Safety and Efficacy of Aliskiren in Post Myocardial Infarction Patients (ASPIRE): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Aliskiren in Post Myocardial Infarction Patients (ASPIRE) (NCT00414609), a randomized phase 3 study. The primary outcome is Core Study: Change From Baseline in Left Ventricular End Systolic Volume (LVESV) as Measured by Echocardiography at End of Study..

2. Clinical Question

3. Trial Design

ASPIRE was a phase 3 randomized, double-blind, parallel-group, placebo-controlled study sponsored by Novartis. The registry lists enrollment of 820 and describes the core study as lasting 36 weeks. Participants received aliskiren or placebo in addition to optimized standard therapy. The ascending aliskiren regimen began at 75 mg for the first week, increased to 150 mg for the second week, and then reached 300 mg for the next 34 weeks. Placebo was given once daily in the morning for 36 weeks.

The primary endpoint was evaluated at baseline and at the final visit, after 26 to 36 weeks of treatment. The primary analysis population was restricted to patients with acceptable echocardiographic measurements both at baseline and after treatment, and who had received at least 26 weeks of treatment. This means that the endpoint results are not described as results for every enrolled participant. The registry record does not report the number excluded from this endpoint population or the reasons for unavailable measurements.

The study also included a 2 year extension. The record says that patients from both core-study arms who completed the core study and signed informed consent were included in the extension arm described for aliskiren. That extension structure should be distinguished from the randomized core comparison: the posted primary results compare the core aliskiren and placebo groups, while extension outcomes are described separately. The registry record does not report the original sample-size justification, detailed allocation procedures, or the full statistical analysis plan. Its completion status is listed as completed.

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.

Core Study

Reasons for not completing this period:

Extension Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Echocardiogram evaluable set (patients who had acceptable echocardiogram measurements both at baseline and at post-baseline after receiving at least 26 weeks of treatment)

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 Core Study: Change From Baseline in Left Ventricular End Systolic Volume (LVESV) as Measured by Echocardiography at End of Study., measured over Baseline and final visit (after 26 to 36 weeks of treatment).

The primary endpoint was change from baseline in left ventricular end systolic volume (LVESV), measured by echocardiography at the end of the core study. LVESV is the volume of blood in the left ventricular chamber at the end of contraction. The registry says measurements were made by the echocardiography lab and that baseline LVESV was included as a covariate.

The official study description frames the question around prevention of left ventricular remodeling after a high-risk acute myocardial infarction. In that context, an echocardiographic measure of ventricular volume is used to assess structural change over follow-up. As a general statistical point, a continuous endpoint such as volume retains information about the amount of change rather than reducing each participant to a binary category. The reported least-squares means represent adjusted group averages, and their difference describes the estimated contrast between groups under the reported endpoint analysis.

The registry lists normal LVESV values as 22 to 58 mL for men and 19-49 mL for women. Those reference ranges do not, on their own, determine whether a group-average change is clinically meaningful. The posted primary comparison is an average-change result in the echocardiogram-evaluable population, not a report of every participant’s measurement or a direct measure of how an individual feels or functions.

7. Results Posted in the Registry

• Aliskiren_Core: mean -4.13 versus -3.14 on control; difference -0.99 (95% CI -3.73 to 1.75), standardized effect d = -0.05; z-test p = 0.480.

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.

Core Study: 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 errors.
• Result:
  • Aliskiren_Core: mean -3.08 versus -1.37 on control; difference -1.71 (95% CI -4.95 to 1.53), standardized effect d = -0.08; z-test p = 0.301.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Aliskiren_Core and the control. The interval gives the range of effects that remain compatible with the data.

Core Study: 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 errors.
• Result:
  • Aliskiren_Core: mean 2.24 versus 2.12 on control; difference 0.12 (95% CI -0.61 to 0.85), standardized effect d = 0.02; z-test p = 0.749.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Aliskiren_Core and the control. The interval gives the range of effects that remain compatible with the data.

Core Study: Change From Baseline to End of Study in Infarction Segment Length (ISL) as Measured by Echocardiography

• 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 errors.
• Result:
  • Aliskiren_Core: mean -5.04 versus -4.30 on control; difference -0.74 (95% CI -2.18 to 0.70), standardized effect d = -0.08; z-test p = 0.314.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Aliskiren_Core and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists a broader set of secondary measures, including other echocardiographic volumes and function measures, infarction segment length, wall motion score, and time to first occurrence for composite endpoints. The posted continuous secondary comparisons show a mixed pattern rather than a consistent separation across every measure. Some estimated changes are numerically more negative in the aliskiren group, while the ejection-fraction contrast is small and positive. The secondary intervals include values on both sides of no difference, and their unadjusted p-values do not give a clear pattern of strong between-group evidence.

This overall pattern is compatible with the primary result’s uncertainty: point estimates vary by endpoint, while the available interval estimates do not establish a robust, consistent difference across the reported cardiac measures. Secondary outcomes can offer context about whether different ways of measuring cardiac structure or function tell a coherent story, but they do not replace the prespecified primary endpoint.

Unadjusted secondary results carry less weight because testing many outcomes increases the chance that some estimates will appear notable even when no underlying effect exists. The registry record does not report a multiplicity adjustment or a prespecified hierarchy for interpreting secondary outcomes. Their results should therefore be regarded as exploratory or supportive rather than as independent confirmation of the primary finding. The registry also lists extension outcomes, but extension observations have a different follow-up context from the randomized core comparison and should not be treated as equivalent evidence from the core study.

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

• Core Study: Time to First Occurrence for the Composite Endpoints of Echocardiogram and Adjudicated Outcomes
• Core Study: Change From Baseline in Left Ventricular End Diastolic Volume (LVEDV)
• Core Study: Change From Baseline in Left Ventricular Ejection Fraction (LVEF)
• Core Study: Change From Baseline to End of Study in Infarction Segment Length (ISL) as Measured by Echocardiography
• Core Study: Change From Baseline to End of Study in Wall Motion Score (WMS) as Measured by Echocardiography
• Extension Study: Change From Baseline in Left Ventricular End Systolic Volume (LVESV) at Month 12
• Extension Study: Change From Baseline in Left Ventricular End Diastolic Volume (LVEDV) at Month 12
• Extension Study: Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Month 12

9. Statistical Interpretation

10. Statistical Methods Explained

The primary measure is continuous, so the registry reports a least-squares mean change for each core-study arm. A least-squares mean is a model-based group average; the registry specifically notes that baseline LVESV was a covariate. This adjustment is intended to account for baseline measurement when estimating follow-up change. The exact model specification beyond that covariate is not reported in the registry record.

What does the standard error describe?

The reported standard errors are 1.01 mL for placebo and 0.97 mL for aliskiren. A standard error describes the statistical uncertainty around an estimated mean, rather than the spread of individual patient measurements. It generally becomes smaller when an estimate is based on more information or when the underlying measurements are less variable. It should not be interpreted as a range containing most participants’ values. The registry does not report standard deviations for the primary endpoint; the calculations use an approximate standard deviation derived from the posted summaries.

How should the between-group estimate be read?

The estimated contrast is -0.99 mL for aliskiren versus placebo. The negative sign indicates that the estimated change in the aliskiren group was more negative than the estimated change in the placebo group. This sign describes the numerical contrast, not its clinical importance. An interval from -3.735 to 1.755 mL expresses uncertainty around that contrast. Because the interval reaches both negative and positive values, the posted summary does not precisely establish which direction the underlying difference takes.

What does the p-value tell the reader?

The unadjusted p-value is 0.48. In general, a p-value measures how unusual data at least as incompatible with a specified null model would be if that model were correct, given the test’s assumptions. It is not the probability that the null hypothesis is true, the chance that the observed result is due to chance, or a measure of clinical importance. The registry record does not report a sponsor-reported primary p-value or detailed test specification in its listed analyses, so the posted unadjusted value should be read as a summary-based calculation rather than as a complete account of the sponsor’s inferential analysis.

Why does the analysis population matter?

The endpoint population requires acceptable echocardiograms at baseline and after treatment, as well as at least 26 weeks of treatment. Restricting analysis to evaluable measurements can be important for measurement quality, but it can also make the analysed group differ from the full enrolled population. If missing outcomes are related to health status, treatment, or the outcome itself, an analysis limited to observed measurements may be affected. The record does not report the missing-data method, the number of participants without endpoint measurements, or a sensitivity analysis addressing missing outcomes. The available description therefore does not establish how robust the result is to missing data.

Why can over-dispersion matter?

As a general statistical concept, over-dispersion means that observed variability is greater than a model assumes. When a model understates variability, standard errors can be too small and uncertainty intervals can be too narrow. The primary endpoint is continuous, and the posted calculations use an approximate standard deviation based on summary statistics. The registry does not report an over-dispersion assessment or enough model detail to evaluate that issue directly. It is therefore more appropriate to treat the summary-based interval as an approximate description than to assume it reproduces every feature of the original analysis.

What is the role of the recalculated statistics?

The displayed contrast and interval are simple, unadjusted recalculations from posted group summaries; the planning illustrations are also derived from the observed contrast. These calculations help readers understand the scale and uncertainty of the reported summaries, but they do not recreate an individual-level analysis. If a discrepancy between a recalculation and the sponsor’s own analysis were identified, the sponsor’s analysis would take precedence. No discrepancy is flagged in this record. The registry does not report the full protocol statistical plan, including detailed model diagnostics, prespecified handling of every analysis population, or a complete set of multiplicity procedures.

11. Confidence Intervals and Precision

The primary comparison is estimated as -0.99 mL, with an interval from -3.735 to 1.755 mL. An interval estimate conveys a range of values compatible with the data and the calculation method; it is more informative about precision than the point estimate alone. The interval crosses no difference, so the posted result is compatible with a contrast favoring either direction. Its breadth relative to the point estimate means that the exact size and direction of any difference remain uncertain.

The group standard errors are 1.01 mL for placebo and 0.97 mL for aliskiren. These quantify uncertainty in the estimated group means, not the variability of individual LVESV changes. The interval around the comparison is based on a summary-statistic recalculation using an approximate standard deviation. The registry record does not report a confidence level for that interval or the complete sponsor model details, so a confidence level should not be inferred from the listed bounds.

The unadjusted p-value of 0.48 is consistent with substantial uncertainty about the contrast, but the p-value and interval answer related rather than identical interpretive questions. Neither establishes that the groups are equivalent. The analysis population also limits how broadly the precision estimate can be applied: it concerns the echocardiogram-evaluable set specified for the endpoint, not necessarily every enrolled participant. Missing-data methods and sensitivity results are not reported in the registry record, leaving additional uncertainty about the impact of unavailable measurements.

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 for the primary endpoint are participants per arm, not total events. The planning illustration assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It uses the observed effect as its starting point, then considers planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. For planning for 100% of the observed effect, the figures are 5,271 participants per arm for 80% power and 7,056 participants per arm for 90% power. For planning for 75% of the observed effect, they are 9,369 and 12,543 participants per arm, respectively. For planning for 50% of the observed effect, they are 21,081 and 28,221 participants per arm, respectively.

The 80% power column describes a design intended to have an 80% chance of detecting the specified effect under the stated assumptions if that effect is the true one. The 90% column uses a higher target chance under the same kind of assumptions. These are planning targets, not guarantees for a particular study. Smaller effects require more participants to be detected with the same target power, which is why the planning figures increase as the assumed fraction of the observed effect decreases.

These values are a planning illustration based on the observed result, not the trial’s original design assumptions. The original sample-size justification is not reported in the registry record. This is not observed power: the calculation does not measure how much power the completed trial actually had, and it should not be used to reinterpret the primary p-value.

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 = -0.990; pooled standard deviation σ = 18.139.
2. n = 2 × (1.96 + 0.842)² × 18.139² / -0.990² = 5,270.0, rounded up to 5,271 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 <- -0.99                      # observed difference in means
sigma <- 18.1393547006288                     # 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(414609)
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 = 5,271 (80% power), 7,056 (90% power)
 75% of observed effect: n per arm = 9,369 (80% power), 12,543 (90% power)
 50% of observed effect: n per arm = 21,081 (80% power), 28,221 (90% power)
power.t.test: 5271 
Simulated power at n = 5,271 per arm: 0.795 (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 multiple secondary outcomes spanning echocardiographic measurements, composite endpoints, and extension follow-up. When many outcomes are examined, the chance of at least one apparently unusual result can increase. Statistical procedures can control this multiplicity, or a prespecified testing hierarchy can define which results are confirmatory. Such procedures and a hierarchy are not reported in the registry record. Consequently, unadjusted secondary p-values should not be interpreted as if they came from a single isolated test.

The record lists no reported analyses in its analysis listing, and it does not give a complete statistical analysis plan. It is therefore not possible from this record to establish which analyses were prespecified, how all outcome families were handled, whether interim analyses occurred, or what multiplicity strategy the sponsor may have used. Those details are not reported in the registry record.

Missing-data information is also limited. The primary endpoint population consists of patients with acceptable echocardiographic measurements at baseline and after treatment who received at least 26 weeks of treatment. The record does not report the number of missing endpoint values, reasons for missing measurements, imputation methods, or sensitivity analyses. It also does not provide enough information to compare the endpoint-evaluable population with those not included in that analysis. These omissions matter because missing measurements can affect both the estimated group contrast and its precision, particularly if missingness is related to prognosis or treatment experience.

The trial’s original sample-size assumptions and justification are not reported in the registry record. The planning figures based on the observed effect are not a substitute for that design information. Together, the missing analysis-plan, multiplicity, and missing-data details limit how fully the registry summaries can be assessed as confirmatory evidence.

15. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cardiac failure (4.3%), angina pectoris (3.8%), angina unstable (2.1%), myocardial infarction (1.7%), non-cardiac chest pain (1.7%).

The registry reports serious adverse events as the number at risk and the number affected in each listed group. In the core placebo group, 397 were at risk and 92 were affected; in the core aliskiren group, 422 were at risk and 107 were affected. For the extension aliskiren group, 422 were at risk and 126 were affected. These are the registry’s reported counts; they are not recalculated rates, and the extension group should be read as a separate follow-up category rather than added to the core groups.

The serious terms listed include cardiac failure at 4.3%, angina pectoris at 3.8%, angina unstable at 2.1%, myocardial infarction at 1.7%, non-cardiac chest pain at 1.7%, and pneumonia at 1.7%. The record does not specify in the posted summary how these term percentages should be compared across the core and extension groups. Death counts are not reported in the registry record. These safety summaries describe reported events and do not, on their own, establish that an event was caused by the study drug or permit a complete benefit-risk assessment.

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

The primary result describes average change in LVESV among the endpoint-evaluable patients in the core study. The estimated group contrast is -0.99 mL, and its interval ranges from -3.735 to 1.755 mL. The point estimate is numerically more negative for aliskiren than placebo, but the interval includes no difference and values in the opposite direction. The unadjusted p-value is 0.48. Taken together, the posted summaries do not precisely determine the direction or size of the underlying group difference.

This does not mean the two groups have been shown to be equivalent. A finding that is not statistically distinguishable from no difference is not the same as evidence that any difference is small enough to be clinically unimportant. Equivalence or non-inferiority requires a specific design, margins, and analysis, which are not reported in the registry record. The result also does not establish that treatment does or does not work; it reports an uncertain comparison on a particular echocardiographic measure over the core-study follow-up.

The primary endpoint is a surrogate measure of cardiac structure, not a direct report of symptoms, daily functioning, or all clinical events. Other outcomes were included, but their interpretation is limited by the lack of a reported multiplicity plan and by uncertainty about missing data and analysis methods. The echocardiogram-evaluable population further means that the endpoint result should not automatically be generalized to all enrolled participants.

For readers, the appropriate conclusion is bounded: the registry reports group-average changes and an imprecise between-group estimate, with no clear separation in the summary-based comparison. It does not resolve whether a clinically meaningful difference exists, nor does it support a broad conclusion beyond the endpoint, population, and follow-up described.

17. Why This Trial Matters Statistically

This trial is statistically instructive because its central endpoint is continuous and model-adjusted, while the posted summaries include both group means and a between-group estimate. Reading the point estimate together with its interval emphasizes why the numerical direction alone is insufficient. The uncertainty range is essential: it includes contrasts on either side of no difference, so the reported point estimate should not be mistaken for a precise treatment effect.

The endpoint analysis also illustrates the importance of population definitions. The primary result applies to patients with acceptable measurements at baseline and after treatment and at least 26 weeks of treatment. That is a narrower description than enrollment alone. Without counts and reasons for missing measurements, readers cannot assess whether endpoint availability could affect representativeness or precision.

The secondary outcomes and extension follow-up raise common interpretation challenges. Numerous outcomes can generate a collection of unadjusted comparisons, and those results need a multiplicity context before being treated as confirmatory. Extension observations also have a different place in the study structure from the randomized core comparison. Treating every listed estimate as equally strong evidence would obscure these design distinctions.

Finally, the registry’s observed-effect planning illustration demonstrates why planning calculations should be kept separate from trial design and from post hoc claims about power. The original design justification is not reported, while the illustration is driven by the observed contrast. Keeping those concepts distinct prevents a planning example from being mistaken for evidence about the completed trial’s ability to detect an effect.

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 posted result has several trial-specific limitations for interpretation. The primary analysis is restricted to an echocardiogram-evaluable population, requiring acceptable baseline and post-baseline measurements and at least 26 weeks of treatment. The registry does not report how many participants lacked measurements, why those data were unavailable, or whether missingness differed between groups. Without that information, the effect of exclusions on the estimated comparison cannot be assessed.

The registry record does not provide the full statistical analysis plan, detailed model specification, or sponsor-reported analyses for the primary endpoint in its analyses listing. The posted contrast and interval are summary-based recalculations and use an approximate standard deviation. They are useful for understanding the reported means, but do not reproduce an individual-level model or all sponsor analysis decisions.

The record also does not report the trial’s original sample-size justification, multiplicity approach, or detailed handling of secondary outcomes. These omissions make it difficult to determine which comparisons were intended to be confirmatory and how the broader outcome set was controlled. The extension population is described as including core participants who completed the core study and consented, so extension follow-up should not be conflated with the randomized core comparison.

Finally, the primary endpoint is an echocardiographic measure over the core-study period. It is not itself a complete measure of clinical experience, and the posted summaries cannot establish the clinical importance of the observed average change. The registry record does not report death counts in the safety summary.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Safety and Efficacy of Aliskiren in Post Myocardial Infarction Patients (ASPIRE) — NCT00414609.
• Registry record last updated 2012-07-13; status last verified 2012-07.
• Results first posted 2011-07-13.
• 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.

22. Record Summary

The registry record describes ASPIRE, a completed phase 3 randomized, double-blind, parallel-group, placebo-controlled study sponsored by Novartis. It enrolled 820 participants with high-risk acute myocardial infarction and evaluated aliskiren added to optimized standard therapy. The core regimen used ascending aliskiren doses, with placebo as the comparator, over 36 weeks.

The primary outcome was change from baseline in echocardiographic LVESV at the final visit after 26 to 36 weeks of treatment. The estimated mean difference was -0.99 mL, with an interval from -3.735 to 1.755 mL and an unadjusted p-value of 0.48. The interval indicates substantial uncertainty about the direction and size of the contrast. Additional echocardiographic outcomes and safety counts are listed, while important details on multiplicity, missing data, and the original sample-size justification are not reported in the registry record.