This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Effects of Perioperative Nesiritide or Milrinone Infusion on Recovery From Fontan Surgery (NCT00543309), a randomized phase 2 study. The primary outcome is Days Alive and Out of the Hospital Within 30 Days of Surgery..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00543309 |
| Phase | Phase 2 |
| Condition | Heart Defects, Congenital |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 106 |
| Arms in the primary outcome | 3 |
| Lead sponsor | John M Costello |
| Results posted | Yes |
2. Clinical Question
Population
Children undergoing Fontan surgery for congenital heart defects. The staged surgical pathway for children with single ventricle heart defects culminates in the Fontan operation, which reroutes systemic venous return directly to the pulmonary arteries. The registry record describes a single-center study and lists an enrollment of 106 participants.
Intervention
Perioperative intravenous nesiritide or milrinone infusion. The planned nesiritide regimen included a loading dose followed by an infusion, while the milrinone regimen included a bolus followed by an infusion. Both were administered for at least 12 hours after cardiac intensive care unit admission and up to five days, unless prespecified lack-of-efficacy criteria were met.
Comparator
Placebo infusion, described as dextrose in water. The placebo regimen also began with a bolus, followed by an infusion for at least 12 hours after cardiac intensive care unit admission and up to five days, unless prespecified lack-of-efficacy criteria were met.
Primary question
Whether perioperative nesiritide, compared with milrinone or placebo, is associated with more days alive and out of the hospital within 30 days after surgery. The registry record describes this as the investigators’ hypothesis; it does not report a sponsor-led comparative estimate for the primary outcome.
3. Trial Design
This was a randomized, parallel-group, phase II clinical trial with three assigned groups: nesiritide, milrinone and placebo. The registry describes the study as single-center, double-blind and quadruple-masked. The masking label does not identify which specific roles were masked. The recorded enrollment was 106.
The active regimens were given by intravenous infusion after surgery. Nesiritide was described as a loading dose followed by infusion; milrinone was described as a bolus followed by infusion. The placebo group received a dextrose-in-water bolus and infusion. Each regimen was planned to continue for at least 12 hours after cardiac intensive care unit admission and up to five days, subject to prespecified lack-of-efficacy criteria. The registry record does not report further details about how those criteria were applied.
The primary outcome was days alive and out of the hospital within 30 days of surgery. The registry reports a median and full range for each assigned group. It also lists secondary outcomes spanning cardiovascular measures, renal function and resource use, including arrhythmia, cardiac index, peak inotrope score, peak lactate level, urine output, change in serum creatinine and duration of mechanical ventilation until initial extubation.
The study status is terminated. The reason for termination is not reported in the registry record. The record lists a start in 2007-10 and primary completion in 2013-01; these dates do not establish why the trial ended or whether the planned analysis was completed. The registry record does not report a sample-size justification or a detailed statistical analysis plan.
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
| Stage | I- Nesiritide | II- Milrinone | III- Placebo |
|---|---|---|---|
| STARTED | 35 | 36 | 35 |
| COMPLETED | 35 | 35 | 35 |
| NOT COMPLETED | 0 | 1 | 0 |
Reasons for not completing this period:
| Reason | I- Nesiritide | II- Milrinone | III- Placebo |
|---|---|---|---|
| Physician Decision | 0 | 1 | 0 |
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.
| Characteristic | Unit | I- Nesiritide | II- Milrinone | III- Placebo | Total |
|---|---|---|---|---|---|
| Participants analysed | 35 | 36 | 35 | 106 | |
| Age, Continuous | years | 2.7 (1.9 to 15.2) | 2.6 (1.8 to 14.4) | 2.7 (1.9 to 4.5) | 2.7 (1.8 to 15.2) |
| Sex: Female, Male: Female | Participants | 15 | 17 | 12 | 44 |
| Sex: Female, Male: Male | Participants | 20 | 19 | 23 | 62 |
| Race/Ethnicity, Customized: Race – White | Participants | 28 | 24 | 22 | 74 |
| Race/Ethnicity, Customized: Race – Black | Participants | 3 | 2 | 4 | 9 |
| Race/Ethnicity, Customized: Race – Hispanic/Latino | Participants | 3 | 7 | 5 | 15 |
| Race/Ethnicity, Customized: Race – Asian | Participants | 0 | 3 | 2 | 5 |
| Race/Ethnicity, Customized: Race – More than one race | Participants | 0 | 0 | 2 | 2 |
| Race/Ethnicity, Customized: Race – Other | Participants | 1 | 0 | 0 | 1 |
| Region of Enrollment: United States | Participants | 35 | 36 | 35 | 106 |
| Weight | kilograms | 12.5 (9.9 to 65.7) | 12.8 (9.1 to 40.6) | 12.6 (9.8 to 20.4) | 12.6 (9.1 to 65.7) |
| Ventricular Morphology: Left dominant | Participants | 15 | 10 | 12 | 37 |
| Ventricular Morphology: Right dominant | Participants | 20 | 25 | 22 | 67 |
| Ventricular Morphology: Two ventricles | Participants | 0 | 1 | 1 | 2 |
| Prior Cardiac Operations | operations | 2 (1 to 4) | 2 (0 to 4) | 2 (1 to 3) | 2 (0 to 4) |
| Prior Interventional Cardiac Catheterization | Participants | 28 | 30 | 30 | 88 |
| History of Arrhythmias | Participants | 9 | 5 | 2 | 16 |
| Noncardiac congenital anomaly | Participants | 4 | 7 | 6 | 17 |
| Chromosomal abnormality or syndrome | Participants | 3 | 1 | 1 | 5 |
6. Primary Endpoint
The registry lists the primary outcome as Days Alive and Out of the Hospital Within 30 Days of Surgery., measured over 30 days.
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | Full Range |
| Unit | days |
| Endpoint classification | Time-to-Event Analysis |
The primary endpoint counts days alive and out of the hospital during the 30 days after surgery. It combines survival and time spent outside the hospital over a defined follow-up period. A higher value represents more days meeting both conditions within that period, but the endpoint alone does not show which component—survival or hospitalization—accounts for a group’s result.
The registry record reports this endpoint as a median with a full range. A median describes the middle observation when values are ordered; it is not the average. The full range gives the lowest and highest reported values, but does not show how observations are distributed between those extremes. For example, a range can be wide even when most participants’ values are clustered together.
This outcome is relevant to early postoperative recovery because it captures both being alive and being out of the hospital in the first 30 days after surgery. It is not a direct measure of a single physiological process, and the registry record does not provide a decomposition of the endpoint into deaths and hospital days. Nor does it report a confidence interval or sponsor-reported comparative estimate for the primary endpoint. The arm-level medians and ranges therefore describe the recorded groups, but do not by themselves establish the precision of a between-group difference.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record reports a median of 20 days alive and out of the hospital in the nesiritide group, with a full range of 0 to 24. The milrinone group had a median of 18 days, with a range of 0 to 23. The placebo group had a median of 20 days, with a range of 0 to 23. These are descriptive summaries of the participants recorded in each group.
The medians are not identical across all three groups, but the registry record does not report a sponsor-led statistical comparison for this primary outcome. It gives no primary-outcome confidence interval, p-value or hazard ratio. The record also notes that values were missing or not estimable for a two-arm comparison of this median-time endpoint. Consequently, the arm-level summaries do not establish whether the observed differences are compatible with chance variation, nor do they quantify the precision of any between-group contrast.
Ranges extend from 0 to the reported upper value in each group. A range is sensitive to the most extreme observations and does not indicate how many participants had values near either endpoint. It cannot substitute for a confidence interval, which would describe uncertainty around an estimate under a specified statistical method. No such interval is reported for the primary outcome.
The trial’s stated hypothesis concerned whether the nesiritide group would have more days alive and out of the hospital than the milrinone and placebo groups. The registry’s median summaries do not show a higher median for nesiritide than placebo, while the milrinone median is lower than the other two medians. Those descriptive comparisons should not be treated as a formal test of the hypothesis: no comparative primary analysis is reported, and the record does not explain the missing or non-estimable comparison.
Interpretation is also limited by the terminated status. The registry does not report the reason for termination, whether recruitment or follow-up differed from plan, or how the analysis population was defined. The planned enrollment and recorded enrollment are not accompanied by a reported sample-size justification. These gaps make it difficult to assess whether the trial was designed to estimate a particular effect with a specified precision, or whether the posted outcome summaries represent the full intended analysis.
In short, the posted primary results describe the observed medians and ranges in the three groups. They do not provide the inferential comparison needed to judge the uncertainty around differences between groups. The appropriate reading is descriptive rather than confirmatory, without drawing a treatment conclusion from these summaries.
9. Statistical Methods Explained
The primary outcome is reported as a median with a full range. The median is the central observation after values are ordered, so it is less influenced by extreme observations than an arithmetic mean. A full range reports the smallest and largest observed values. It is useful for showing the span of recorded results, but it does not indicate the typical spread of most participants’ results or the uncertainty in a group median.
Why are there no primary-outcome confidence intervals or p-values?
The registry record does not include a sponsor-reported comparative analysis for the primary outcome. It also states that values were missing or not estimable for a two-arm comparison of this median-time endpoint. The reason for that limitation is not reported in the registry record. Without a reported analysis method and comparative estimate, the posted medians cannot be converted into a valid confidence interval or p-value by simply comparing their values.
General statistical explanation: a confidence interval expresses uncertainty around an estimate under a particular model and analysis method. Its width depends on the data and method, and it helps distinguish a precise estimate from one that remains uncertain. A p-value addresses compatibility between observed data and a specified null hypothesis under stated assumptions. Neither can be reconstructed reliably from the group medians and ranges alone. The registry record does not provide the information needed for a sponsor-led primary comparison.
What does the secondary-outcome analysis show methodologically?
The registry includes unadjusted comparisons for arrhythmia between each active-treatment group and placebo. A risk difference is an absolute contrast between the observed event proportions in two groups. The posted estimates are accompanied by confidence intervals and unadjusted p-values. Such estimates are descriptive of these comparisons and should not be confused with a prespecified, multiplicity-adjusted analysis. The registry record does not report a sponsor-led analysis for these comparisons.
General statistical explanation: a confidence interval that includes the null value for a risk difference is compatible with no difference under the interval’s method, but it may also include effects in either direction. Wide intervals indicate limited precision. A p-value does not measure the probability that a treatment effect is real, nor does it describe the size or clinical importance of an effect. The posted secondary comparisons therefore need to be read alongside their uncertainty intervals rather than as isolated significance labels.
How should the planning illustrations be read?
The posted planning illustrations are calculated from the observed arrhythmia effects, not from the trial’s own design assumptions. They use a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. The illustrations consider planning for 100%, 75% and 50% of the observed effect and report participants per arm for 80% power and 90% power. These are hypothetical planning scenarios, not observed power and not evidence that the study was designed with those sample sizes.
General statistical explanation: planning based on an observed effect can be unstable because the observed estimate itself is uncertain. A smaller assumed effect generally requires a larger planned sample to achieve a given power under the same other assumptions. This is an illustration of planning dependence, not a claim about the trial’s original rationale. The registry record does not report the trial’s own sample-size justification, target effect, or planned power.
The posted secondary comparisons are unadjusted. If several outcomes or comparisons are examined, the chance of at least one apparently unusual result can increase. General statistical practice may address this by prespecifying a limited set of primary comparisons or by adjusting inference for multiplicity. The registry record does not report a multiplicity procedure, so the secondary p-values should not be treated as if they were adjusted or as definitive evidence.
10. Multiplicity, Missing Data and Analysis Populations
The registry record does not report a multiplicity adjustment or describe a hierarchy for testing the primary and secondary outcomes. The secondary outcomes span multiple clinical and resource-use domains, and the posted arrhythmia comparisons are unadjusted. When many outcomes or comparisons are examined, isolated results may appear notable by chance. Without a reported testing strategy, the secondary p-values do not have a documented family-wise or other multiplicity-adjusted interpretation.
Missing-data handling for the primary endpoint is not reported in the registry record. The record indicates that values were missing or not estimable for a two-arm comparison of the median-time endpoint, but does not explain which observations were unavailable, why they were unavailable, or how any missing values were handled. It does not report sensitivity analyses or an assessment of whether missingness could affect the estimates.
The analysis population is also not reported in the registry record. Although the study is described as randomized and arm-level sample sizes are posted, the record does not say whether the results use an intention-to-treat population, a per-protocol population or another defined set of participants. The reason for the terminated status is not reported, and the registry does not describe whether termination affected enrollment, follow-up or outcome availability.
These omissions matter because the meaning of an estimate depends on who was included, how incomplete observations were handled, and whether the statistical testing plan accounted for multiple comparisons. The registry record does not provide enough detail to assess those issues or determine whether the posted summaries follow the originally intended analysis. No conclusion about the impact of missing data or multiplicity can be drawn from the record alone.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| I- Nesiritide | 0 | 35 | 0.0% |
| II- Milrinone | 0 | 36 | 0.0% |
| III- Placebo | 0 | 35 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| I- Nesiritide | 1 of 35 |
| II- Milrinone | 0 of 36 |
| III- Placebo | 0 of 35 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| I- Nesiritide | 24 of 35 |
| II- Milrinone | 27 of 36 |
| III- Placebo | 24 of 35 |
Most frequent non-serious adverse event terms
| Event term | Organ system | I- Nesiritide | II- Milrinone | III- Placebo |
|---|---|---|---|---|
| Hypotension | Cardiac disorders | 24 of 35 | 27 of 36 | 24 of 35 |
| Acute renal insufficiency | Renal and urinary disorders | 2 of 35 | 1 of 36 | 3 of 35 |
The registry reports zero serious adverse events in each of the three groups. It also records one death in the nesiritide group and zero deaths in the milrinone and placebo groups. These figures are counts from the recorded groups; the registry does not provide a comparative safety analysis, confidence intervals or an explanation of the relationship, if any, between the death and study treatment.
The record separately reports other adverse events affecting 24 participants in the nesiritide group, 27 in the milrinone group and 24 in the placebo group. These counts should not be combined with the serious adverse-event figures. The registry does not provide serious adverse-event terms, and its list of top serious terms is empty. Definitions, severity details, timing and event-level descriptions are not reported in the registry record.
Counts alone do not show whether groups differed beyond what could arise from sampling variability, and they do not establish causation. The arm sizes are also modest, so zero recorded serious events should not be interpreted as proof that such events cannot occur. These safety figures are descriptive registry reports, not a complete comparative assessment of risks.
12. What the Result Does, and Does Not, Mean
The posted primary results mean that the registry records arm-level medians and ranges for days alive and out of the hospital within 30 days after surgery. The median was 20 days for nesiritide, 18 days for milrinone and 20 days for placebo. The full ranges were 0 to 24, 0 to 23 and 0 to 23, respectively. These figures describe the recorded observations; they do not quantify a statistically tested treatment effect.
The record does not report a sponsor-led comparative estimate, confidence interval or p-value for the primary outcome. Therefore, it does not establish how precisely the groups differed, whether any observed difference is compatible with chance variation, or whether the investigators’ stated hypothesis was supported by a formal analysis. The record also does not report the reason the trial was terminated or the analysis population and missing-data procedures.
The result does not establish that one infusion improves postoperative recovery, nor does it establish that the groups are equivalent. A lack of a reported comparative analysis is not evidence of no effect. Equivalence or non-inferiority would require a suitable design, prespecified margins and an appropriate analysis; those details are not reported in the registry record.
The secondary findings should also be interpreted cautiously. The posted arrhythmia comparisons are unadjusted, and the registry does not describe a multiplicity strategy. The broader set of listed secondary outcomes does not have a complete detailed numerical comparison in the record, limiting the ability to assess consistency across outcomes. Safety counts are descriptive and do not establish whether events were caused by an assigned infusion.
Overall, the registry supports a description of the trial design and selected posted results, but not a firm comparative conclusion about the primary endpoint. The statistical evidence is limited by the absence of a reported primary analysis and by missing information about the analysis plan, missing observations and termination.
13. Why This Trial Matters Statistically
This trial is statistically informative because it illustrates the difference between reporting group summaries and reporting a comparative analysis. The primary endpoint is summarized with medians and ranges, but the registry does not provide an estimate of the between-group contrast or its uncertainty. Descriptive values can show what was recorded in each group, yet they do not by themselves answer whether the observed differences are precise or statistically compatible with a range of possible effects.
The endpoint also combines survival and time outside the hospital. That makes it a clinically interpretable summary of early postoperative experience, while also making clear why an analysis needs to be specified carefully: the outcome is not simply a single measurement such as a laboratory value. The registry record does not report the statistical method used for a primary comparison or a decomposition of the endpoint into its components.
The study’s randomized, masked, placebo-controlled design provides an important framework for comparing assigned groups, but design features alone do not supply the missing inferential results. The terminated status, absent primary comparison and unreported analysis details limit what can be learned from the posted summaries. They also show why registry records should be read for both the results and the completeness of the analysis description.
Finally, the secondary comparisons and planning illustrations demonstrate why exploratory results and planning calculations need distinct labels. Unadjusted comparisons across outcomes can be uncertain, while sample-size illustrations based on observed effects are not evidence of the original design rationale or of achieved power. Keeping those distinctions clear helps readers avoid treating descriptive or exploratory statistics as definitive trial conclusions.
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 principal limitation is the absence of a sponsor-reported comparative analysis for the primary endpoint. The registry provides arm-level medians and full ranges, but no primary confidence interval, p-value or reported hazard ratio. It notes that values were missing or not estimable for a two-arm comparison and does not explain why.
The record does not report the reason for termination, the planned or achieved analysis population, the handling of missing observations, or whether recruitment and follow-up proceeded as intended. It also does not provide the trial’s sample-size justification or a detailed statistical plan. These gaps prevent assessment of whether the study had a prespecified target effect and precision, and whether the posted summaries represent all randomized participants.
Secondary outcomes are broad, but the registry record does not provide detailed numerical comparative results for all listed measures. The available arrhythmia comparisons are unadjusted, and no multiplicity procedure is reported. Thus, the secondary results cannot establish an overall consistent pattern across cardiovascular, renal and resource-use outcomes.
The primary endpoint’s full range gives only the extremes and does not describe the distribution of participant values. Arm-level medians do not provide uncertainty around a group contrast. Safety reporting is similarly limited: counts are posted, but event terms and a comparative safety analysis are not reported. These limitations are specific to the information available in the registry record and restrict interpretation of efficacy and safety.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Effects of Perioperative Nesiritide or Milrinone Infusion on Recovery From Fontan Surgery — NCT00543309.
- Registry record last updated 2018-06-25; status last verified 2018-05.
- Results first posted 2018-06-25.
- 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.
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18. Record Summary
The registry record describes NCT00543309, a randomized, parallel-group, phase II, quadruple-masked trial of perioperative nesiritide, milrinone and placebo in children undergoing Fontan surgery. The planned study was single-center, and recorded enrollment was 106. The status is terminated; the reason for termination is not reported in the registry record.
The primary endpoint was days alive and out of the hospital within 30 days of surgery, reported by group as a median and full range. The registry does not report a sponsor-led comparative analysis for this endpoint. Secondary outcomes include cardiovascular, renal and resource-use measures; numerical comparative results are posted for arrhythmia. Safety records include serious adverse-event counts, other adverse-event counts and deaths, without a comparative safety analysis.
The registry record does not report the primary analysis plan, sample-size justification, multiplicity procedure, missing-data handling or analysis population. Interpretation is therefore limited to the posted descriptive results and the unadjusted secondary comparisons.