A Study to Compare the Effects of Coreg CR and Coreg IR on Heart Function in Subjects With Stable Chronic Heart Failure: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Compare the Effects of Coreg CR and Coreg IR on Heart Function in Subjects With Stable Chronic Heart Failure (NCT00323037), a randomized phase 3 study. The primary outcome is Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI) Characterized by 2-D Echocardiography.

2. Clinical Question

3. Trial Design

The registry describes a phase 3, randomized, double-blind, parallel-group study of carvedilol controlled release and carvedilol immediate release in subjects with stable chronic heart failure. The official title calls the study multicenter and double dummy, and the record lists double masking. Participants were assigned to one of the two formulations. The posted arm descriptions contain no additional information about treatment administration, dose, titration, or other care.

The study is listed as completed. Its recorded start was 2006-03, and primary completion was 2008-04. Enrollment was 318. The registry identifies congestive heart failure as the condition and gives the purpose as comparing the formulations’ effects on heart function.

The primary outcome was the change from baseline in left ventricular end systolic volume index, characterized by two-dimensional echocardiography. The endpoint was assessed at Maintenance Visit 3, described as 24 weeks after entry into the maintenance period. The maintenance period began after a titration period of variable duration, so the stated follow-up is relative to entry into maintenance rather than a fixed interval from randomization.

The primary analysis population was modified intent to treat: subjects needed both a baseline and an evaluable end-of-study echocardiogram. The posted primary results include group means and standard deviations for 128 immediate-release participants and 125 controlled-release participants. The registry record does not report the trial’s original sample-size rationale, allocation ratio, detailed randomization procedure, treatment adherence, or planned statistical model.

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

Analysis population for the primary outcome, as defined in the registry: Analysis was performed on the modified intent to treat population (mITT), which were those subjects with both a Baseline and an evaluable End of Study echocardiogram.

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 Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI) Characterized by 2-D Echocardiography, measured over 24 weeks after entry into the maintenance period.

Left ventricular end systolic volume index (LVESVI) is a continuous echocardiographic measure of the volume remaining in the left ventricle at the end of contraction, indexed to body surface area. The registry gives the unit as mL/m^2 and identifies two-dimensional echocardiography as the measurement method. The endpoint is change from baseline, calculated as Maintenance Visit 3 minus baseline.

Assessing change allows the comparison to focus on how the measure differed from each participant’s starting value by the end of the stated follow-up. An indexed volume expresses the measurement relative to body surface area, supporting comparison across participants of different body sizes. These are general measurement principles; the registry record does not describe the imaging acquisition, central reading, or quality-control procedures.

The endpoint was assessed 24 weeks after entry into the maintenance period. Because the titration period before maintenance had variable duration, that timing does not specify a common number of weeks from initial study entry. The registry identifies LVESVI as the primary outcome, making its group contrast the principal posted comparison for interpreting the study’s central question.

7. Results Posted in the Registry

• Coreg Immediate Release: mean -18.36 versus -20.81 on control; difference 2.45 (95% CI -3.08 to 7.98), standardized effect d = 0.11; z-test p = 0.385.

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.

Change From Baseline in Left Ventricular Ejection Fraction (LVEF)

• 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:
  • Carvedilol Immediate Release: mean 0.08 versus 0.08 on control; difference 0.00 (95% CI -0.02 to 0.02), 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 Carvedilol Immediate Release and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline in Left Ventricular End Diastolic Volume (LVEDV)

• 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:
  • Carvedilol Immediate Release: mean -36.61 versus -42.22 on control; difference 5.61 (95% CI -8.31 to 19.53), standardized effect d = 0.10; z-test p = 0.429.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Carvedilol Immediate Release and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline in Left Ventricular End Systolic Volume (LVESV)

• 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:
  • Carvedilol Immediate Release: mean -36.61 versus -43.00 on control; difference 6.39 (95% CI -5.95 to 18.73), standardized effect d = 0.13; z-test p = 0.310.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Carvedilol Immediate Release and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists secondary measures of left ventricular function, volumes, dimensions, wall thickness, and mass. The posted secondary results include changes in ejection fraction and ventricular volumes. They offer related views of cardiac structure and function, but they are not interchangeable with the primary LVESVI outcome: each measures a different characteristic and may have different variability and interpretation.

The overall pattern in the posted secondary comparisons does not provide a clear, precise separation between the formulations. The mean contrasts are small relative to their uncertainty, and the confidence intervals for the posted secondary comparisons include zero. This broad pattern is directionally consistent with the primary result’s uncertainty, but it should not be treated as independent confirmation because the outcomes are related and are drawn from the same trial population.

The registry lists 16 secondary outcome measures, while only a subset of their results is included in the posted secondary summaries. The record reports no analyses for the posted secondary outcomes. Therefore, the available summaries do not establish that each secondary endpoint was tested according to a prespecified model or interpreted under a prespecified hierarchy.

Unadjusted secondary results carry less weight because examining multiple outcomes increases the chance of finding an apparently notable result by chance. Without a reported multiplicity strategy, the secondary comparisons should be treated as exploratory or descriptive rather than as a set of confirmatory tests. Their role is to provide context for the primary endpoint, not to override its estimate and uncertainty or to establish a separate treatment conclusion.

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

• Change From Baseline in Left Ventricular Ejection Fraction (LVEF)
• Change From Baseline in Left Ventricular End Diastolic Volume (LVEDV)
• Change From Baseline in Left Ventricular End Systolic Volume (LVESV)
• Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)
• Change From Baseline in Intraventricular Septal Thickness (IVST)
• Change From Baseline in Posterior Wall Thickness (PWT)
• Change From Baseline in Left Ventricular Mass (LVM)
• Change From Baseline in End Diastolic Dimension (EDD)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous, so the registry reports a mean change and standard deviation for each group. A mean summarizes the central value of the observed changes, while the standard deviation describes the spread of individual observations around that group mean. These quantities answer different questions: the mean describes the group average, and the standard deviation describes variation among participants.

What does the group contrast represent?

The reported contrast is the immediate-release mean minus the controlled-release mean. The estimated mean difference is 2.45 mL/m^2. A positive contrast means the immediate-release group’s mean change was numerically higher than the controlled-release group’s mean change under this subtraction order. It does not mean that each participant had a change of that size, nor does it describe the distribution of individual responses.

The comparison is unadjusted in the posted calculation. It is based on the group summary statistics and does not account for covariates or other model terms. The registry record does not report a detailed prespecified statistical model for the primary endpoint, any covariate adjustment, or the original analysis plan. The unadjusted comparison should therefore be understood as the posted summary contrast, not assumed to reproduce a more complex analysis that is not described.

How should a confidence interval be read?

A confidence interval describes uncertainty in an estimated population quantity. In general, a 95% confidence interval is produced by a procedure that, under its assumptions, would cover the true quantity in 95% of repeated samples. It is not a range containing 95% of individual participant outcomes, and it does not assign a 95% probability to the fixed true difference after the data have been observed.

For the primary mean difference, the interval runs from -3.075 to 7.975 mL/m^2. Because it spans zero, the data are compatible with a negative difference, no mean difference, or a positive difference over the range of values in the interval. The interval communicates both direction and precision more fully than the point estimate alone. It is not an equivalence interval: the registry record does not state a clinical equivalence margin against which to judge its endpoints.

What does the p-value add?

The unadjusted p-value is 0.385. In general, a p-value measures how unusual the observed data, or data more extreme, would be under a specified null hypothesis and statistical model. It is not the probability that the null hypothesis is true, nor a measure of the size or importance of a difference. A p-value above a conventional threshold does not establish equality; the estimate and its confidence interval remain important for judging what differences are compatible with the data.

The registry does not report whether the trial used a prespecified significance threshold for the primary comparison or whether any interim analyses were planned. Those details are not reported in the registry record. The posted p-value is explicitly unadjusted, so it should not be described as accounting for multiple outcome comparisons.

Why can variability affect precision?

Standard deviations indicate substantial participant-to-participant spread relative to the group means, but the study’s main inferential uncertainty is expressed by the confidence interval for the group contrast. In general, greater variability makes a mean difference harder to estimate precisely when other design features are held constant. Unequal variability between groups may also matter for the choice of statistical method. The posted summaries show standard deviations of 18.84 for immediate release and 25.43 for controlled release; the registry record does not describe a variance model or a diagnostic assessment.

In general, over-dispersion means that observed variability is greater than a statistical model assumes. It can make standard errors too small if the model fails to allow for the extra variability. That concept is relevant when assessing whether a model fits the data, but the primary endpoint is continuous and the record does not identify a count model or report an over-dispersion assessment. No such issue should be inferred from the summaries alone.

What does the analysis population imply?

The primary outcome analysis used the modified intent-to-treat population, defined as participants with both a baseline and an evaluable end-of-study echocardiogram. This definition links inclusion to availability of particular measurements. In general, excluding participants without evaluable follow-up can affect a comparison if the availability of measurements is related to outcomes or group assignment. The registry does not report the reasons for missing measurements, a missing-data method, or sensitivity analyses, so the extent and direction of any resulting bias cannot be assessed from the record.

The registry lists no reported analyses for the posted secondary outcomes. Accordingly, the available statistical evidence is limited to the registry’s group summaries and the simple unadjusted comparisons presented for the outcomes. More detailed modeling choices, protocol deviations, and sensitivity analyses are not reported in the registry record.

11. Confidence Intervals and Precision

The primary estimated mean difference is 2.45 mL/m^2, with a 95% confidence interval from -3.075 to 7.975 mL/m^2. The interval crosses zero, so the posted results do not clearly establish the direction of a population mean difference. Its width also indicates that the estimate is not precise enough to distinguish a small difference from a broader range of possible differences.

Precision concerns the uncertainty around the estimated group contrast, not whether a result is clinically important. The confidence interval does not state where most individual participant changes fell; the group standard deviations describe observed variation, while the interval addresses uncertainty in the estimated difference between means. Both kinds of information matter, but they answer different questions.

The unadjusted p-value of 0.385 is consistent with the interval including zero. Neither statistic proves that the formulations have the same effect. To support an equivalence conclusion, an analysis would need an appropriate prespecified equivalence margin and a design and inference directed at that question. The margin and such an analysis are not reported in the registry record.

The primary result also applies to the defined modified intent-to-treat population: participants with both baseline and evaluable end-of-study echocardiograms. Without registry entries on missing measurements or sensitivity analyses, the confidence interval does not resolve uncertainty arising from participants excluded from this analysis. Its precision should therefore be interpreted in the context of the population actually analyzed and the information available in the registry record.

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 planning figures are participants per arm, not total events. They are illustrations based on the observed effect, not the trial’s original design calculation. 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 trial’s own original sample-size assumptions and justification are not reported in the registry record.

The 80% power column describes the number of participants per arm a planning calculation would require to have an 80% chance of detecting the specified effect under those assumptions, if that effect were the true one and the model assumptions held. The 90% power column gives the corresponding planning target for a 90% chance. These are prospective planning probabilities, not probabilities that the observed result is true.

Rows use 100%, 75%, and 50% of the observed effect as alternative effects to detect. A smaller target effect is harder to distinguish from random variation, so the planning calculation calls for more participants per arm. The posted figures use an effect estimated from this study, which is itself uncertain; planning around an observed estimate should not be mistaken for a validated design target.

These figures are not observed power. Observed power is not a useful substitute for interpreting the result’s estimate and confidence interval. The sample-size illustrations describe hypothetical future planning under stated assumptions, rather than establishing what the completed trial was designed to detect or what its data prove.

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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 2.450; pooled standard deviation σ = 22.340.
2. n = 2 × (1.96 + 0.842)² × 22.340² / 2.450² = 1,305.2, rounded up to 1,306 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 <- 2.45                      # observed difference in means
sigma <- 22.3399146830915                     # 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(323037)
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 = 1,306 (80% power), 1,748 (90% power)
 75% of observed effect: n per arm = 2,321 (80% power), 3,107 (90% power)
 50% of observed effect: n per arm = 5,221 (80% power), 6,990 (90% power)
power.t.test: 1306.1 
Simulated power at n = 1,306 per arm: 0.800 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and 16 secondary outcome measures. It does not report a multiplicity-control procedure, a hierarchy among secondary outcomes, or a prespecified strategy for interpreting multiple comparisons. When multiple outcomes are examined, the chance of at least one apparently unusual result can increase; in general, statistical methods may control that risk by adjusting thresholds or specifying an ordered testing plan. No particular approach can be attributed to this study from the registry record.

The posted p-value for the primary comparison is unadjusted, and the secondary comparisons are also presented without reported analyses or a stated multiplicity adjustment. The primary endpoint remains the principal focus, but the record does not clarify whether secondary endpoints were intended as confirmatory, exploratory, or supportive. Multiple unadjusted results should not be interpreted as though each were the sole prespecified test.

The primary analysis population was modified intent to treat, requiring both a baseline and an evaluable end-of-study echocardiogram. The registry does not report how many otherwise eligible participants lacked one of these measurements, why measurements were unavailable, or how missingness was handled. It also does not report imputation, sensitivity analyses, or a comparison of included and excluded participants. Without those details, it is not possible to assess whether the analyzed participants represent all randomized participants for the endpoint.

The registry record does not report an interim-analysis plan, stopping boundaries, or an adjustment for interim looks. It also does not report the original statistical analysis plan, sample-size justification, or a detailed missing-data plan. These absences limit assessment of whether the posted analyses follow prespecified procedures; they do not establish that such procedures were absent from the full study documentation.

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

The posted primary results describe average change in LVESVI among participants with the required echocardiograms. The immediate-release group mean was -18.36 mL/m^2 and the controlled-release group mean was -20.81 mL/m^2. The estimated difference between those means was 2.45 mL/m^2, with a 95% confidence interval from -3.075 to 7.975 mL/m^2. The interval includes differences in both directions and zero, leaving the size and direction of a population difference uncertain.

These results do not establish that the formulations are equivalent, and they do not establish that one is superior. A nonsignificant p-value is not proof of no difference. Equivalence or noninferiority conclusions require a prespecified margin and an analysis designed for that question; neither is reported in the registry record. The study’s stated purpose of comparing whether Coreg CR is as effective as Coreg IR should not be mistaken for evidence that an equivalence criterion was formally tested.

The findings apply to the measured endpoint and analysis population at the specified follow-up: 24 weeks after entry into the maintenance period, following a titration period of variable duration. They do not by themselves describe outcomes outside that time point, other populations, or outcomes not reported in the registry. The registry’s primary population definition excludes participants without both baseline and evaluable end-of-study echocardiograms, and the record does not detail missing-data analyses.

Secondary outcomes provide additional descriptive context, but they are not a substitute for the primary comparison and carry less inferential weight when multiplicity procedures are unreported. The registry record also does not provide detailed methods for treatment adherence, imaging review, or covariate adjustment. Interpretation should remain limited to the posted summaries and their stated uncertainty, without extending them to clinical recommendations.

16. Why This Trial Matters Statistically

This study illustrates why a treatment comparison is not interpreted from the difference in group means alone. The point estimate is one summary of the observed contrast, while the confidence interval communicates how much uncertainty remains around that estimate. Here, the interval includes zero and spans values on either side, so a reader needs both the estimated difference and its precision to understand what the posted result can support.

The trial also highlights the distinction between a conventional difference test and an equivalence question. A study may be described as asking whether two formulations are as effective, but that wording does not establish that the analysis was designed to demonstrate equivalence. A margin, a suitable design, and an analysis tied to that margin are needed to support such a conclusion; they are not reported in the registry record.

Finally, the analysis population and the timing of measurement matter. The primary outcome was evaluated in participants with both baseline and evaluable end-of-study echocardiograms, and follow-up was counted from entry into a maintenance period after titration. These details define what the comparison represents. The record’s missing information on missing-data handling, multiplicity, and the original analysis plan also shows why registry summaries should be read with attention to what is documented and what remains uncertain.

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 leaves several trial-specific details unclear. Although it identifies randomized, double-blind, parallel-group design and the official title describes a double-dummy study, it does not report the randomization sequence, allocation concealment, or further masking procedures. Arm descriptions are blank, and the record does not give dosing or treatment-administration details.

The primary endpoint depends on echocardiographic measurement. The record does not describe who performed or read the images, whether readers were centrally blinded, how measurement quality was assessed, or how variability in the imaging measure was managed. It also does not provide baseline endpoint values or participant-level distributions, so the posted means and standard deviations offer only limited information about the observed data.

The modified intent-to-treat definition requires an evaluable end-of-study echocardiogram as well as a baseline measure. Reasons for missing or unevaluable imaging, the number of participants excluded from the primary analysis, and sensitivity analyses are not reported in the registry record. This limits assessment of how the analysis population may differ from the randomized population.

The record also does not report the original sample-size justification, prespecified statistical analysis plan, multiplicity strategy, interim-analysis plan, or a detailed method for the primary comparison. Only some secondary results are posted, and the registry lists no reported analyses for them. These limits describe gaps in the registry information and should not be taken as evidence that the full study documentation lacked those details.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Study to Compare the Effects of Coreg CR and Coreg IR on Heart Function in Subjects With Stable Chronic Heart Failure — NCT00323037.
• Registry record last updated 2023-03-28; status last verified 2023-03.
• Results first posted 2009-03-13.
• 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

NCT00323037 is a completed phase 3 randomized, double-blind, parallel-group study comparing carvedilol controlled release with carvedilol immediate release in subjects with stable chronic heart failure. The registry lists enrollment of 318 and a primary completion date of 2008-04.

The primary endpoint was change from baseline in LVESVI measured by two-dimensional echocardiography, assessed 24 weeks after entry into the maintenance period. The modified intent-to-treat analysis required baseline and evaluable end-of-study echocardiograms. The estimated mean difference was 2.45 mL/m^2, with a 95% confidence interval from -3.075 to 7.975 and an unadjusted p-value of 0.385. The interval includes zero and does not establish equivalence. The registry record does not report the original sample-size rationale, multiplicity plan, or detailed missing-data methods.