Extracellular Matrix Marker of Arrhythmia Risk (EMMA): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Extracellular Matrix Marker of Arrhythmia Risk (EMMA) (NCT00376532), a registered phase not stated study. The primary outcome is MMP-2.

2. Clinical Question

The central statistical question is whether a blood biomarker measured at enrollment is associated with subsequent or otherwise recorded device treatment. The registry describes the event groups by whether a participant did or did not experience pacing or shock. It does not report when those events occurred relative to measurement, how event ascertainment was performed, or whether the primary analysis compared group means or used another association measure.

The brief summary mentions both MMP-2 and MMP-9, while the listed primary outcome is MMP-2. The registry record does not report a result for either marker. It therefore supports describing the research question and group definitions, but not determining whether marker levels differed between groups or how precisely any relationship was estimated.

3. Trial Design

EMMA, identified as NCT00376532, is recorded as a completed study sponsored by Thomas Jefferson University. The record gives a start date of 2006-09 and a primary completion date of 2008-09. Enrollment is listed as 63. The study concerns patients with implanted cardioverter defibrillator devices and asks whether serum matrix metalloproteinase levels are associated with ventricular tachycardia or fibrillation events treated by the device.

The two described groups are defined by whether participants experienced a pacing or shock event. One group consists of subjects who experienced a device treatment, defined as a pacing event or shock event; the other consists of subjects who did not experience such a treatment. These are event-defined groups, not treatment arms assigned by the study. The record explicitly indicates that this is not a randomized comparison, and allocation is not stated.

This distinction matters for interpretation. In a randomized trial, assignment to an intervention is designed to make treatment groups comparable in expectation. Here, the groups are distinguished by observed device events. Any difference in a biomarker between them would be an association in the recorded groups, not by itself evidence that the biomarker caused an event or that changing the biomarker would change event risk. The registry record does not report adjustment for participant characteristics or other potential differences between groups.

The record lists two outcome measures, with MMP-2 identified as the primary outcome. It describes measurement at enrollment using Aushon Biosystems Searchlight® Protein Array Analysis. The registry record does not report additional details about eligibility criteria, follow-up duration, event adjudication, blinding, or the planned statistical model. Those details should not be inferred from the event-group labels or the study’s completed status.

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

Reasons for not completing this period:

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.

Population: Baseline analysis population was determined by the enrolled subjects for whom the MMP2 and MMP9 assays were completed.

6. Primary Endpoint

The registry lists the primary outcome as MMP-2, measured over At time of enrollment.

The primary endpoint is serum MMP-2 concentration, measured in pg/ml at the time of enrollment. The registry describes the outcome as a continuous measure summarized by its mean and standard deviation. Measurement is stated to use Aushon Biosystems Searchlight® Protein Array Analysis. The primary outcome description does not include a numeric mean or standard deviation for either event group.

MMP-2 is included as a marker of interest in a study examining risk stratification for ventricular tachycardia or fibrillation among patients with implanted cardioverter defibrillator devices. The research question is whether its level is related to whether a participant experienced a device pacing or shock event. A continuous biomarker can be compared across event-defined groups or analyzed in relation to an event outcome, but the registry record does not specify which analysis was planned or performed.

The brief summary also mentions MMP-9, but the primary outcome listed is MMP-2. The registry record does not report a numeric MMP-2 result, a group contrast, or an estimate of association. The endpoint definition explains what was measured and when; it does not establish that the marker predicts events or that a relationship was observed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous biomarker concentration, expressed in pg/ml and summarized in the registry as a mean with a standard deviation. The mean describes the arithmetic average of measured values. The standard deviation describes how dispersed individual values are around that average. These statistics answer different questions: the mean gives a measure of the group’s central level, while the standard deviation describes variability among measurements. Neither is reported numerically for the event groups in the registry record.

What would a group comparison tell us?

A comparison of mean MMP-2 levels between the event-defined groups would estimate how far apart their average measured concentrations are. Such a comparison describes the groups in the study; it does not, by itself, show that MMP-2 caused a device event or that it can accurately predict an event in new patients. The record defines groups by whether a device pacing or shock event occurred, but does not state the statistical model used to compare them. A raw difference, adjusted difference, correlation, or other measure is not reported in the registry record.

General statistical interpretation also depends on the data distribution and the assumptions of the analysis. A mean and standard deviation are often useful summaries, but a strongly asymmetric distribution or unusual observations can make the mean less representative of a typical value. The registry record does not report the distribution of MMP-2 measurements, diagnostic checks, transformations, or a rationale for the chosen summary. It is not possible to determine whether those issues affected the analysis.

How should uncertainty be understood?

An effect estimate gives the size and direction of a relationship under a specified analysis. A confidence interval is a general way to express uncertainty around that estimate: narrower intervals indicate greater precision, while wider intervals indicate less precision. A p-value, when reported, summarizes how compatible the observed data are with a specified null hypothesis under the test assumptions; it is not the probability that the null hypothesis is true. No effect estimate, confidence interval, or p-value is reported for MMP-2 in the registry record, so neither magnitude nor statistical uncertainty can be evaluated.

Statistical significance and clinical or scientific importance are distinct general concepts. A small estimated association can be statistically distinguishable from a null value in some settings, while a larger estimate can remain imprecise in others. In this record, neither the estimate nor its uncertainty is available. Consequently, it is not possible to judge whether any observed difference was small or large, precise or uncertain, or compatible with no association.

What do the planning assumptions mean?

The record describes sample-size illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is defined as a stated fraction of the observed effect. For time-to-event tables, the stated quantity is the total number of events using the Schoenfeld approach; other tables use participants per arm. These are planning illustrations, not observed power, and they are not evidence that the study was designed with those assumptions. The registry record does not report numerical sample-size illustration results or the study’s own sample-size justification. Because the observed effect itself is not reported, the assumptions cannot be used to infer a target enrollment or to assess whether enrollment was adequate.

In general, power is a design concept describing the chance that a planned test will detect an effect of a specified size under stated assumptions. A retrospective calculation based on an observed effect is not the same as a prospective design justification and should not be treated as a measure of the strength of the results. No observed MMP-2 effect is reported, so no study-specific power conclusion is possible.

Why does the nonrandomized comparison matter?

Random assignment can reduce systematic differences between groups, on average, for factors other than the assigned treatment. In this study, group membership is based on the occurrence of a device treatment, rather than random assignment. General observational comparisons may therefore be affected by confounding: a factor related both to biomarker levels and to event occurrence could contribute to an apparent association. Adjustment can sometimes address measured factors, but it cannot automatically remove bias from unmeasured or poorly measured factors. The registry record does not report covariate adjustment, a causal model, or a method for handling confounding.

Timing is also important when interpreting a biomarker as a potential predictor. The primary outcome is measured at enrollment, but the record does not report the event timing or follow-up details needed to establish whether all events occurred after that measurement. Without those details, predictive performance cannot be assessed from the description alone. The registry record does not report measures such as discrimination, calibration, or validation in another population.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("ICD Pacing or Shock Event", "No ICD Pacing or Shock Event")
n   <- c(25, 26)
m   <- c(173493.4, 139012.4)
sp  <- c(110996.7, 68988.4)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  ICD Pacing or Shock Event  25  173493.400  110996.700  127676.214  219310.586
CARM  No ICD Pacing or Shock Event  26  139012.400  68988.400  111147.382  166877.418

11. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures and identifies MMP-2 as the primary outcome. The brief summary also names MMP-9 as a marker of interest, but the record does not give a result for MMP-9 or enough detail to determine how it relates to the two listed outcome measures. The registry record does not report a multiplicity strategy, such as a prespecified hierarchy of tests or an adjustment for testing several outcomes. Without that information, the approach to interpreting multiple comparisons cannot be assessed.

The registry record lists zero analyses. It does not provide analysis results, an analysis population, or information about whether outcome data were missing. The number enrolled is 63, but the adverse-event summaries list 25 and 26 at risk in their respective groups; the record does not explain the relationship between those counts, enrollment, and the number with MMP-2 measurements. Those figures should not be treated as a complete accounting of the primary analysis population.

Missing-data methods are not reported in the registry record. There is no information about the amount or pattern of missing MMP-2 measurements, reasons for missingness, exclusions, imputation, or sensitivity analyses. These details matter because an analysis limited to participants with measured outcomes may differ from an analysis that accounts for missing values, depending on why data are missing. No specific conclusion about missing-data bias can be made from the record.

The registry record also does not report whether the analysis used an intention-to-treat, per-protocol, complete-case, or other population definition. Since the group labels are based on device events rather than randomized assignment, conventional intention-to-treat interpretation may not apply, but the actual analysis population remains unreported.

12. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The adverse-event summary lists zero serious adverse events and zero other adverse events for the ICD Pacing or Shock Event group, with 25 at risk. It also lists zero serious adverse events and zero other adverse events for the No ICD Pacing or Shock Event group, with 26 at risk. No serious adverse event terms are listed. Death counts are not reported in the registry record.

These entries describe what the registry reports in its adverse-event fields; they do not establish that no adverse events occurred outside the recorded categories or reporting period. The record does not provide definitions of the adverse-event collection period, methods of ascertainment, completeness of follow-up, or an explanation for the group counts. It also does not explain how the adverse-event groups relate to the total enrollment.

The two groups are defined by device-event status, not by assignment to different treatments. Therefore, these figures are not a randomized safety comparison. The counts should be read as registry entries for the specified groups, not as evidence that one group had lower risk or that the device-event classification caused any safety outcome. The absent death values should not be interpreted as zero deaths.

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

The registry record describes a study asking whether serum MMP-2 and MMP-9 levels relate to ventricular tachycardia or fibrillation events treated by an implanted cardioverter defibrillator. It identifies MMP-2 at enrollment as the primary outcome and defines groups according to whether a participant experienced device pacing or shock. These details establish the question and the measurement framework.

The record does not report the MMP-2 means or standard deviations, an estimated group contrast, a confidence interval, or a p-value. It also lists zero analyses. As a result, the posted registry information does not establish whether MMP-2 levels differed between the event-defined groups, what direction any difference took, or how precisely an association was estimated. The absence of reported results is not evidence that the groups were the same.

The record also does not report an MMP-9 result, missing-data handling, an analysis population, or adjusted analyses. Although enrollment is listed as 63, the relationship between enrollment and the adverse-event at-risk counts is not explained, and those counts cannot be assumed to be the MMP-2 analysis sample sizes.

Even with numerical results, a group association in this nonrandomized comparison would not establish a causal effect. Participants were categorized by whether a device event occurred, and allocation to the groups was not randomized. Other differences between participants might contribute to an observed relationship. The record does not describe methods to address those differences.

The study’s completed status and biomarker measurement method do not answer the statistical question on their own. The record supports a precise account of what investigators set out to examine, but not a conclusion about the observed relationship, predictive performance, or clinical usefulness of either marker.

14. Why This Trial Matters Statistically

This study raises a common statistical challenge in clinical research: distinguishing a biologically plausible marker from a marker that has demonstrated an association with a clinically defined event. MMP-2 is measured at enrollment, while the comparison is framed around whether a device pacing or shock event occurred. Linking a biomarker to such events requires clear timing, complete outcome information, and an analysis that matches the research question.

The group definitions also illustrate why study design matters. Participants were not randomized to event status; they were classified according to whether a device treatment was experienced. A comparison between these groups can describe an association, but it does not isolate a causal effect. Potential differences between groups, including factors related to both marker concentrations and event occurrence, can complicate interpretation. The registry record does not report whether any such factors were measured or adjusted for.

Reporting is essential for evaluating evidence. Means and standard deviations would describe the biomarker values, while an effect estimate and uncertainty interval would help readers assess the size and precision of a group relationship. The registry record identifies the outcome and measurement method but does not report these results. It also does not report analyses, missing-data methods, or the analysis population. This leaves the central statistical question unanswered by the registry record.

The record’s sample-size assumptions are described as planning illustrations based on an observed effect, not as the study’s own design justification. That distinction is useful: retrospective illustrations cannot substitute for a prespecified rationale, and they do not establish the reliability of an unreported result. The main statistical lesson is that an explicitly stated biomarker question, a defined comparison, and a completed status are not enough to evaluate evidence without the estimates and methods needed to interpret it.

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 leaves several trial-specific details unreported. It does not provide eligibility criteria, the number of participants with an MMP-2 measurement, or an explanation of how the enrollment of 63 relates to the adverse-event at-risk counts of 25 and 26. Consequently, the analysis population and the extent of outcome availability cannot be established from the record.

The study objective mentions both MMP-2 and MMP-9, but only MMP-2 is identified as the primary outcome and no numerical result is reported for either marker. The record lists two outcome measures, yet does not provide their full results or clarify the relationship between the listed measures and the markers described in the objective. It also does not report a statistical analysis plan, a model, adjustment variables, or a multiplicity approach.

The primary outcome is described as measured at enrollment, but event timing, follow-up duration, and event ascertainment procedures are not reported. This limits interpretation of whether the measurement was intended to precede events and whether the study evaluated association, prediction, or another question. No external validation or predictive-performance measures are reported.

Because the comparison is not randomized and groups are defined by event experience, any group difference could reflect other differences between participants. The registry record does not describe methods for controlling confounding. Missing-data handling, exclusions, sensitivity analyses, and analysis-population definitions are also not reported. Finally, the adverse-event record lists zero events in its specified categories, but does not give collection details, and death counts are not reported. These omissions limit both efficacy-related interpretation and safety interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Extracellular Matrix Marker of Arrhythmia Risk (EMMA) — NCT00376532.
• Registry record last updated 2014-06-04; status last verified 2014-05.
• Results first posted 2014-06-04.
• 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

NCT00376532, Extracellular Matrix Marker of Arrhythmia Risk (EMMA), is recorded as completed and sponsored by Thomas Jefferson University. The registry lists enrollment of 63, a start date of 2006-09, and a primary completion date of 2008-09. The study concerns patients with implanted cardioverter defibrillator devices and examines whether serum matrix metalloproteinase levels relate to ventricular arrhythmia events treated by pacing or shock.

The listed primary outcome is mean serum MMP-2 in pg/ml at enrollment, measured using Aushon Biosystems Searchlight® Protein Array Analysis. Participants are described in event-defined groups, and the comparison is not randomized. The registry lists two outcome measures and zero analyses. Group results, statistical estimates, analysis populations, missing-data methods, and the MMP-9 result are not reported in the registry record. The adverse-event summary records zero serious and zero other adverse events in each listed group; death counts are not reported.