Nitric Oxide in Myocardial Infarction Size: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Nitric Oxide in Myocardial Infarction Size (NCT00568061), a randomized phase 2 study. The primary outcome is Mean Percent of Myocardial Infarction Size to the Fraction of Left Ventricular Size.

2. Clinical Question

The clinical question concerns infarct size after STEMI and successful coronary intervention, rather than a longer-term clinical event. The registry describes the study purpose as assessing whether inhaled nitric oxide can decrease myocardial infarction size at 48-72 hours. Its primary measure expresses infarct size relative to left ventricular size, giving a size-normalized imaging outcome. The posted primary results are group means and their standard deviations, accompanied by a reported mean difference and confidence interval. These data address the stated imaging question at the specified timeframe; they do not, by themselves, describe later health outcomes.

3. Trial Design

This was a randomized, double-blind, parallel-group phase 2 trial. The registry lists Mallinckrodt as sponsor, enrollment of 29, a start date of 2006-06, primary completion in 2008-06, and a status of terminated. Those record details identify the study and its conduct status but do not explain why it was terminated. A reason for termination is not reported in the registry record.

Participants were assigned to inhaled nitric oxide or inhaled nitrogen gas. Nitric oxide was administered at 80 ppm, and nitrogen gas, described as placebo, was also administered at 80 ppm. The posted primary endpoint results list 13 participants in the nitric oxide group and 16 in the nitrogen gas group. The registry identifies the primary endpoint analysis population as intent to treat. Further details about the allocation sequence, concealment, who was masked, treatment duration, or adherence are not reported in the registry record.

The clinical setting was STEMI in patients who underwent successful percutaneous coronary intervention. The primary endpoint was measured at 48-72 hours using contrast-enhanced cardiac MRI. The registry lists 11 outcome measures and posts 10 secondary outcomes, spanning infarct size, perfusion, infarct transmurality, left ventricular function and mass, and resolution of ST segment elevation. It lists no analyses. The trial status and its modest posted arm counts are important context for interpreting the estimate: the primary result is an early imaging comparison, and its precision should be considered alongside the confidence interval rather than inferred from the phase designation or study 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:

Analysis population for the primary outcome, as defined in the registry: Analysis was per intent to treat population

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 Mean Percent of Myocardial Infarction Size to the Fraction of Left Ventricular Size, measured over 48-72 hours.

The primary endpoint is the mean percent of myocardial infarction size relative to left ventricular size at 48-72 hours. The registry says this was measured by contrast-enhanced cardiac magnetic resonance imaging (MRI), and identifies the measure as a continuous outcome reported as a mean with a standard deviation. The primary analysis population is described as intent to treat.

Expressing infarct size in relation to left ventricular size makes the endpoint a relative measure rather than simply an absolute infarct volume. As general statistical context, a continuous measure retains information about the magnitude of the measurement across participants, while its group mean gives a summary of the average observed value. The standard deviation describes variability among the measurements; it is not a confidence interval for the mean and does not directly quantify uncertainty in the between-group contrast.

The timeframe matters to interpretation: this endpoint addresses MRI-assessed infarct size at 48-72 hours. It is not a direct measure of later cardiac function, symptoms, survival, or quality of life. The registry lists related secondary outcomes, including other measures of infarct size and left ventricular characteristics, but does not post analyses for them. The primary endpoint therefore provides a focused early imaging comparison, not a complete account of all possible effects or outcomes.

7. Results Posted in the Registry

• Nitrogen Gas: mean 12.50 versus 15.80 on control; difference -3.30 (95% CI -10.83 to 4.23), standardized effect d = -0.31; z-test p = 0.390.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous measurement, and the registry reports each group using a mean and standard deviation. The mean is the arithmetic average of measured values within a group. The standard deviation describes how dispersed individual measurements are around that group mean. It is not the uncertainty around the estimated difference between group means; that uncertainty is represented by the confidence interval for the contrast.

What does the mean difference represent?

A mean difference compares the average outcome in the two groups. Here, the registry reports means of 15.8 for inhaled nitric oxide and 12.5 for nitrogen gas, alongside a mean difference of -3.3. The numerical sign depends on the order used to define a contrast; readers should interpret it with the reported arm means and not assume that a negative sign automatically indicates benefit. The endpoint is the percent of myocardial infarction size relative to left ventricular size, so the estimate concerns that imaging measure at 48-72 hours.

What does the standard deviation tell us?

The posted standard deviations are 8.99 for inhaled nitric oxide and 11.68 for nitrogen gas. As general statistical context, a larger standard deviation signals greater spread in measured values within a group. Spread matters because participants can have quite different measurements even when the group averages are close. It also contributes to uncertainty in a comparison. The observed standard deviations are not themselves a test of whether the group means differ, and a comparison should not be judged by looking at the means alone.

What is a confidence interval?

A confidence interval gives a range of values that are reasonably compatible with the data and the statistical procedure used to calculate it. In repeated use of the same procedure under its assumptions, the stated confidence level describes how often intervals would cover the true parameter. It is not a probability statement that the true value lies inside this particular interval. The reported interval for the mean difference is -10.83 to 4.226. Because it crosses zero, the posted data are compatible with no mean difference as well as with contrasts in either direction. The interval's breadth conveys uncertainty that a single point estimate cannot show.

How should the p-value be read?

The reported p-value is 0.39 and is identified as unadjusted. In general, a p-value measures how inconsistent the observed data, or more extreme data, would be with a specified null hypothesis under the analysis assumptions. It is not the probability that the null hypothesis is true, nor is it a measure of the size or clinical importance of a result. A p-value above a conventional threshold does not establish equivalence. The registry does not report whether the primary analysis included covariate adjustment or other model details, so the reported value should be interpreted as posted rather than treated as a complete statistical specification.

Why does variability matter for this comparison?

When an outcome is variable within groups, the mean difference can be estimated imprecisely unless the study has enough information to distinguish the contrast from that background spread. General statistical reasoning links precision to both variation and the amount of data available. The posted arm sizes are 13 and 16, and the standard deviations are large in relation to the reported contrast. The confidence interval reflects the resulting uncertainty. This is a description of the posted estimates, not a calculation of observed power.

Some continuous outcomes may show more variability than a simple normal model assumes, especially when measurements are skewed or have unusually large values. As general context, over-dispersion means observed variability exceeds what a chosen model expects; ignoring it can make standard errors too small and confidence intervals too narrow. The registry does not report that over-dispersion was assessed for this endpoint, nor does it provide distributional diagnostics. It would therefore be inappropriate to claim that the endpoint was skewed or that a particular model was used.

What does the analysis population mean?

The registry states that the primary endpoint was analyzed in the intent-to-treat population. In general, intent-to-treat analysis seeks to compare participants according to assigned group, regardless of treatment received, preserving the randomized comparison. The label alone does not reveal how unavailable MRI measurements were addressed, whether all randomized participants contributed endpoint data, or how protocol deviations were handled. Those details are not reported in the registry record.

The primary comparison is accompanied by an unadjusted p-value, and the registry lists 11 outcome measures, including the primary and secondary measures. Multiple outcomes create a general multiplicity issue: when many hypotheses are assessed, the chance of at least one apparently noteworthy result can increase if each is tested without adjustment. The registry does not report a multiplicity correction, a hierarchy among outcomes, or a prespecified statistical analysis plan. The 10 posted secondary outcomes are not accompanied by analyses in the record. Accordingly, the primary result should be interpreted in the context of the stated endpoint while recognizing that the wider analysis strategy is not documented.

The sample-size figures are planning illustrations derived from the observed effect under stated assumptions, not a report of the trial's own design calculation. The original design assumptions, including any planned effect size or target enrollment rationale, are not reported in the registry record. Such illustrations can help show how the amount of information required changes with the effect one wishes to detect, but they do not retroactively establish what the trial was designed to answer.

10. Confidence Intervals and Precision

The reported mean difference is -3.3, and its 95% confidence interval extends from -10.83 to 4.226. This interval is broad enough to include zero and values on both sides of zero. It therefore indicates limited precision about the direction and magnitude of the underlying mean contrast. The point estimate is only one plausible value within that range; it should not be treated as though it were known without uncertainty.

Confidence intervals describe uncertainty in an estimate under the assumptions of the analysis. They are not ranges containing most individual participant measurements, which are instead reflected by the group standard deviations of 8.99 and 11.68. Nor does the interval state that each value within it is equally plausible. As general context, a narrower interval indicates greater precision, while a wider interval leaves more uncertainty about the parameter.

The interval includes the null value of zero, consistent with the unadjusted p-value of 0.39. That does not show that the true difference is exactly zero, or that clinically meaningful differences have been ruled out. The interval permits effects in either direction, and the registry does not provide a threshold for clinical importance that would allow the range to be classified as clinically negligible or important.

The posted group sizes, 13 for inhaled nitric oxide and 16 for nitrogen gas, and the observed within-group variability provide context for the width of the interval. The registry does not report additional interval estimates for other endpoints or a detailed model specification. Precision should therefore be judged from this reported confidence interval and interpreted as uncertainty around the primary mean difference, not as certainty about no effect.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are expressed as participants per arm, not total events. They use the observed effect as a reference and show planning scenarios for detecting 100% of that effect, 75% of the observed effect, or 50% of the observed effect. For each scenario, the displayed values give the participants per arm associated with 80% power and with 90% power.

In plain language, 80% power describes a design that, under the planning assumptions and if the target effect were the true effect, would have an 80% chance of producing a statistically significant result at the stated significance level. The 90% power column represents a higher chance under those same conditions. Neither column is a guarantee of a significant result, and both depend on the assumptions being appropriate.

The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. The planning values are 162 participants per arm for 80% power and 216 for 90% power when planning for 100% of the observed effect; 287 and 384 when planning for 75% of the observed effect; and 645 and 863 when planning for 50% of the observed effect.

The pattern illustrates a general design principle: smaller effects are harder to distinguish from random variation and require more participants for a given power target. The figures are planning illustrations based on the observed effect, not the trial's original sample-size rationale. That original rationale is not reported in the registry record. This is not observed power.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -3.300; pooled standard deviation σ = 10.569.
2. n = 2 × (1.96 + 0.842)² × 10.569² / -3.300² = 161.0, rounded up to 162 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -3.3                      # observed difference in means
sigma <- 10.5693077666736                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(568061)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 162 (80% power), 216 (90% power)
 75% of observed effect: n per arm = 287 (80% power), 384 (90% power)
 50% of observed effect: n per arm = 645 (80% power), 863 (90% power)
power.t.test: 162 
Simulated power at n = 162 per arm: 0.805 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists 11 outcome measures and posts 10 secondary outcomes. The primary endpoint concerns MRI-measured infarct size relative to left ventricular size at 48-72 hours. The secondary outcomes cover other aspects of infarct size, normalization to area at risk, myocardial perfusion, infarct transmurality, left ventricular function and mass, and ST segment resolution. The registry lists no analyses, and no results for the posted secondary outcomes are included in the record.

When a study assesses multiple outcomes or makes multiple comparisons, chance findings can become more likely if each test is considered independently without a correction or prespecified hierarchy. This is a general statistical concern, not a claim that a particular error occurred in this trial. The registry does not report a multiplicity adjustment, a testing hierarchy, or a detailed statistical analysis plan. The primary p-value is expressly unadjusted. It should therefore be read as the result of the reported primary comparison, without assuming that a family-wise or other multiplicity procedure was applied.

The primary endpoint description names the intent-to-treat population. However, the record does not report the method for handling missing MRI outcomes, the number of participants with endpoint measurements, or whether any sensitivity analyses were conducted. It also does not explain how exclusions, withdrawals, or protocol deviations were addressed. The intent-to-treat label communicates the stated analysis population but is not enough to reconstruct how incomplete outcome data were treated.

The record does not report whether interim analyses were planned or performed, how the endpoint was selected from the listed outcomes, or whether outcome definitions and analysis methods were finalized before unblinding. These matters should be treated as unknown rather than inferred from the phase, randomization, or reported result. The absence of these details limits assessment of the analysis strategy, especially for the secondary endpoints, but does not alter the numerical primary result that is posted.

14. 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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: embolism (7.7%), retropertioneal haemorrhage (6.2%).

The registry posts serious adverse event figures by group. In the inhaled nitric oxide group, 1 participant is listed as at risk and affected by a serious adverse event; in the nitrogen gas group, 1 participant is listed as at risk and affected. The record also lists other adverse events affecting 2 participants in the nitric oxide group and 1 in the nitrogen gas group. These are the reported counts, not a comparison adjusted for follow-up or exposure time.

The listed serious-event terms are Embolism at 7.7% and Retropertioneal Haemorrhage at 6.2%. The registry does not provide enough detail in these entries to establish how each listed term maps to a particular group or whether the terms represent all serious events. The spelling is retained as recorded. Death counts are not reported in the registry record.

These figures are descriptive. With the posted group sizes and without additional information about event definitions, observation time, severity, relatedness, or completeness of reporting, they do not support a broad safety comparison. A count of events should not be interpreted as an estimate of risk over a specified period unless the relevant follow-up and denominator details are available. The adverse-event entries also do not establish whether an event was caused by treatment.

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

The posted result describes an early imaging comparison of mean myocardial infarction size relative to left ventricular size. At 48-72 hours, the mean was 15.8 in the inhaled nitric oxide group and 12.5 in the nitrogen gas group. The reported mean difference is -3.3, with a 95% confidence interval from -10.83 to 4.226 and an unadjusted p-value of 0.39. The interval crosses zero and leaves uncertainty about both the direction and magnitude of the difference.

The result does not establish that the groups are equivalent. A non-significant p-value cannot by itself show that any difference is absent or small enough to be unimportant. An equivalence conclusion requires a defined margin and an analysis designed to evaluate that margin; such a design is not reported in the registry record. The interval also does not rule out all potentially important contrasts, because the registry does not state a threshold for clinical importance.

The result concerns a specific endpoint, imaging method, population, and timeframe. It does not directly establish what happened to later cardiac function, symptoms, survival, or other clinical outcomes. Although the registry lists secondary measures relevant to some of these domains, it does not post their analyses. Nor should the primary imaging result be taken as an overall assessment of treatment effects beyond the reported measurement.

General statistical interpretation also distinguishes absence of strong evidence from strong evidence of absence. The confidence interval is the key display of precision: it encompasses a range of possible differences rather than identifying a precise effect. The posted means and p-value are useful summaries, but none can resolve the uncertainty alone. The status is recorded as terminated, while the reason for termination is not reported in the registry record. That status does not, without further information, explain the primary estimate or establish why the trial ended.

16. Why This Trial Matters Statistically

This trial is statistically instructive because its central result combines a simple continuous-outcome comparison with considerable uncertainty. The group means are easy to describe, but the mean difference and its confidence interval show why a difference between observed averages is not the same as a precise estimate of the underlying contrast. The interval crosses zero and spans values in both directions, so the conclusion should remain cautious rather than being reduced to a binary claim based on the p-value.

The study also illustrates the distinction between variability among participants and uncertainty about a group comparison. The standard deviations describe spread in the measured infarct-size proportions, while the confidence interval describes uncertainty around the mean difference. These quantities answer related but distinct questions. Interpreting them together gives a fuller account of how much the posted data resolve the primary question.

Another statistical issue is the relationship between a trial's observed effect and future planning. The registry's planning illustrations show how sample requirements change when targeting fractions of the observed effect. Smaller effects require more participants under the stated assumptions. These are not the trial's design justification and do not measure its achieved power; they are prospective illustrations based on the observed estimate.

Finally, the record makes clear why reporting detail matters. The intent-to-treat label is useful, but missing-data methods, the full analysis plan, and multiplicity handling are not reported. Those omissions do not invalidate the reported summary, but they limit how completely readers can assess the analysis decisions. The posted result is best read as an imprecise early MRI comparison, with its scope and uncertainty made explicit.

17. 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 offers limited information for evaluating the primary result beyond the posted summary statistics. It identifies an intent-to-treat analysis population, but does not report how many participants had usable MRI measurements, how missing endpoint data were handled, or whether sensitivity analyses were undertaken. The group counts in the primary results do not on their own establish the completeness of endpoint measurement or explain any exclusions.

The record does not report the randomization sequence or allocation concealment procedures, the details of masking, treatment duration, adherence, or protocol deviations. Although the trial is designated randomized and double-blind, the registry entry does not provide enough detail to assess how these procedures were implemented. The reason for the terminated status is also not reported.

The statistical analysis plan is not reported in detail. The registry does not specify whether covariates were included, what assumptions were checked, whether interim analyses occurred, or whether multiplicity was addressed. It lists 11 outcome measures and 10 posted secondary outcomes but no analyses. As a result, the primary estimate can be described, while the broader analytic context cannot be reconstructed from this record.

The primary outcome is an imaging measurement at 48-72 hours. It does not directly capture longer-term clinical outcomes, and the posted record does not establish how well this measure predicts those outcomes in this trial. The confidence interval is broad, leaving uncertainty about the mean difference. No threshold for clinical importance is reported, so the range cannot be judged against a stated clinical margin. These limitations concern what can be learned from the registry entry; they should not be replaced with assumptions about the trial's conduct or the unreported results.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Nitric Oxide in Myocardial Infarction Size — NCT00568061.
• Registry record last updated 2019-11-21; status last verified 2016-05.
• Results first posted 2010-08-27.
• 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.

21. Record Summary

NCT00568061, titled “Nitric Oxide in Myocardial Infarction Size,” is listed as a randomized, double-blind, parallel-group phase 2 study sponsored by Mallinckrodt. The registry records a status of terminated, enrollment of 29, a start date of 2006-06, and primary completion in 2008-06.

The trial compared inhaled nitric oxide at 80 ppm with inhaled nitrogen gas at 80 ppm in patients with STEMI who underwent successful percutaneous coronary intervention. The primary endpoint was mean myocardial infarction size as a percentage of left ventricular size, measured by contrast-enhanced cardiac MRI at 48-72 hours.

The posted means were 15.8 for inhaled nitric oxide and 12.5 for nitrogen gas. The reported mean difference was -3.3, with a 95% confidence interval from -10.83 to 4.226 and an unadjusted p-value of 0.39. The interval reflects substantial uncertainty about the contrast. The registry lists 11 outcome measures, posts 10 secondary outcomes, and lists no analyses. Further analysis details, the reason for termination, and the handling of missing MRI data are not reported in the registry record.