Glutamate for Metabolic Intervention in Coronary Surgery: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Glutamate for Metabolic Intervention in Coronary Surgery (NCT00489827), a randomized phase 3 study. The primary outcome is Number of Participants With Perioperative Myocardial Infarction, Postoperative Heart Failure or Postoperative Mortality.

2. Clinical Question

3. Trial Design

This was a phase III, randomized, parallel-group trial with quadruple masking, according to the registry record. It is listed as completed, with a start date of 2005-10 and primary completion in 2009-12. The record names University Hospital, Linkoeping as the sponsor. It does not describe the specific randomization procedure, allocation concealment, or which trial roles were included in the quadruple masking.

Participants were assigned to intravenous glutamate or saline during surgery for unstable coronary artery disease. The recorded glutamate solution was 0.125 M and was infused at 1.65 ml/hour and kg body weight. The infusion began with institution of anesthesia and stopped 2 hours after unclamping of the aorta. The saline arm had the same recorded rate and timing. The registry record does not report additional details about adherence, treatment interruptions, or whether dosing varied by participant.

The primary outcome was a count of participants with perioperative myocardial infarction, postoperative heart failure, or postoperative mortality within 30 days. Secondary outcomes covered myocardial injury, hemodynamic state, renal function, stroke, intensive care unit stay, atrial fibrillation, and severe circulatory failure in participants in CCS Class IV. The record lists ten secondary outcomes, while numerical summaries are available for selected outcomes. Details of the trial’s original sample-size rationale and statistical analysis plan are not reported in the registry record.

4. Participant Flow and Accounting

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

Overall Study

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 Number of Participants With Perioperative Myocardial Infarction, Postoperative Heart Failure or Postoperative Mortality, measured over 30 days.

The primary endpoint counts participants who experienced at least one of three clinical events: perioperative myocardial infarction, postoperative heart failure, or postoperative mortality. The registry record specifies a 30-day timeframe. Combining events creates a composite endpoint: it captures whether a participant had an event in the defined group, rather than presenting each component as the primary outcome on its own. The record does not state how multiple events in one participant were handled for this count, or provide component-specific primary results.

A composite can represent a broader clinical question than a single outcome and can increase the number of participants with an endpoint event. However, its interpretation depends on the components: they may differ in clinical importance, frequency, and how reliably they are identified. A combined count does not reveal whether any observed pattern was driven mainly by one component. Component-specific results for this primary endpoint are not reported in the registry record.

The posted primary summaries show 31 participants with an event in the glutamate group and 25 in the saline group. The comparison is reported as a risk difference, with the saline group compared with glutamate. The registry record does not provide further detail about event definitions, outcome adjudication, or whether ascertainment was blinded.

7. Results Posted in the Registry

• Saline Infusion: 5.8% (25/433) versus 7.2% (31/428) on control; risk difference -1.5 percentage points (95% CI -4.8 to 1.8), risk ratio 0.80 (0.48–1.33); unadjusted two-proportion z-test p = 0.382.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Postoperative Hemodynamic State in Patients With Severely Reduced Left Ventricular Ejection Fraction (LVEF<0.40)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Saline Infusion: 6.7% (5/75) versus 1.4% (1/71) on control; risk difference 5.3 percentage points (95% CI -1.0 to 11.5), risk ratio 4.73 (0.57–39.53); unadjusted two-proportion z-test p = 0.110.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Saline Infusion and the control. The interval gives the range of effects that remain compatible with the data.

Postoperative Renal Function

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Saline Infusion: mean 106.00 versus 106.00 on control; difference 0.00 (95% CI -6.68 to 6.68), standardized effect d = 0.00; z-test p = 1.000.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Saline Infusion and the control. The interval gives the range of effects that remain compatible with the data.

Number of Participants With Postoperative Stroke < 24 Hours

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Saline Infusion: 1.4% (6/433) versus 0.9% (4/428) on control; risk difference 0.5 percentage points (95% CI -1.0 to 1.9), risk ratio 1.48 (0.42–5.22); unadjusted two-proportion z-test p = 0.537.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Saline Infusion and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes address several different aspects of perioperative course, including myocardial injury, hemodynamic state, renal function, stroke, intensive care unit stay, atrial fibrillation, and severe circulatory failure in CCS Class IV. The registry record lists ten secondary outcomes and reports numerical summaries for selected outcomes. Taken together, the available summaries do not establish a consistent direction of difference across the varied endpoints. They should be read as additional context rather than as a single confirmation of the primary comparison.

The secondary outcomes are related to the primary question, but they do not measure the same thing. Some concern events or states at particular times, while the renal outcome is a continuous measurement. Differences in endpoint definition, timing, and frequency mean that their estimates and uncertainty are not directly interchangeable. The primary composite remains the central result for the trial’s stated main question; secondary summaries can help describe other outcomes but do not replace it.

Unadjusted secondary results carry less weight when several endpoints are examined and no multiplicity strategy or prespecified hierarchy is reported. With multiple comparisons, some apparently notable findings may arise by chance even if there is no underlying group difference for those outcomes. The registry record does not report a multiplicity adjustment, so individual secondary p-values, where available, should not be treated as definitive evidence on their own. The record also does not report analyses for every listed secondary outcome. These limitations make it more appropriate to view the secondary pattern as descriptive and exploratory than to select one result as decisive.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Degree of Perioperative Myocardial Injury
• Postoperative Hemodynamic State
• Postoperative Hemodynamic State in Patients With Severely Reduced Left Ventricular Ejection Fraction (LVEF<0.40)
• Postoperative Renal Function
• Number of Participants With Postoperative Stroke < 24 Hours
• ICU Stay
• Atrial Fibrillation
• Severe Circulatory Failure in CCS Class IV Patients

9. Statistical Interpretation

10. Statistical Methods Explained

What does a risk difference represent?

A risk difference compares the proportion of participants with an event in one group with the proportion in another. Its scale is absolute: it describes the difference in event risk rather than a relative ratio. The posted comparison is saline relative to intravenous glutamate. A negative value means the observed event risk is lower in saline under that direction of subtraction; a positive value means it is higher. A value of zero represents equal risks. The estimate is -0.015, and its confidence interval ranges from -0.048 to 0.018.

The arm summaries also report event counts and group sizes. The comparison reports p0 as 0.072 and p1 as 0.058. These are the posted arm-level risk values, not separately calculated quantities. They help place the risk-difference estimate in context, while the confidence interval conveys how uncertain that estimate is.

What does the confidence interval add?

A confidence interval describes the uncertainty associated with an estimate under the statistical method used. In repeated use of a method under its assumptions, intervals constructed in this way would contain the underlying value at the stated confidence level at the corresponding rate. It is not a range containing every plausible individual outcome, nor does it assign a probability to a treatment being effective. For this comparison, the interval includes zero, so the data do not pin down whether the difference is negative or positive. The interval also shows that the point estimate alone should not be read as a precise estimate of the group difference.

What does the unadjusted p-value mean?

The unadjusted p-value is 0.382. A p-value describes how unusual data at least as discrepant as those observed would be under a specified null model and the assumptions of the test. It does not give the probability that the null hypothesis is true, and it does not measure clinical importance. The registry record does not report a multiplicity adjustment or a full statistical analysis plan, so this value should be understood as an unadjusted comparison rather than as a complete account of the trial’s planned inferential framework.

Why do event counts matter?

Binary outcomes record whether each participant did or did not experience the specified event. The primary measure is a count of participants with at least one event in the composite. Counts are informative, but by themselves they do not show the uncertainty of a group comparison. The risk difference and its interval add a measure of magnitude and precision. A composite outcome also requires care: a single participant counted in the endpoint may have experienced different components from another participant, and the registry record does not supply component-specific results for the primary endpoint.

What do the secondary summaries contribute?

Secondary endpoints address additional aspects of perioperative injury and recovery. They include binary outcomes, such as participant counts, and a continuous measure of postoperative renal function. For continuous outcomes, the posted summary uses a mean and standard deviation; the reported comparison is a mean difference. A mean difference compares group averages, while the standard deviation describes variation among individual measurements within a group. The equal reported group means for the renal measure do not, on their own, establish equivalence or rule out a difference outside the precision of the comparison.

Secondary analyses can add context, but multiple outcomes create multiple opportunities for apparently notable results. When no adjustment strategy or outcome hierarchy is reported, individual unadjusted results require caution. A secondary result should not override the primary comparison merely because its point estimate appears more striking. The record does not report a multiplicity procedure or the investigators’ original decision rules for secondary analyses.

What does a planning calculation mean?

The sample-size illustrations use the observed effect as a reference and consider smaller fractions of that effect. They apply a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The displayed figures are participants per arm for this binary endpoint. They are planning illustrations under those stated assumptions, not a record of the trial’s own design calculations. The original design assumptions are not reported in the registry record.

Power is the probability that a specified study design would detect an effect of a specified size under its assumptions. It is not a property that can be read from the observed p-value alone. The planning figures address hypothetical future designs with specified effect sizes and assumptions. Their role is to show how the required sample size changes with the effect being targeted, not to recast the observed trial as having a particular probability of success.

11. Confidence Intervals and Precision

For the primary outcome, the posted risk difference comparing saline with intravenous glutamate is -0.015. Its 95% confidence interval extends from -0.048 to 0.018. The interval contains zero and includes both negative and positive values. In the comparison’s direction, that means the data are compatible with lower event risk in saline, no difference, or higher event risk in saline. The interval is therefore important alongside the point estimate: the point estimate gives one central value, while the interval indicates substantial uncertainty about the direction and size of the difference.

The unadjusted p-value is 0.382. It does not replace the interval, and it should not be read as a measure of the probability that a group difference exists. Nor does the interval establish that the groups are equivalent. Establishing equivalence or non-inferiority requires a prespecified margin and an analysis designed for that purpose; such a margin or analysis is not reported in the registry record.

Precision depends on the amount of information in the data and on the frequency and variability of the outcome. For binary outcomes, relatively few events can leave estimates uncertain, even when the group sizes are substantial. The registry record does not report a precision target or the original sample-size assumptions, so the confidence interval is the most direct posted indication of uncertainty for this comparison. It should be considered with the event counts, the composite endpoint definition, and the absence of reported component-specific primary results.

12. 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 primary-outcome planning figures are participants per arm, not total event counts. The sample-size assumptions state a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The calculations use the observed effect as a reference and illustrate planning for 100% of that observed effect, 75% of the observed effect, and 50% of the observed effect. The trial’s own original sample-size assumptions are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm under which a study would have an 80% probability of detecting the specified effect, if the planning assumptions held. The 90% power column describes the corresponding target with a 90% probability. For planning for 100% of the observed effect, the figures are 4,424 participants per arm for 80% power and 5,921 for 90% power. For planning for 75% of the observed effect, they are 8,071 and 10,804 participants per arm, respectively. For planning for 50% of the observed effect, they are 18,622 and 24,929 participants per arm, respectively.

The pattern illustrates a general planning principle: smaller effects are harder to distinguish from random variation, so detecting them at the same power generally requires more participants. The figures are planning illustrations, not observed power. They do not show the probability that the completed trial detected an effect, and they should not be interpreted as the trial’s actual recruitment target or as evidence about the success of the intervention.

13. 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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.072; treatment proportion p₁ = 0.058; average p̄ = 0.065.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.3488 = 0.6837.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.3487 = 0.2935.
4. n = (0.6837 + 0.2935)² / (-0.0147)² = 4,423.2, rounded up to 4,424 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
p0 <- 0.0724299065420561                          # control proportion
p1 <- 0.0577367205542725                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(489827)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 4,424 (80% power), 5,921 (90% power)
 75% of observed effect: n per arm = 8,071 (80% power), 10,804 (90% power)
 50% of observed effect: n per arm = 18,622 (80% power), 24,929 (90% power)
power.prop.test: 4423.2 
Simulated power at n = 4,424 per arm: 0.800 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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.

14. Multiplicity, Missing Data and Analysis Populations

The registry record lists multiple secondary outcomes in addition to the primary composite. It does not report a multiplicity adjustment, a hierarchy for testing outcomes, or another strategy for controlling the chance of false-positive findings across the set of comparisons. In the absence of that information, unadjusted secondary comparisons should be treated cautiously. The record does not state whether the investigators planned to designate any secondary outcome as confirmatory or exploratory.

The registry record does not report a full statistical analysis plan, covariate-adjusted analyses, or the methods used to define the analysis populations. It does not specify whether the primary comparison followed an intention-to-treat approach, whether participants were analyzed according to treatment assignment, or whether per-protocol or other populations were used. The randomized design is reported, but details of allocation procedures and concealment are not reported in the registry record.

Missing-data handling is also not reported in the registry record. The available arm summaries do not explain whether all randomized participants had endpoint information, how missing outcomes were handled, or whether any imputation or sensitivity analyses were conducted. The record does not describe outcome adjudication procedures or the handling of participants with incomplete follow-up. These omissions matter because conclusions can depend on how missing outcomes and analysis populations are defined.

The registry record reports zero analyses in its analysis listing, while it contains arm-level summaries and comparison estimates for the primary and selected secondary outcomes. This means there is no detailed reported analysis narrative to clarify model choices, assumptions, protocol deviations, or prespecified decision rules. The original sample-size justification, interim analysis plans, and stopping rules are not reported in the registry record. Their absence should be treated as missing information, not as evidence that such procedures were or were not used.

15. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: reoperation for bleeding (5.1%), severe circulatory failure (4.2%), perioperative myocardial infarction (2.6%), infection (1.8%), stroke < 24 hours (1.4%).

The adverse-event record reports serious adverse events for 54 participants in the intravenous glutamate group and 59 in the saline group. Other adverse events were reported for 164 and 165 participants, respectively. The death counts in this adverse-event record are 126 and 131, respectively. These are distinct safety summaries and should not be treated as interchangeable with the primary endpoint count; the registry record does not give further detail about how the death listing relates in timing or definition to the primary composite.

The listed serious-event terms include reoperation for bleeding (5.1%), severe circulatory failure (4.2%), perioperative myocardial infarction (2.6%), infection (1.8%), stroke < 24 hours (1.4%), and postoperative dialysis (1.4%). The record does not provide enough detail to infer from these figures whether an event was caused by an infusion, or to determine the full event definitions, observation periods, severity criteria, or attribution procedures. The counts describe the adverse-event record; they do not establish comparative safety on their own.

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

The trial record answers a defined statistical question: how the number of participants with perioperative myocardial infarction, postoperative heart failure, or postoperative mortality within 30 days compared between randomized groups receiving glutamate or saline during surgery. The posted results include event counts, a risk-difference estimate, a confidence interval, and an unadjusted p-value. These summaries indicate that the observed group difference is uncertain in both direction and magnitude.

The confidence interval includes zero and extends to values on both sides. That does not demonstrate equivalence, and it does not prove that a difference exists. It means the posted estimate is not precise enough to settle the direction of the group difference. The p-value likewise does not quantify the probability that the treatment works, or the probability that the null hypothesis is true. The registry record’s limited analysis details also prevent a complete assessment of the investigators’ prespecified inferential approach.

The composite endpoint provides a single count for three outcomes, but does not reveal which component contributed to the observed counts. Component-specific results for the primary endpoint are not reported in the registry record. Secondary outcomes and adverse-event summaries offer additional descriptive information, but they address other measures and have their own uncertainty. Without a reported multiplicity strategy, unadjusted secondary comparisons should not be used to make a firm claim about a particular effect.

Accordingly, the posted data should not be presented as proof that glutamate is beneficial, harmful, or equivalent to saline. They describe the trial groups’ recorded outcomes and the uncertainty around a primary comparison. The record does not report enough information to resolve questions about missing outcomes, analysis populations, or the original statistical plan. Any broader conclusion would require information beyond the registry summaries and should not be inferred from the point estimate alone.

17. Why This Trial Matters Statistically

This trial illustrates why interpreting a clinical comparison requires more than looking at the two event counts. The primary outcome is a composite, the comparison is expressed as a risk difference, and the confidence interval communicates uncertainty that the point estimate alone cannot. The interval includes zero and spans negative and positive differences, so a single directional reading of the estimate would overstate what the posted data establish.

The trial also illustrates the distinction between a primary endpoint and multiple secondary endpoints. Secondary outcomes can describe related aspects of care, but an assortment of unadjusted results is not equivalent to a single confirmatory test. When the registry record does not report how multiplicity was handled, the strength of evidence from individual secondary comparisons is harder to assess. Keeping the primary question distinct from exploratory patterns is therefore important to avoid overstating a selected result.

Finally, planning calculations and observed results answer different questions. The sample-size illustrations show what hypothetical designs would require under stated assumptions and effect targets; they do not indicate the probability that the completed trial detected an effect. This distinction is useful when reading a trial with an uncertain estimate: a planning exercise is not a retrospective verdict on whether the study “had enough power.” The record’s missing design and analysis details further underline the value of transparent reporting alongside outcome estimates and confidence intervals.

18. 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 important trial-specific information unreported. It does not provide the original sample-size justification, planned analysis populations, missing-data methods, multiplicity strategy, interim analysis plan, or detailed statistical analysis plan. It also does not describe the randomization procedure, allocation concealment, masking roles, outcome adjudication, or how the primary composite’s components were handled. These gaps limit evaluation of whether the posted comparisons follow the original prespecified methods.

The primary endpoint combines perioperative myocardial infarction, postoperative heart failure, and postoperative mortality, but component-specific primary results are not reported. The combined count therefore cannot show whether one component contributed more to the observed comparison or whether the component outcomes had different patterns. The registry record also does not report detailed event definitions or additional information about follow-up completeness.

Only selected secondary outcomes have numerical summaries in the registry record, despite the record listing ten secondary outcomes. The available secondary comparisons are unadjusted, and a multiplicity approach is not reported. That limits the weight that can be placed on isolated secondary findings. Safety summaries are reported as counts and listed terms, but detailed definitions, observation periods, and attribution methods are not reported in the registry record.

Finally, registry summaries alone do not provide the same level of detail as a complete trial report. The posted information does not resolve whether all randomized participants were included in each analysis or how any protocol deviations were handled. These limitations do not invalidate the reported counts, but they restrict how fully the trial methods and results can be independently assessed.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Glutamate for Metabolic Intervention in Coronary Surgery — NCT00489827.
• Registry record last updated 2024-05-22; status last verified 2024-05.
• Results first posted 2019-06-07.
• 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.

22. Record Summary

The registry record describes a completed, randomized, parallel-group phase III trial with quadruple masking, comparing intravenous glutamate with saline during surgery for unstable coronary artery disease. It reports 865 enrolled participants and a primary 30-day composite of perioperative myocardial infarction, postoperative heart failure, or postoperative mortality.

The primary summaries report 31 participants with an event in the glutamate group and 25 in the saline group. The risk difference comparing saline with glutamate is -0.015, with a 95% confidence interval from -0.048 to 0.018 and an unadjusted p-value of 0.382. The interval includes zero and indicates uncertainty about the direction and size of the difference.

The record also lists secondary outcomes and adverse-event summaries, but does not report a full statistical analysis plan, missing-data methods, analysis populations, or a multiplicity strategy. Those omissions limit interpretation of the full trial analysis beyond the posted summaries.