Lisinopril or Coreg CR® in Reducing Side Effects in Women With Breast Cancer Receiving Trastuzumab: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Lisinopril or Coreg CR® in Reducing Side Effects in Women With Breast Cancer Receiving Trastuzumab (NCT01009918), a randomized phase 2 study. The primary outcome is Number of Participants With Trastuzumab-Induced Cardiotoxicity After 52 Weeks of Treatment.

2. Clinical Question

The central statistical comparison is each active-treatment group against placebo. The posted primary counts are 45 participants in the lisinopril group, 43 in the Coreg CR® group, and 46 in the placebo group. The corresponding denominators are 152, 147, and 144. These counts are the basis for the recalculated, unadjusted comparisons discussed in the statistical interpretation.

The question concerns a measured cardiac outcome during trastuzumab treatment, not whether either study drug changes cancer outcomes. The registry also records outcomes concerning trastuzumab-course interruption, quality-of-life change, and cardiotoxicity-free survival. Those secondary measures provide related but distinct perspectives; they do not replace the primary cardiotoxicity measure.

3. Trial Design

This was a phase II, randomized, double-masked, parallel-group trial sponsored by the University of South Florida. The registry lists an enrollment of 468 and a completed status. The three arms were lisinopril, Coreg CR®, and placebo, with each treatment given orally once daily. The stated study context was breast cancer treatment with trastuzumab, including (neo)adjuvant chemotherapy.

The registry lists primary-outcome denominators of 152 for lisinopril, 147 for Coreg CR®, and 144 for placebo. These are the denominators attached to the posted primary endpoint counts, not a reconciliation of the overall enrollment. The registry record does not explain why these endpoint denominators differ from the enrollment figure or from one another. Adverse-event groups have separate denominators.

Random assignment and masking describe the trial’s broad design, but the registry record does not report the randomization procedure, how masking was maintained, or whether any departures from masking occurred. It also does not report details of allocation concealment, site structure, eligibility criteria, or treatment adherence in the information used for these results. These details should not be inferred from the design labels.

The primary outcome is titled as the number of participants with trastuzumab-induced cardiotoxicity after 52 weeks of treatment, and its description refers to cardiotoxicity after 52 weeks as measured by preservation of left ventricular ejection fraction. Its registry timeframe, however, is listed as 2 years. That difference matters when interpreting exactly when the primary outcome was assessed. No additional endpoint timing clarification is reported in the registry record.

The original trial’s sample-size rationale, target effect, and planned analysis methods are not reported in the registry record. The sample-size illustrations associated with the posted comparisons are retrospective planning illustrations based on observed effects, not documentation of the trial’s original design.

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: Number of participants who experienced cardiotoxicity

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 Trastuzumab-Induced Cardiotoxicity After 52 Weeks of Treatment, measured over 2 years.

The primary endpoint is the number of participants who experienced trastuzumab-induced cardiotoxicity. The description says cardiotoxicity was measured through preservation of left ventricular ejection fraction (LVEF), a measure of the heart’s pumping function. In this endpoint, the registry reports counts of participants with cardiotoxicity rather than a mean LVEF value or an estimate of change in LVEF.

A binary event count is useful for comparing how often a specified outcome was recorded in each randomized group. The registry posts 45 participants with cardiotoxicity among 152 in the lisinopril group, 43 among 147 in the Coreg CR® group, and 46 among 144 in the placebo group. The group denominators are important context for the event counts; counts alone do not express the frequency within each group.

The outcome title refers to 52 weeks of treatment, but the listed timeframe is 2 years. The record does not explain whether these refer to different stages of follow-up or reflect an inconsistency in outcome reporting. The interpretation should therefore retain that ambiguity rather than assume a single assessment time.

In general, a binary cardiotoxicity endpoint summarizes whether participants met the stated event definition by the assessment time. It does not, by itself, describe the timing or duration of an event, the degree of LVEF change, or the clinical course of each participant. Those details are not reported as part of the posted primary result.

7. Results Posted in the Registry

• Arm I Lisinopril: 29.6% (45/152) versus 31.9% (46/144) on control; risk difference -2.3 percentage points (95% CI -12.9 to 8.2), risk ratio 0.93 (0.66–1.30); unadjusted two-proportion z-test p = 0.663.
• Arm II Coreg CR®: 29.3% (43/147) versus 31.9% (46/144) on control; risk difference -2.7 percentage points (95% CI -13.3 to 7.9), risk ratio 0.92 (0.65–1.29); unadjusted two-proportion z-test p = 0.618.

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.

Number of Patients With Trastuzumab Course Interruption

• 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:
  • Arm I Lisinopril: 17.8% (27/152) versus 27.8% (40/144) on control; risk difference -10.0 percentage points (95% CI -19.5 to -0.5), risk ratio 0.64 (0.42–0.98); unadjusted two-proportion z-test p = 0.040.
  • Arm II Coreg CR®: 16.3% (24/147) versus 27.8% (40/144) on control; risk difference -11.5 percentage points (95% CI -20.9 to -2.0), risk ratio 0.59 (0.37–0.92); unadjusted two-proportion z-test p = 0.018.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Arm I Lisinopril than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Arm II Coreg CR® than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Quality-of-life Changes Between Baseline and 52-weeks

• 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:
  • Arm I Lisinopril: mean 1.00 versus 5.00 on control; difference -4.00 (95% CI -9.58 to 1.58), standardized effect d = -0.18; z-test p = 0.160.
  • Arm II Coreg CR®: mean 2.00 versus 5.00 on control; difference -3.00 (95% CI -7.89 to 1.89), standardized effect d = -0.16; z-test p = 0.229.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Arm I Lisinopril and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Arm II Coreg CR® and the control. The interval gives the range of effects that remain compatible with the data.

Number of Participants With Cardiotoxicity-free Survival at 750 Days From Baseline

• 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:
  • Arm I Lisinopril: 9.9% (15/152) versus 11.8% (17/144) on control; risk difference -1.9 percentage points (95% CI -9.0 to 5.2), risk ratio 0.84 (0.43–1.61); unadjusted two-proportion z-test p = 0.592.
  • Arm II Coreg CR®: 16.3% (24/147) versus 11.8% (17/144) on control; risk difference 4.5 percentage points (95% CI -3.4 to 12.5), risk ratio 1.38 (0.78–2.46); unadjusted two-proportion z-test p = 0.268.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Arm I Lisinopril and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Arm II Coreg CR® and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes cover different aspects of the treatment experience. The interruption endpoint addresses whether trastuzumab treatment was interrupted; quality-of-life change describes average score change; and the cardiotoxicity-free survival endpoint is posted as participant counts at 750 days from baseline. These are related to the primary cardiac-safety question, but each measures a distinct outcome and uses different information.

Across the secondary comparisons, the pattern is mixed. The recalculated unadjusted comparisons for trastuzumab-course interruption favor the active arms in direction and have p-values of 0.04 and 0.018. The quality-of-life comparisons are less conclusive, and the cardiotoxicity-free survival counts do not show a consistent direction across the two active arms. This broad pattern does not overturn the primary result, which did not show a clear difference in cardiotoxicity between either active arm and placebo.

Secondary outcomes can add context, but they carry less inferential weight when their analysis plan and multiplicity handling are not reported. Examining several outcomes and comparisons increases the possibility of finding at least one apparently notable result by chance. The registry record does not state whether these endpoints were prioritized, whether any were exploratory, or whether the trial adjusted for multiple comparisons. The unadjusted p-values therefore should not be interpreted as if each were the sole planned test.

The secondary results also differ in form and timing. A mean score comparison, a treatment-interruption count, and a count bearing a survival label cannot be collapsed into one summary without additional assumptions. The registry provides no reported analysis that combines them or formally tests whether they support a common effect. Their role is descriptive and hypothesis-generating alongside the primary endpoint, rather than a substitute for it.

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

• Number of Patients With Trastuzumab Course Interruption
• Quality-of-life Changes Between Baseline and 52-weeks
• Number of Participants With Cardiotoxicity-free Survival at 750 Days From Baseline

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary: each participant is counted as having experienced cardiotoxicity or not. For a binary outcome, a risk is the proportion of participants with the event in a group. A risk difference compares those proportions by subtracting the placebo-group risk from the active-treatment-group risk. A negative risk difference means the observed event proportion is lower in the active group than in placebo; a positive value means it is higher. This is a general explanation of the measure, not a statement about the trial’s original analysis plan.

What do the posted comparisons represent?

The comparisons accompanying the primary counts are unadjusted recalculations from the group summaries. The lisinopril-versus-placebo risk difference is -0.023 and the Coreg CR®-versus-placebo risk difference is -0.027. The registry record reports no sponsor analysis for these comparisons. The p-values are also unadjusted: they do not account for other endpoints or comparisons. The original statistical analysis plan and the method used for any sponsor analysis are not reported in the registry record.

A p-value describes how compatible the observed data are with a specified null comparison under the assumptions of the test. It is not the probability that a treatment has no effect, and it does not express the size or importance of a difference. The primary p-values, 0.663 and 0.618, are not small in the usual sense, but interpretation should not rest on a threshold alone. The estimated differences and their confidence intervals describe the range of effects compatible with the summaries more directly.

How should a confidence interval be read?

In general, a confidence interval is a range of estimates reflecting sampling uncertainty under the method used to construct it. For a risk difference, zero represents no difference between the two group risks. Both primary confidence intervals include zero and extend to values on either side, which means the posted summaries are compatible with an advantage in either direction as well as little difference. The intervals do not establish that the true difference is exactly zero.

The registry also posts risk ratios and odds ratios with confidence intervals. These are alternative measures for binary outcomes. A risk ratio compares the event risks directly, while an odds ratio compares the event odds. For either ratio measure, the value corresponding to no group difference is 1. The estimates and intervals are not needed to replace the more directly interpretable risk-difference results, and the registry record does not report an adjusted model using these measures.

What do the secondary measures add?

The course-interruption endpoint is also a binary count. Its comparisons are reported as risk differences and unadjusted p-values. Quality-of-life change is continuous: the registry reports group means and standard deviations, and the accompanying recalculation compares each active group’s mean with placebo. In general, a mean difference gives the difference between group averages, while the standard deviation describes the spread of participant scores within a group. A difference in average scores does not show how every participant’s score changed.

The cardiotoxicity-free survival outcome is posted as participant counts at 750 days from baseline. Although its title uses the word survival, the posted values are counts, and no time-to-event analyses are reported. In general, a time-to-event analysis uses the timing of events and can account for differing follow-up, but such an analysis cannot be reconstructed from a count alone. The registry record does not provide a reported survival model or analysis for this endpoint.

For binary outcomes, over-dispersion is generally a concern when observed variation exceeds what a model’s assumptions allow, particularly in clustered or otherwise dependent data. The record does not report a cluster structure or a model that would allow an assessment of over-dispersion. No correction for it should be assumed. More generally, these recalculated comparisons do not adjust for covariates, clustering, or repeated measurements.

What remains unknown about the analysis?

The registry record lists no reported analyses for the primary outcome and no reported analyses for the secondary outcomes. It does not report the original statistical analysis plan, the test or model selected by the trial team, covariate adjustment, handling of missing observations, or the analysis population. It also does not report whether the statistical analyses followed an intention-to-treat approach or another population definition. Those omissions limit comparison between the posted recalculations and the trial’s planned inferential analysis.

The calculations are based on summary counts or summary means and standard deviations, rather than individual participant data. They cannot account for participant-level factors or verify the definitions applied to individual outcomes. This is a general limitation of recalculation from aggregate summaries. The record’s absence of a reported analysis does not establish that no analysis was performed; it means an analysis is not reported in the registry record.

11. Confidence Intervals and Precision

Precision concerns how narrowly the data locate an estimated difference. The primary risk-difference confidence intervals are -0.129 to 0.082 for lisinopril versus placebo and -0.133 to 0.079 for Coreg CR® versus placebo. Both intervals include zero, and each spans values below and above zero. Thus, the posted summaries do not pin down whether the active-group event risk was lower or higher than placebo, or how large a difference might be.

The unadjusted p-values of 0.663 and 0.618 are consistent with this uncertainty: neither comparison provides a clear statistical separation from placebo. These values should be read alongside the estimates and intervals, not as a replacement for them. A non-small p-value is not evidence that a difference is impossible, and a confidence interval that includes zero is not proof of equivalence.

The secondary estimates also have varying precision. For example, the course-interruption confidence intervals exclude zero for the recalculated active-versus-placebo comparisons, while the quality-of-life mean-difference intervals include zero. Those findings remain unadjusted and should be considered in the context of multiple secondary comparisons. The registry record does not report an analysis designed to provide simultaneous confidence intervals across outcomes.

In general, wider intervals indicate less precision and narrower intervals indicate more precision, conditional on the analysis method and assumptions. Precision is influenced by event frequency, sample size, and variability. The primary denominators are 152, 147, and 144, and the intervals still cover a range of possible effects. The registry record does not report a formal precision target or a trial-specific margin for deciding what range would be clinically negligible.

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 sample-size illustrations use the observed effect as a planning reference and show alternative targets based on 100%, 75%, and 50% of that effect. For these outcomes, the figures are participants per arm. The note about total events applies to time-to-event tables; the results are not presented as time-to-event sample-size calculations.

The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The target effect is the stated fraction of the observed effect. The original trial’s own design assumptions and sample-size justification are not reported in the registry record, so these illustrations should not be read as the enrollment target used to design the trial.

The 80% power column gives the illustrated number of participants per arm for a future study to have an 80% chance of detecting the specified effect under those assumptions, if that effect and the assumptions were correct. The 90% power column gives the corresponding planning number for a 90% chance. These are prospective planning concepts, not statements about the chance that the completed trial found a true effect. This is not observed power.

Rows using a smaller fraction of the observed effect require more participants per arm. That is expected in general: smaller differences are harder to distinguish from random variation, so a study needs more information to detect them with the same planned power. The illustrations are sensitive to the observed effect, which itself is uncertain, and should not be treated as a new definitive sample-size recommendation.

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 = 0.319; treatment proportion p₁ = 0.296; average p̄ = 0.308.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6527 = 1.2794.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6525 = 0.5492.
4. n = (1.2794 + 0.5492)² / (-0.0234)² = 6,110.6, rounded up to 6,111 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 <- 0.319444444444444                          # control proportion
p1 <- 0.296052631578947                          # 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(1009918)
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 = 6,111 (80% power), 8,180 (90% power)
 75% of observed effect: n per arm = 10,922 (80% power), 14,620 (90% power)
 50% of observed effect: n per arm = 24,701 (80% power), 33,067 (90% power)
power.prop.test: 6110.6 
Simulated power at n = 6,111 per arm: 0.803 (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 does not report how the trial handled multiplicity. There are two active-versus-placebo comparisons for the primary endpoint and multiple secondary endpoints, with comparisons for the active arms. When multiple statistical tests are conducted, the chance of at least one apparently notable result can increase. In general, a multiplicity strategy may define which outcomes are confirmatory, adjust significance thresholds, or specify a testing sequence. No such strategy is reported, so the secondary p-values should be treated as unadjusted evidence rather than as results controlling an overall error rate.

The record lists no reported analysis for the primary or secondary outcomes. It does not report whether interim analyses were planned or performed, whether stopping rules were used, or whether the analyses followed a prespecified statistical plan. These items are not reported in the registry record; their absence does not show that they were not considered elsewhere.

Missing-data methods are also not reported. The primary endpoint denominators are 152, 147, and 144, whereas the adverse-event denominators are 158, 156, and 154. The quality-of-life endpoint has denominators of 128, 129, and 111. The registry record does not explain the differences in denominators, how missing outcome measurements were handled, or whether participants without an observed outcome were included in any analysis. No imputation method or sensitivity analysis is reported.

The analysis populations are not described. In particular, the registry record does not state whether participants were analyzed according to randomized assignment, treatment received, or another definition. Randomization supports comparison of assigned groups when analyses preserve that assignment, but the analysis approach cannot be assumed from the design label alone. Without a stated population and missing-data approach, the recalculated summaries should be understood as comparisons of the posted group-level data, not as confirmation of a specific trial analysis population.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neutrophil count decreased (1.3%), dehydration (1.3%), palpitations (0.6%), chest pain - cardiac (0.6%), dyspnea (0.6%).

The registry reports serious adverse events among 158 participants at risk in the lisinopril group, 156 in the Coreg CR® group, and 154 in the placebo group. The numbers with a serious adverse event were 5, 4, and 6, respectively. These are counts within the registry’s listed at-risk groups. They do not by themselves establish that an event was caused by a study drug.

For other adverse events, the registry reports 104 participants affected in the lisinopril group, 89 in the Coreg CR® group, and 82 in the placebo group, using the same respective at-risk denominators. Deaths are listed separately as 1, 2, and 2. The registry does not report comparative statistical tests for these safety counts in the record used for these results.

The listed serious-event terms include Neutrophil Count Decreased and Dehydration, each reported as 1.3%, and Palpitations, Chest pain - cardiac, Dyspnea, and Dizziness, each reported as 0.6%. These terms describe the posted safety record; they do not identify causality or provide a complete account of event timing, duration, or participant-level clinical context.

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

The primary data show similar observed cardiotoxicity counts across the three groups, with unadjusted recalculated risk differences close to zero and confidence intervals that include zero. They do not establish a statistically clear difference between lisinopril or Coreg CR® and placebo on the posted primary endpoint. At the same time, the intervals leave room for differences in either direction, so the results should not be translated into a claim of equivalence or no possible effect.

The secondary results add a more favorable direction for the active arms on trastuzumab-course interruption, but those comparisons are unadjusted and arise among several secondary outcomes. Quality-of-life and cardiotoxicity-free survival results do not create a uniformly consistent pattern. Taken together, the registry data are not a single convergent demonstration across all reported outcomes.

These findings describe the posted trial results and their statistical uncertainty. They do not establish whether an observed difference is clinically important, because the registry record does not provide a threshold for clinical importance. Nor do they determine the cause of an individual participant’s cardiac or other adverse event. The aggregate counts do not provide patient-level trajectories or detailed event histories.

The primary outcome timing is unclear because the title and description refer to 52 weeks while the timeframe is listed as 2 years. The endpoint should not be assigned a more precise assessment time without clarification. In addition, the registry does not report the sponsor’s inferential analyses, multiplicity approach, missing-data handling, or analysis population. These gaps limit what can be concluded from the posted summaries.

In general, statistical interpretation separates the observed estimate from the uncertainty around it and from the clinical meaning of an effect. Here, the recalculated estimates summarize the available group counts; the confidence intervals describe uncertainty; and the registry does not state a threshold that would make a particular difference clinically meaningful. No medical recommendation follows from these statistical summaries.

17. Why This Trial Matters Statistically

This trial illustrates why a randomized design and a posted result need to be read together with the endpoint definition, denominators, and analysis details. The three-arm design offers active-versus-placebo comparisons, while the primary outcome is recorded as a binary cardiotoxicity count. The resulting estimates are straightforward to describe, but the confidence intervals show that the data do not narrowly identify the size or direction of a difference.

It also illustrates the distinction between an outcome title and its operational reporting. The primary outcome title and description specify 52 weeks, but the timeframe field says 2 years. That discrepancy affects interpretation of what period the event counts represent and cannot be solved from the counts alone.

The secondary outcomes demonstrate another central statistical issue: findings across endpoints may not align. A result on treatment interruption is not the same as a result on cardiotoxicity or quality of life. Without a reported multiplicity plan, the nominal unadjusted secondary p-values carry more uncertainty as a group than an isolated test would suggest.

Finally, the registry record provides enough group summaries for transparent unadjusted recalculations, but not enough information to reconstruct a full analysis plan. Missing-data handling, analysis populations, and sponsor-reported inferential methods are not reported. Distinguishing what can be recalculated from what cannot be verified is essential for a calibrated reading of clinical-trial statistics.

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.

Several limitations are specific to the posted record. The primary outcome timing is internally unclear: its title and description refer to 52 weeks, whereas the listed timeframe is 2 years. The record does not clarify the intended assessment time, so the timing should remain qualified in interpretation.

The primary arm denominators differ, and they do not match the overall enrollment figure. The record does not explain the reasons, whether all randomized participants contributed outcome data, or how missing measurements were handled. Denominators also differ across other outcomes, particularly quality of life. These differences may reflect outcome availability or other reasons, but the registry does not report an explanation.

No sponsor-reported analyses are listed for the primary or secondary outcomes. The posted statistical comparisons are unadjusted recalculations from aggregate summaries. The registry does not report the original statistical plan, analysis population, covariate adjustment, interim analyses, multiplicity handling, or missing-data methods. Consequently, the recalculations cannot confirm whether the trial’s planned analyses produced the same estimates or inferences.

The outcome counts do not provide individual-level information. For example, they do not describe when cardiotoxicity occurred, the magnitude of LVEF change, or the sequence of a treatment interruption and a cardiac event. The cardiotoxicity-free survival outcome is posted as counts rather than a reported time-to-event analysis. The record also does not provide a clinical-importance threshold for interpreting the size of differences.

These limitations do not erase the posted results, but they constrain conclusions about endpoint timing, analysis procedures, precision, and the meaning of secondary findings. They should be kept distinct from the trial’s randomized, double-masked, parallel-group design, which is reported in the registry.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Lisinopril or Coreg CR® in Reducing Side Effects in Women With Breast Cancer Receiving Trastuzumab — NCT01009918.
• Registry record last updated 2021-03-30; status last verified 2019-04.
• Results first posted 2021-03-30.
• 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 describes a completed phase II, randomized, double-masked, parallel-group trial of lisinopril, Coreg CR®, and placebo in patients with breast cancer receiving trastuzumab. Enrollment is listed as 468. The primary endpoint is the number of participants with trastuzumab-induced cardiotoxicity, measured by preservation of LVEF; its title refers to 52 weeks, but the listed timeframe is 2 years.

Primary counts were 45 of 152 for lisinopril, 43 of 147 for Coreg CR®, and 46 of 144 for placebo. Recalculated unadjusted comparisons against placebo had p-values of 0.663 and 0.618, with confidence intervals for both risk differences including zero. Secondary results were mixed, and the registry record does not report a multiplicity plan, missing-data methods, analysis populations, or sponsor-reported analyses.