, and those pathways may have different clinical interpretations.
The blanking period changes what counts
The three-month blanking period is embedded in the endpoint definition. An event during the blanking period is therefore not automatically equivalent to an event contributing to the registered primary efficacy endpoint. Any statistical reconstruction must follow the registry definition rather than substituting a generic recurrence definition.
Safety and efficacy answer different questions
The efficacy endpoint addresses recurrence or subsequent management after ablation, while the safety endpoint concerns a composite of serious clinical outcomes. A statistical comparison should keep these questions separate. There is no single numerical statistic that replaces the distinct efficacy and safety analyses.
15. What a Complete Statistical Result Would Contain
For educational purposes, a complete analysis of the two primary endpoints would ideally report the following for each randomized procedure comparison:
Event information
Number of participants with the endpoint and the population at risk, together with follow-up information.
Effect estimate
An appropriate relative or absolute treatment-effect measure matching the prespecified estimand.
Precision
A confidence interval showing statistical uncertainty around the treatment-effect estimate.
Hypothesis test
A p-value only when a formal hypothesis test is part of the prespecified analysis, interpreted separately from effect magnitude.
The ClinicalTrials.gov record does not contain these formal statistical-analysis outputs. That absence is why this page uses a Planned Analysis framework rather than constructing numerical efficacy results from incomplete information.
16. Statistical Concepts in This Trial
Learn more about the methods used to understand this trial:
17. Related Statistical Calculators
18. Sources
- ClinicalTrials.gov: NCT01490814 — FIRE AND ICE.
- PubMed: PMID 27042964.
- PubMed: PMID 37071112.
- PubMed: PMID 29700058.
- PubMed: PMID 28751544.
- PubMed: PMID 27381589.
Continue through Clinical Biostats
Connect this trial's randomized design, time-to-event endpoints, composite safety outcome, and statistical concepts with deeper tutorials and statistical calculators.
19. Record Summary
FIRE AND ICE is a randomized, parallel-group trial of two pulmonary-vein isolation procedures in symptomatic paroxysmal atrial fibrillation. The registry identifies two primary endpoints over 33 months: a post-blanking efficacy endpoint based on recurrence of atrial arrhythmias, anti-arrhythmic drug prescription, or re-ablation, and a composite primary safety endpoint consisting of death, all-cause stroke/TIA, and serious adverse events of special interest.
The ClinicalTrials.gov record reports serious adverse events in both procedure groups, with 129/374 affected participants for Cryoballoon Ablation and 158/376 for Radiofrequency Ablation. They do not, however, provide formal statistical-analysis estimates for either primary endpoint. The appropriate statistical interpretation is therefore to distinguish the documented trial design and endpoint definitions from numerical treatment-effect claims that cannot be supported by the ClinicalTrials.gov record.