Neuroprotective Goal Directed Hemodynamic Optimization in Post-cardiac Arrest Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Neuroprotective Goal Directed Hemodynamic Optimization in Post-cardiac Arrest Patients (NCT02541591), a randomized na study. The primary outcome is % of Ischaemic Voxels With an ADC<0.65 mm2/s on Day 4-5 (Diffusion Weighted MRI).

2. Clinical Question

3. Trial Design

The NEUROPROTECT Post-CA Trial was registered as a randomized, parallel-group study with no masking. It was classified as phase NA and is marked completed. The registry record lists an enrollment of 112, a start date of 2015-08, and primary completion in 2018-06. The sponsor was Universitaire Ziekenhuizen KU Leuven.

The two arms were Neuroprotect and Control. The Neuroprotect strategy targeted MAP between 85-100mmHg and SVO2 between 65-75%; the Control description specified MAP >65mmHg. The record categorizes both interventions as other. Additional details about treatment delivery, duration, adherence, co-interventions, or protocol changes are not reported in the registry record.

The primary outcome was assessed at day 4-5 after cardiac arrest using diffusion-weighted MRI. The record describes measurement across 11 pre-specified brain regions: frontal cortex, parietal cortex, temporal cortex, occipital cortex, precentral cortex, postcentral cortex, caudate nucleus, putamen, thalamus, cerebellum, and pons. The outcome population is identified as the Full Analysis Set.

For the primary outcome, the registry reports 52 participants in the Neuroprotect arm and 55 in Control. These are the group sizes accompanying the posted endpoint results; the record does not explain how they relate to the enrollment figure or detail the flow of participants from enrollment to analysis. Definitions of the Full Analysis Set, exclusions from it, and handling of participants without an endpoint measurement are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as % of Ischaemic Voxels With an ADC<0.65 mm2/s on Day 4-5 (Diffusion Weighted MRI), measured over day 4-5.

The primary endpoint was the percentage of ischaemic voxels with an apparent diffusion coefficient (ADC)<0.65 mm2/s on diffusion-weighted MRI, assessed at day 4-5 after cardiac arrest. ADC is a quantitative MRI measure of water diffusion. In general, diffusion-weighted imaging can help characterize areas of restricted water movement, and an ADC threshold can be used to classify voxels according to a prespecified imaging rule. The threshold and imaging time point define what this trial counted; they do not by themselves establish a clinical diagnosis or a patient's longer-term outcome.

The registry describes assessment of ADC scores in 11 pre-specified brain regions and expresses the endpoint as a percentage of ischaemic voxels. The reported summary measure is the median, with an inter-quartile range (IQR). In the Neuroprotect group, the median was 10.6 and the IQR was 8.0-18.4. In Control, the median was 11.0 and the IQR was 8.4-14.8.

Using a defined imaging measure gives the trial a quantitative way to assess cerebral ischemia at a specified time after cardiac arrest. As a surrogate imaging endpoint, it describes the MRI finding rather than a direct measure of survival, neurological function, or quality of life. The registry record does not report validation details connecting this specific endpoint to those clinical outcomes.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is summarized by medians and inter-quartile ranges. A median is the midpoint of ordered observations: half of the values lie at or below it and half at or above it, subject to ties and the way the sample median is calculated. The IQR describes the span from the first to the third quartile, covering the middle half of the observed distribution under the usual definition. Unlike a standard deviation, an IQR is not a measure of average distance from the mean. These summaries can be useful when a distribution is skewed or contains extreme observations, but they do not reveal the complete distribution.

The Neuroprotect median was 10.6 (IQR 8.0-18.4), and the Control median was 11.0 (IQR 8.4-14.8). Those are descriptive group summaries. They are not themselves a formal test of the difference between groups, and subtracting the displayed medians would not reproduce the reported analysis. A comparison based on individual observations, a model, or a prespecified rank-based method can have an uncertainty estimate that is not recoverable from the medians and IQRs alone.

The registry labels the reported method ANOVA and describes its parameter as a median ratio of final values. ANOVA is a broad family of analysis-of-variance methods. The record does not specify the model form, any transformation, covariate adjustment, handling of ties, or the exact construction of the median ratio. It is therefore not possible to infer those details from the method label. In general, analysis labels should be read alongside the outcome scale and model definition; a short registry label does not communicate every modeling choice.

The reported ratio estimate is 1.37, with a 95% confidence interval of 0.95-1.98 and p=0.088. A ratio compares quantities on a multiplicative scale, rather than expressing an absolute difference. For a ratio, 1 is the conventional value corresponding to no ratio contrast. A confidence interval represents a range of estimates compatible with the data and analysis under its assumptions, using the stated confidence level. It is not a range containing a fixed proportion of individual participant outcomes, and it is not a probability statement about the true value after observing the data.

The record identifies the interval as 95%, but does not give enough detail to reconstruct how it was calculated. Its inclusion of 1 is relevant to interpreting the ratio: the data do not exclude the no-ratio-contrast value at that interval level. The interval's width also matters. It permits a range of ratio values, so a single point estimate should not be treated as exact. The p-value is consistent with evaluating the reported contrast against a null value, but the registry does not report whether it is adjusted or give details of the test implementation.

Randomization is intended, in general, to reduce systematic differences between assigned groups at baseline. It does not guarantee that every characteristic is balanced in a particular trial, and the registry record does not provide baseline characteristics or details of the randomization procedure. No masking was reported. Lack of masking can be relevant to how care is delivered and outcomes are assessed, although an imaging endpoint may have specific assessment procedures; the registry does not report whether image assessors were masked or how readings were standardized.

The sample-size assumptions describe planning illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Such illustrations are planning exercises, not observed power and not evidence of the trial's prospective design. The record does not report the trial's own sample-size justification, and these assumptions should not be treated as the actual design plan. General principle: power calculations depend on assumptions about the effect, variability, allocation, and analysis, so changing those assumptions changes the resulting planning estimate.

The registry names the Full Analysis Set as the primary-outcome population but does not define it. The endpoint group sizes are 52 and 55. The record does not explain how participants with unavailable scans or other missing endpoint data were handled, whether imputation was used, or whether sensitivity analyses were performed. A reported analysis population label alone cannot answer those questions.

10. Analyses Reported by the Sponsor

The registry's own reported analysis is an ANOVA result expressed as a median ratio of final values: 1.37, with a 95% confidence interval of 0.95-1.98 and p=0.088. The ratio convention is not described, so the direction of the contrast cannot be assigned from the estimate alone. The confidence interval includes 1, and the point estimate should be read in light of that uncertainty.

No recalculated two-arm estimate is available for the primary endpoint in the registry record. The posted arm medians and IQRs are descriptive summaries and cannot reproduce the sponsor's inferential analysis. They do not contain enough information to reconstruct its model, standard error, or confidence interval. Accordingly, there is no recalculated estimate to set against the sponsor's result. The registry record does not identify a discrepancy between a recalculation and the reported analysis.

The sponsor's analysis is therefore the inferential comparison to cite, with its method label and reported uncertainty, while keeping the limitations of the brief method description in view. The record does not provide further details about model specification, covariate adjustment, or the ratio's numerator and denominator.

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary outcome measure and one posted analysis. It reports zero secondary outcomes. This describes what is posted in the record; it does not establish that no other outcomes were collected or analyzed outside the registry entry. The record does not report a multiplicity strategy, such as an adjustment for testing several outcomes or a hierarchy for interpreting them.

Multiplicity matters in general when many hypotheses are tested, because repeated testing can increase the chance of at least one apparently notable result under null conditions. A prespecified primary endpoint can help focus interpretation, but the registry information does not say whether there were additional planned endpoints, subgroups, or analyses. It also does not report interim analyses or stopping rules. Those features should not be inferred from the presence of a single posted primary result.

The Full Analysis Set is named for the primary outcome, but its definition is not reported in the registry record. The reported outcome group sizes are 52 for Neuroprotect and 55 for Control. No participant flow, reasons for exclusion, scan availability, or missing-data method is described. It is therefore not possible to determine from the registry record whether endpoint data were missing, why any data might be missing, or how missingness could affect the estimate.

In general, missing-data methods rely on assumptions about why values are absent and how absent values relate to observed information. Complete-case analysis, imputation, and sensitivity analyses answer somewhat different questions and depend on different assumptions. The record does not say which approach was used, or whether sensitivity analyses assessed departures from the main assumptions. The label Full Analysis Set should not be taken as proof of a particular missing-data strategy.

The registry also does not report the prespecified statistical analysis plan or a sample-size justification. The stated planning assumptions are described as illustrations based on the observed effect, not the trial's own design. They cannot establish whether multiplicity, missing data, or interim monitoring was addressed in the study protocol.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: arrhythmia (23.6%), atrial fibrillation (7.3%), pulmonary congestion (3.6%), emd (1.9%), limb ischaemia (1.8%).

The registry reports serious adverse events in 7 participants in Neuroprotect, with 52 at risk, and 21 participants in Control, with 55 at risk. Other adverse events are listed as 0 in each group, with the same at-risk counts. Deaths are reported as 31 in Neuroprotect and 29 in Control. These counts are safety summaries, not the primary imaging endpoint.

The record also lists serious-event terms with percentages: arrhythmia 23.6%, Atrial fibrillation 7.3%, Pulmonary congestion 3.6%, EMD 1.9%, Limb ischaemia 1.8%, and death 1.8%. The denominator and event-counting rules behind these term percentages are not reported in the registry record. The term list should not be assumed to be exhaustive or directly comparable with the group-level serious-event counts.

These figures do not establish that an event was caused by an assigned strategy. The record does not provide event definitions, timing, follow-up duration, severity criteria, adjudication procedures, or details about repeated events in the same participant. Counts alone also do not describe the clinical circumstances of an event. The safety figures should therefore be read as registry-reported summaries, not as causal estimates or a complete account of comparative safety.

13. What the Result Does, and Does Not, Mean

The primary result describes a specific imaging outcome: the percentage of ischaemic voxels with an ADC<0.65 mm2/s on diffusion-weighted MRI at day 4-5 after cardiac arrest. The arm medians and IQRs provide descriptive summaries, and the registry's inferential result provides a median ratio estimate with a confidence interval and p-value. Taken together, they characterize the recorded endpoint and the uncertainty around the sponsor-reported comparison.

The reported ratio is 1.37, with a 95% confidence interval of 0.95-1.98 and p=0.088. Since the interval includes 1 and the ratio convention is not stated, the estimate should not be presented as a precisely established directional difference. A non-significant result, in general, is not proof that groups are equivalent or that no effect exists. Equivalence or non-inferiority requires an appropriate design, margin, and analysis, none of which is reported for this endpoint in the registry record.

The result does not establish an effect on survival, neurological recovery, or quality of life. The primary outcome is an MRI measure recorded at day 4-5, and no secondary outcomes are posted. The registry's death counts are safety summaries, not a reported inferential analysis of survival. They should not be combined with the imaging result to infer a treatment effect on patient-centered outcomes.

Nor does the endpoint alone tell whether a difference, if present, would be clinically important. The record does not report a minimal clinically important difference or validation linking this particular MRI measure to later outcomes. Statistical uncertainty and clinical importance are distinct: a result can be estimated with varying precision, while its practical meaning depends on context and evidence not stated in this registry entry.

The appropriate scope of interpretation is thus limited to the randomized comparison as registered, the posted Full Analysis Set outcome summaries, and the sponsor's reported analysis. Details about missing data, analytic assumptions, and assessment procedures are not reported in the registry record, which limits a fuller assessment of robustness.

14. Why This Trial Matters Statistically

This trial raises a useful statistical issue: the endpoint is an imaging measure summarized by medians and IQRs, while the registry's inferential analysis is labeled ANOVA and reported as a median ratio. Such combinations make careful reading of the analysis description important. A method name alone may not reveal the exact model or how its parameter relates to the arm-level summaries.

The distinction between a descriptive summary and an inferential comparison is central. Medians describe group distributions in a compact way, but the reported ratio, confidence interval, and p-value depend on an analysis of the data beyond those summary values. Readers cannot reconstruct that analysis from medians and IQRs alone. The absent details about the model and ratio convention also illustrate why transparent reporting should state the contrast, analysis population, missing-data handling, and assumptions.

The trial also focuses on a surrogate imaging endpoint at a specified post-arrest time point. This allows a quantitative assessment of cerebral ischemia, but does not directly answer questions about survival or longer-term neurological function. Distinguishing a measured biological or imaging outcome from a patient-centered outcome is important when interpreting the reach of a result.

Finally, the record shows the limits of registry reporting for a completed randomized study. It records group summaries, one primary analysis, and safety counts, yet leaves the analysis plan, outcome missingness, assessor masking, and multiplicity handling unreported. Those omissions do not negate the posted data, but they constrain independent evaluation of how the result was produced and how robust it may be.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record gives limited detail about the primary analysis. It names ANOVA and reports a median ratio, but does not specify the model, the ratio's numerator and denominator, any covariates, or the exact estimation procedure. This makes it difficult to interpret the ratio's direction or reconstruct the confidence interval and p-value from the posted arm summaries.

The primary endpoint is an imaging measure assessed at day 4-5. The registry describes the use of 11 pre-specified brain regions but does not give imaging acquisition details, image-reading procedures, quality control, or whether assessors were masked. The record also does not report evidence validating the particular threshold and percentage measure against longer-term neurological outcomes.

The analysis population is called the Full Analysis Set, but its membership rules are not described. Although endpoint group sizes are reported, there is no account of participant flow, missing scans, exclusions, or the handling of absent measurements. The effect of these unknowns on the reported estimate cannot be evaluated from the registry record.

The trial is marked unmasked. The record does not clarify whether masking was used for endpoint assessment, nor does it describe adherence, treatment exposure, or care received alongside the assigned strategy. These omissions limit assessment of how treatment assignment and outcome measurement were implemented.

Only one primary analysis and no secondary outcomes are posted. A multiplicity plan, interim analyses, sample-size justification, and full statistical analysis plan are not reported. The registry also lists serious adverse event and death counts without details about timing, definitions, adjudication, or the denominator for the serious-event term percentages. These reporting gaps limit interpretation beyond the specific posted summaries.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Neuroprotective Goal Directed Hemodynamic Optimization in Post-cardiac Arrest Patients — NCT02541591.
• Registry record last updated 2024-04-12; status last verified 2018-06.
• Results first posted 2024-04-12.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The NEUROPROTECT Post-CA Trial was a completed randomized, parallel-group study with no masking, sponsored by Universitaire Ziekenhuizen KU Leuven. It enrolled 112 participants and compared Neuroprotect hemodynamic optimization, targeting MAP between 85-100mmHg and SVO2 between 65-75%, with Control, described as MAP >65mmHg.

The primary endpoint was the percentage of ischaemic voxels with an ADC<0.65 mm2/s on diffusion-weighted MRI at day 4-5. In the Full Analysis Set, the Neuroprotect median was 10.6 (IQR 8.0-18.4), and the Control median was 11.0 (IQR 8.4-14.8). The registry reports an ANOVA median ratio of 1.37 (95% CI 0.95-1.98; p=0.088); the ratio convention is not stated.

The record does not post secondary outcomes or a recalculated two-arm estimate for the primary endpoint. Analysis-plan details, missing-data handling, and several safety-reporting definitions are not reported in the registry record.