Angiotensin Converting Enzyme Inhibitors During Cardiopulmonary Bypass in Infants and Children: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Angiotensin Converting Enzyme Inhibitors During Cardiopulmonary Bypass in Infants and Children (NCT00848250), a randomized na study. The primary outcome is (PAI-1) Plasminogen Activator Inhibitor -1 Antigen.

2. Clinical Question

The clinical question concerns exposure to an ACE inhibitor around surgery, rather than starting treatment in patients who were not already taking one. The groups therefore represent continuation until the day of surgery versus stopping 48 hours beforehand among patients on ACE inhibitors who were randomized. The record does not describe treatment after surgery or any additional rules for resuming medication.

Alongside PAI-1, the registry lists interleukin-6, interleukin-8, mean arterial blood pressure, postoperative bleeding, and postoperative renal function as secondary outcomes. These measures cover inflammatory, hemodynamic, and postoperative domains. The registry does not report numerical results for those outcomes in the information available for this analysis. The primary question can therefore be stated from the design and outcome description, but the direction and size of any measured difference cannot be established from the record.

3. Trial Design

The study is identified as NCT00848250, with the title “Angiotensin Converting Enzyme Inhibitors During Cardiopulmonary Bypass in Infants and Children.” Its official title describes effects of angiotensin converting enzyme inhibition during and after cardiopulmonary bypass in infants and children with congenital heart defects. The registry lists Vanderbilt University Medical Center as sponsor, the condition as congenital heart disease, and the study status as completed. The listed enrollment is 21. The start is recorded as 2008-09 and primary completion as 2010-07.

The design is randomized, parallel-group, and unmasked. A parallel-group design assigns participants to one of the strategies and compares the groups rather than having each participant receive both strategies in sequence. Randomization is intended, in general, to reduce systematic differences between groups at assignment. The registry record does not report the method used to generate the random sequence, how assignments were concealed, or whether any stratification was used. Masking is listed as none; further details about who knew the assignments are not reported in the registry record.

The ACE inhibitor group continued existing ACE inhibitor treatment until the day of surgery. The no-ACE-inhibitor group consisted of patients taking ACE inhibitors who were randomized to stop 48 hours prior to surgery. The record does not describe the specific drugs or doses, adherence, treatment changes after surgery, or co-interventions. Phase is listed as NA.

The primary outcome is PAI-1 antigen, expressed as a mean of a continuous measure in ng/ml with standard error as the dispersion measure. It has measurements at several perioperative time points, rather than one single observation. The registry reports seven outcome measures and six analyses. It does not explain how those measures correspond to the analyses or give a full analysis plan. Numerical primary outcome results and effect estimates 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.

Before assignment: 29 participants were eligible, 8 refused participation

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.

6. Primary Endpoint

The registry lists the primary outcome as (PAI-1) Plasminogen Activator Inhibitor -1 Antigen, measured over Baseline (prior to surgery), On CPB for 30 minutes, At completion of CPB, and postoperative day 1 (at 8:00AM)postoperative day 1.

PAI-1 antigen is a measure associated with the fibrinolytic system, which is involved in the breakdown of blood clots. The study’s stated purpose included assessing whether ACE inhibitors alter the fibrinolytic response to cardiopulmonary bypass, making PAI-1 relevant to the biological question. This general description explains the endpoint’s role; it does not establish that a change in PAI-1 would necessarily correspond to a particular clinical outcome.

The registry defines the primary outcome as a mean of a continuous measure, with units of ng/ml and standard error as the reported dispersion type. It specifies measurement at baseline before surgery, during cardiopulmonary bypass for 30 minutes, at completion of bypass, and on postoperative day 1 at 8:00AM. These repeated observations can describe how the measure varies over the perioperative course. The record does not specify whether the primary comparison was based on a single time point, a change from baseline, a group-by-time contrast, or another summary.

Because the endpoint has multiple time points, its interpretation depends on the comparison and analysis used. A mean describes the group’s central value, while a standard error describes the precision of an estimated mean under the analysis assumptions; it is not the spread of individual measurements. The actual means, standard errors, group contrasts, and confidence intervals are not reported in the registry record. Thus, the endpoint definition and its rationale can be described, but the magnitude or precision of the observed group difference cannot be assessed from the information available.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help interpret this trial, even though the registry record does not report the numerical primary outcome comparison. The explanations below are general; they describe how such methods are commonly understood and do not imply that a particular method was used in this study.

What does randomization contribute?

In general, random assignment aims to make treatment groups comparable at the point of assignment, including with respect to factors that were measured and factors that were not measured. It supports a causal comparison when the allocation process is implemented as intended and the analysis follows an appropriate plan. Randomization does not guarantee that small groups will be balanced on every characteristic, and it does not eliminate uncertainty. The registry identifies the study as randomized but does not report the sequence-generation or allocation-concealment procedures. Those details are therefore not reported in the registry record.

How should a mean and standard error be read?

In general, a mean summarizes the central level of a continuous outcome across observations. The standard error describes uncertainty in an estimated mean, rather than the variability of individual participants’ measurements. A standard deviation, in contrast, describes variation among individual observations. The registry specifies means and standard errors for PAI-1 antigen but does not give the numerical values. A reader therefore cannot judge the observed levels or the precision of the means from this record.

A group difference is often more directly relevant than the two group means considered separately. Its estimate describes the size and direction of the contrast, while a confidence interval expresses a range of values compatible with the data and analysis assumptions. A narrow interval generally indicates greater precision than a wide interval. A p-value addresses compatibility with a specified null model, but it does not measure the size or clinical importance of an effect. No primary-outcome contrast, confidence interval, or p-value is reported in the registry record.

Why do multiple measurements matter?

PAI-1 was specified at baseline, during bypass, at bypass completion, and on postoperative day 1. Repeated measurements can show whether a measure changes over time and whether its pattern differs between groups. Analyses may focus on a particular time point, change from baseline, an overall trajectory, or a treatment-by-time interaction. Those approaches answer related but distinct questions and can produce different estimates. The registry record does not report which contrast or model was used for the primary outcome.

Repeated observations from the same participant are generally correlated: a participant’s measurements over time are not independent in the way measurements from different participants might be. General methods for repeated measures account for this dependence. The registry does not describe a covariance structure, model, transformation, or other analysis details. It would not be appropriate to infer a particular repeated-measures method from the endpoint schedule alone.

What does over-dispersion mean?

In general, over-dispersion occurs when the observed variability in data is greater than a statistical model assumes. It is especially relevant to count outcomes when a simple model expects a particular relationship between the mean and variance. If over-dispersion is ignored, standard errors can be too small and confidence intervals too narrow. This can make evidence appear more precise than it is. The registry record does not report an over-dispersion assessment or a count-data model; this general concept should not be taken to mean that over-dispersion occurred in this trial.

What are planning illustrations?

Sample-size planning uses assumptions about the effect to be detected, significance level, allocation, and statistical model to illustrate how much information a future study might need. These are planning calculations, not observed study results and not evidence of the power actually achieved. The planning assumptions associated with this record specify a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect expressed as a stated fraction of the observed effect. The record describes participant counts per arm for non-time-to-event outcomes and total event counts for time-to-event outcomes. Numerical planning values are not reported in the registry record. The illustration should not be confused with the trial’s own design justification, which is not reported.

These distinctions matter because a planning calculation based on an observed effect is conditional on that effect estimate and its uncertainty. It does not establish that the study was adequately powered, nor does it provide an observed treatment effect. The trial’s sample-size justification and any prospective assumptions are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome is measured at multiple perioperative times, and the registry lists several secondary outcomes. In general, testing multiple outcomes or multiple time-point contrasts increases the chance of at least one apparently unusual result if each test is interpreted without accounting for the number of comparisons. Multiplicity strategies can include prespecifying one primary contrast, adjusting significance thresholds, or treating secondary analyses as exploratory. The registry record does not report whether a multiplicity procedure was planned or used, or how the multiple PAI-1 time points were handled.

The record reports seven outcome measures and six analyses, but does not explain how they map to each other. It does not provide a complete statistical analysis plan, identify all prespecified contrasts, or state which outcomes were primary for inference beyond naming PAI-1 antigen as the primary outcome. Any multiplicity adjustment is not reported in the registry record. The available information therefore does not support a claim that all comparisons were prespecified or that any particular error-rate control was applied.

Missing-data handling is also not described. The record does not report how many observations were available at each PAI-1 time point, whether any measurements were missing, why they might be missing, or how missing values were handled. In general, missingness can affect a comparison if the probability of missing data is related to participants’ health status, treatment assignment, or observed outcome values. Methods such as complete-case analysis, imputation, or likelihood-based approaches rely on different assumptions; none should be attributed to this study without documentation.

Analysis populations are not specified. The registry record does not report whether the primary analysis followed intention-to-treat principles, included only participants with measured outcomes, or used another population definition. It also does not report exclusions or protocol deviations. These omissions limit assessment of how participants were retained in the analysis and how robust the comparisons may be to missing information.

11. 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

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: surgical re-exploration (27.3%), ecmo (9.1%).

The registry lists serious adverse event counts by group. For ACE Inhibitor, 11 were listed as at risk and 4 as affected; for No ACE Inhibitor, 9 were listed as at risk and 2 as affected. The listed number of deaths is zero for each group. These entries are counts, not adjusted comparative estimates, and the registry does not report a statistical test or confidence interval for the group comparison.

The registry also lists Surgical re-exploration at 27.3% and ECMO at 9.1% among the top serious adverse event terms. These percentages are registry entries and should be read as such; the record does not explain the denominator or provide event-level timing and descriptions. It does not report whether any participant experienced more than one event, or how recurrent events were handled. No total should be inferred from the listed terms.

Serious adverse event summaries are not equivalent to a complete assessment of all harms. The record does not provide detailed definitions, severity grading, relatedness assessments, exposure duration, or a full account of non-serious events. The figures describe what was recorded in the registry, but do not by themselves establish a causal relationship to either strategy or demonstrate a difference in risk.

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

This trial addresses a specific perioperative question: whether continuing an existing ACE inhibitor until the day of surgery, rather than stopping 48 hours prior to surgery, is associated with differences in physiologic responses to cardiopulmonary bypass in infants and children with congenital heart disease. The randomized parallel-group design is relevant to that comparison. The registry states the intended outcome domains and identifies PAI-1 antigen as the primary outcome.

However, the record does not report numerical primary-outcome results. It also does not report numerical results for the listed secondary outcomes. As a result, no direction or magnitude of a difference in PAI-1, inflammatory markers, blood pressure, bleeding, or renal function can be concluded from this information. Without outcome estimates and measures of precision, a reader cannot determine which effect sizes remain compatible with the data.

The serious adverse event counts are descriptive. They indicate the group-specific registry entries but do not establish that one strategy caused more or fewer events. The record does not report a formal comparative safety estimate, detailed event circumstances, or confidence intervals. The zero-death entries describe the registry listing; they do not establish the absence of other clinically important safety concerns.

These limits should not be mistaken for evidence that the strategies had the same effects. A missing estimate is not a zero estimate, and a lack of a reported statistical test is not a nonsignificant test. Conversely, the study’s purpose and randomized design do not establish that either strategy changed a biological or clinical outcome. Statistical interpretation requires the actual estimates, their uncertainty, and information about the analysis.

The trial is also specific to the population and treatment circumstances described in the registry: patients with congenital heart disease undergoing cardiopulmonary bypass who were already taking ACE inhibitors. The record does not describe the drugs, doses, detailed eligibility criteria, or post-surgical management. Its description should not be generalized beyond that context based on this registry information alone. The findings, insofar as they are numerically available, would need to be interpreted in light of the study’s size, methods, and completeness of outcome reporting.

13. Why This Trial Matters Statistically

This trial is statistically interesting because it poses a randomized comparison around a defined perioperative decision while measuring a continuous biological outcome repeatedly over time. Such a design raises several important analytic questions: which time-point contrast is primary, how within-participant correlation is handled, and how multiple outcomes and time points are interpreted. The registry identifies the primary measure and schedule but does not report those analytic details.

The record also illustrates the difference between a trial’s stated purpose and its reported results. A registry entry can describe the hypothesis, design, outcomes, and safety counts without providing the estimates needed to judge effect size or precision. For this study, PAI-1 antigen is named as the primary outcome, but numerical means and group comparisons are not reported in the registry record. The design alone cannot fill that gap.

Safety reporting presents a related challenge. Group-specific counts are useful descriptive information, but they are not a substitute for a comparative estimate with uncertainty and clear event definitions. The listed serious adverse events should not be treated as proof of a causal difference between strategies. This distinction is especially important in a study with a listed enrollment of 21, where estimates for uncommon outcomes could be uncertain.

Finally, sample-size illustrations based on an observed effect have a different role from prospective design justification. They can show how planning requirements vary under stated assumptions, but they do not reveal the study’s observed power or establish that its design was adequate. The trial’s own sample-size justification is not reported in the registry record. Separating design assumptions, observed results, and descriptive safety counts is essential for a careful statistical reading.

14. 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 primary limitation for interpreting efficacy is that numerical PAI-1 results are not reported in the registry record. Although the measure, units, summary type, and several time points are specified, no group means, standard errors, contrasts, confidence intervals, or p-values are included in the available information. The registry also does not report numerical results for the listed secondary outcomes. This prevents assessment of effect direction, size, and precision.

The record gives limited detail about how the randomized comparison was conducted. Random-sequence generation, allocation concealment, and the specific participants or staff aware of treatment assignment are not reported. Masking is listed as none, but further operational details are absent. Medication identities and doses, adherence, concomitant care, and post-operative treatment are also not described.

The endpoint schedule involves multiple observations, but the primary contrast and model are not specified. The handling of within-participant correlation, missing measurements, multiplicity, analysis populations, and protocol deviations is not reported in the registry record. The record’s listing of seven outcome measures and six analyses is not accompanied by enough information to reconstruct the analysis plan.

Safety information is limited to group-level entries and selected event terms. Event definitions, timing, recurrence, relatedness, and a comparative statistical analysis are not reported. The serious adverse event figures therefore offer a narrow descriptive account rather than a comprehensive harm assessment. The registry lists enrollment as 21, but a formal sample-size justification is not reported; the enrollment alone does not establish precision for the primary or safety outcomes.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Angiotensin Converting Enzyme Inhibitors During Cardiopulmonary Bypass in Infants and Children — NCT00848250.
• Registry record last updated 2017-07-26; status last verified 2017-06.
• Results first posted 2017-07-26.
• 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.

18. Record Summary

NCT00848250 is a completed randomized, unmasked, parallel-group study sponsored by Vanderbilt University Medical Center. It concerns ACE inhibitor use during cardiopulmonary bypass in infants and children with congenital heart disease. The registry lists enrollment as 21, phase as NA, a start of 2008-09, and primary completion of 2010-07.

Participants already taking an ACE inhibitor either continued it until the day of surgery or were assigned to stop it 48 hours prior to surgery. The primary outcome was mean PAI-1 antigen in ng/ml, with standard error specified and measurements scheduled before surgery, during bypass, at completion, and on postoperative day 1. Secondary outcomes included interleukin-6, interleukin-8, mean arterial blood pressure, postoperative bleeding, and postoperative renal function.

The registry lists serious adverse event counts and selected event terms, but does not report numerical primary or secondary outcome comparisons in the information available for this analysis. Details of the statistical plan, missing-data handling, and sample-size justification are not reported in the registry record.