This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Aliskiren in Combination With Losartan Compared to Losartan on the Regression of Left Ventricular Hypertrophy in Overweight Patients With Essential Hypertension (NCT00219141), a randomized phase 3 study. The primary outcome is Change in Left Ventricular Mass Index (LVMI) From Baseline to End of Study (Week 36).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00219141 |
| Phase | Phase 3 |
| Condition | Hypertension, Left Ventricular Hypertrophy, Overweight |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 460 |
| Arms in the primary outcome | 3 |
| Lead sponsor | Novartis Pharmaceuticals |
| Results posted | Yes |
2. Clinical Question
Population
Overweight patients with essential hypertension and left ventricular hypertrophy were eligible for the study. The primary outcome analysis used an efficacy population: patients with a baseline measurement and at least one post-baseline efficacy measurement, treated for at least 28 weeks, and with evaluable MRI assessments at baseline and the end of the study.
Intervention
The combination group received aliskiren with losartan. The arm description says treatment began at 150 mg of aliskiren with 50 mg of losartan for two weeks, followed by force-titration to 300 mg and 100 mg, respectively, for 34 weeks.
Comparator
The active comparator was losartan alone. Its arm description says patients began at 50 mg for two weeks and were then force-titrated to 100 mg for 34 weeks. The study also included an aliskiren-only arm, beginning at 150 mg and then force-titrated to 300 mg.
Primary question
Over 36 weeks, how did change in MRI-measured left ventricular mass index differ between the aliskiren-only group and losartan alone, and between the aliskiren-plus-losartan group and losartan alone? A decrease in this measure represents a reduction in indexed left ventricular mass; the registry description notes that an increase indicates hypertrophy.
The trial was designed to compare efficacy and safety in overweight patients with essential hypertension. Its primary endpoint was change in left ventricular mass index from baseline to the end of the study, measured in g/m^2 by MRI. The registry also lists changes in other MRI measurements of ventricular structure and function as secondary outcomes. The posted primary results therefore address a specific imaging-based question over the study period, rather than every possible consequence of hypertension or treatment.
3. Trial Design
This was a Phase 3, randomized, double-blind, multi-center, parallel-group study. The registry lists enrollment of 460 and a completed status. The study compared three active-treatment groups: aliskiren 300 mg, losartan 100 mg, and aliskiren/losartan 300/100 mg. The arm descriptions report a two-week starting period at lower doses, followed by force-titration to the listed doses for 34 weeks. The official title describes a 36-week study.
The intervention list also includes placebo preparations for aliskiren and losartan. The arm descriptions explain that participants took multiple study tablets and capsules or matching placebos to support blinding. This is consistent with a double-blind design, but the registry record does not report further details about the practical conduct of blinding or its assessment.
The primary endpoint was change in MRI-measured left ventricular mass index from baseline to the end of the study. The primary efficacy population was narrower than all enrolled participants: it required a baseline measurement, at least one post-baseline efficacy measurement, at least 28 weeks of treatment, and evaluable MRI assessments at both baseline and study end. The arm-level primary analyses included 132 participants in the aliskiren group, 123 in the losartan group, and 136 in the combination group.
The registry record does not report the original sample-size justification, the planned allocation ratio, the number of study centers, or details of any interim analyses. It also does not report the full statistical analysis plan. Those design details should not be inferred from the enrollment figure or from the posted arm-level results.
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
| Stage | Aliskiren 300 mg | Losartan 100 mg | Aliskiren/Losartan 300/100 mg |
|---|---|---|---|
| STARTED | 154 | 152 | 154 |
| COMPLETED | 140 | 131 | 142 |
| NOT COMPLETED | 14 | 21 | 12 |
Reasons for not completing this period:
| Reason | Aliskiren 300 mg | Losartan 100 mg | Aliskiren/Losartan 300/100 mg |
|---|---|---|---|
| Adverse Event | 4 | 10 | 5 |
| Lack of Efficacy | 3 | 2 | 0 |
| Administrative problems | 0 | 1 | 0 |
| Lost to Follow-up | 2 | 4 | 1 |
| Protocol Violation | 3 | 1 | 1 |
| Withdrawal by Subject | 1 | 3 | 5 |
| Condition no longer requires study drug | 1 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: Efficacy population: All patients who had a baseline measurement and at least one post-baseline efficacy variable measurement patients and who had been treated for at least 28 weeks and had evaluable MRI assessments both at baseline and at the end of the study.
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.
| Characteristic | Unit | Aliskiren 300 mg | Losartan 100 mg | Aliskiren/Losartan 300/100 mg | Total |
|---|---|---|---|---|---|
| Participants analysed | 154 | 152 | 154 | 460 | |
| Age Continuous | years | 58.4 (SD 9.61) | 59.2 (SD 11.00) | 58.8 (SD 10.62) | 58.8 (SD 10.41) |
| Sex: Female, Male: Female | Participants | 42 | 35 | 35 | 112 |
| Sex: Female, Male: Male | Participants | 112 | 117 | 119 | 348 |
6. Primary Endpoint
The registry lists the primary outcome as Change in Left Ventricular Mass Index (LVMI) From Baseline to End of Study (Week 36), measured over Baseline to end of study (Week 36).
| Element | Registry entry |
|---|---|
| Result type | Least Squares Mean |
| Measure of spread | Standard Error |
| Unit | g/m^2 |
| Endpoint classification | Continuous Endpoint |
The primary endpoint was change in left ventricular mass index from baseline to the end of the study at Week 36. Left ventricular mass was measured by magnetic resonance imaging and indexed to body surface area; the unit was g/m^2. The registry reports least-squares means and standard errors for the primary outcome.
Left ventricular mass index is a measure of the mass of the left ventricle relative to body surface area. The registry description states that an increase indicates left ventricular hypertrophy. It also notes that increased mass can reflect different processes, including a potentially reversible response to cardiovascular conditioning or an abnormal response to chronically increased volume or pressure load. This context matters: the measure describes cardiac structure and does not, on its own, identify the cause of a change.
In general, an imaging measure can be useful for assessing a structural change over a defined period because it provides a quantified measure at baseline and follow-up. The endpoint is therefore relevant to the stated question about regression of increased left ventricular size. It does not directly measure symptoms, cardiovascular events, or quality of life. Results for the primary endpoint should be interpreted as evidence about MRI-measured left ventricular mass index in the efficacy population, not as a complete account of clinical outcomes.
7. Results Posted in the Registry
- Losartan 100 mg: mean -4.81 versus -5.51 on control; difference 0.70 (95% CI -1.98 to 3.38), standardized effect d = 0.06; z-test p = 0.608.
- Aliskiren/Losartan 300/100 mg: mean -5.61 versus -5.51 on control; difference -0.10 (95% CI -2.71 to 2.51), standardized effect d = -0.01; z-test p = 0.940.
Mean difference: Losartan 100 mg
95% CI: -1.98 to 3.38
Recalculated from the posted summary statistics
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.
| Secondary outcome | Type | Effect measure | Estimate (95% CI) | Planning size, 80% power |
|---|---|---|---|---|
| Change in the Left Ventricular Hypertrophy (LVH) Parameter Left Ventricular Mass Index as Measured by MRI From Baseline to End of Study (Week 36) | Continuous Endpoint | Mean difference | 0.08 (-2.81 to 2.97) | 340,203 per arm |
| Change in the Left Ventricular Hypertrophy (LVH) Parameter Left Ventricular End Diastolic Volume as Measured by MRI From Baseline to End of Study (Week 36) | Continuous Endpoint | Mean difference | 2.53 (-3.52 to 8.58) | 1,485 per arm |
| Change in the Left Ventricular Hypertrophy (LVH) Parameter Left Ventricular End Systolic Volume as Measured by MRI From Baseline to End of Study (Week 36) | Continuous Endpoint | Mean difference | -1.53 (-5.43 to 2.37) | 1,705 per arm |
Change in the Left Ventricular Hypertrophy (LVH) Parameter Left Ventricular Mass Index as Measured by MRI From Baseline to End of Study (Week 36)
- 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:
- Losartan 100 mg: mean -4.79 versus -4.87 on control; difference 0.08 (95% CI -2.81 to 2.97), standardized effect d = 0.01; z-test p = 0.957.
- Aliskiren/Losartan 300/100 mg: mean -5.81 versus -4.87 on control; difference -0.94 (95% CI -3.65 to 1.77), standardized effect d = -0.08; z-test p = 0.497.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Losartan 100 mg 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 Aliskiren/Losartan 300/100 mg and the control. The interval gives the range of effects that remain compatible with the data.
Change in the Left Ventricular Hypertrophy (LVH) Parameter Left Ventricular End Diastolic Volume as Measured by MRI From Baseline to End of Study (Week 36)
- 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:
- Losartan 100 mg: mean -4.52 versus -7.05 on control; difference 2.53 (95% CI -3.52 to 8.58), standardized effect d = 0.10; z-test p = 0.413.
- Aliskiren/Losartan 300/100 mg: mean -7.03 versus -7.05 on control; difference 0.02 (95% CI -5.88 to 5.92), standardized effect d = 0.00; z-test p = 0.995.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Losartan 100 mg 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 Aliskiren/Losartan 300/100 mg and the control. The interval gives the range of effects that remain compatible with the data.
Change in the Left Ventricular Hypertrophy (LVH) Parameter Left Ventricular End Systolic Volume as Measured by MRI From Baseline to End of Study (Week 36)
- 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:
- Losartan 100 mg: mean -4.73 versus -3.20 on control; difference -1.53 (95% CI -5.43 to 2.37), standardized effect d = -0.10; z-test p = 0.442.
- Aliskiren/Losartan 300/100 mg: mean -5.14 versus -3.20 on control; difference -1.94 (95% CI -5.79 to 1.91), standardized effect d = -0.12; z-test p = 0.323.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Losartan 100 mg 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 Aliskiren/Losartan 300/100 mg and the control. The interval gives the range of effects that remain compatible with the data.
The secondary MRI results broadly show small estimated between-group contrasts relative to their uncertainty, rather than a consistent separation between losartan and the other groups across the structural measurements. This overall pattern is in keeping with the primary comparison, whose recalculated differences were also close to zero and imprecise. The secondary outcomes therefore do not provide a clear contrasting pattern that would change the main reading of the primary result.
The registry lists 12 posted secondary outcomes, including left ventricular mass index, ventricular volumes, wall thickness, ascending aorta diameter, end-diastolic mass, and ejection fraction. The numerical summaries include changes from baseline to Week 36. These measures describe related but distinct aspects of cardiac structure and function; a similar direction of change across some measures does not make them interchangeable or establish a single overall effect.
The secondary comparisons are unadjusted recalculations from arm-level summaries. In general, multiple outcomes create more opportunities for chance findings, particularly when no multiplicity procedure is specified. The registry record does not report a multiplicity-adjustment plan for the secondary results. This means isolated differences or p values among the secondary outcomes should carry less weight than a prespecified primary analysis and should not be treated as confirmatory evidence on their own.
The secondary results can help describe the pattern of MRI measurements during the study, but they do not establish effects on clinical events or patient experience. The registry record does not report a hierarchy of secondary hypotheses or explain whether these measures were intended for confirmatory testing. Interpretation should therefore remain descriptive and aligned with the uncertainty in the estimates.
Secondary outcomes registered for this trial, for reference (only those above were recalculated):
- Change in the Left Ventricular Hypertrophy (LVH) Parameter Left Ventricular Mass Index as Measured by MRI From Baseline to End of Study (Week 36)
- Change in the Left Ventricular Hypertrophy (LVH) Parameter Left Ventricular End Diastolic Volume as Measured by MRI From Baseline to End of Study (Week 36)
- Change in the Left Ventricular Hypertrophy (LVH) Parameter Left Ventricular End Systolic Volume as Measured by MRI From Baseline to End of Study (Week 36)
- Change in the Left Ventricular Hypertrophy (LVH) Parameter Left Ventricular Anteroseptal Wall Thickness as Measured by MRI From Baseline to End of Study (Week 36)
- Change in the Left Ventricular Hypertrophy (LVH) Parameter Left Ventricular Inferolateral Wall Thickness as Measured by MRI From Baseline to End of Study (Week 36)
- Change in the Left Ventricular Hypertrophy (LVH) Parameter Diameter of Ascending Aorta as Measured by MRI From Baseline to End of Study (Week 36)
- Change in the Left Ventricular Hypertrophy (LVH) Parameter Left Ventricular End Diastolic Mass as Measured by MRI From Baseline to End of Study (Week 36)
- Change in the Left Ventricular Hypertrophy (LVH) Parameter Left Ventricular Ejection Fraction as Measured by MRI From Baseline to End of Study (Week 36)
9. Statistical Interpretation
The primary results show decreases in mean left ventricular mass index in all three groups. The least-squares mean change was -5.51 g/m^2 for aliskiren, -4.81 g/m^2 for losartan, and -5.61 g/m^2 for aliskiren plus losartan. These are within-group changes from baseline, not direct estimates of the treatment differences. The relevant comparisons are the differences between each active group and losartan alone.
For aliskiren compared with losartan, the recalculated unadjusted mean difference was 0.7 g/m^2, with a 95% confidence interval from -1.975 to 3.375 and an unadjusted p value of 0.608. For the combination compared with losartan, the recalculated unadjusted mean difference was -0.1 g/m^2, with a 95% confidence interval from -2.706 to 2.506 and an unadjusted p value of 0.94. The confidence intervals include zero, so the posted summary statistics do not establish a clear between-group difference for either comparison.
These comparisons are simple, unadjusted recalculations from the posted arm summaries; they are not presented as sponsor-reported inferential analyses. The registry record does not report pairwise primary-outcome analyses, and it reports no analyses in the analysis field. The estimates should therefore be read as a statistical interpretation of the posted summaries, rather than as a replacement for a prespecified sponsor analysis.
The point estimates are close to zero relative to the uncertainty represented by their intervals. That does not demonstrate that the groups are equivalent. A confidence interval spanning zero is compatible with a range of possible differences in either direction, including differences that may be meaningful or negligible; the registry record does not state a threshold for clinical importance. The data support a cautious description: the observed average changes were similar, and the available summary-based comparisons are imprecise enough that they do not rule out a range of between-group effects.
All three groups had negative average changes, but that pattern alone does not show that one treatment caused more regression than another. A within-group change can reflect the intervention, other changes during follow-up, measurement variability, or other influences. The randomized comparisons are the more relevant basis for comparing treatments, and the posted summaries do not show a clear separation between either active comparison and losartan.
10. Statistical Methods Explained
In general, a randomized parallel-group trial compares outcomes across groups assigned to different treatments. Random allocation is intended to reduce systematic differences between groups at the start of the study. Double blinding is intended to limit the influence of treatment knowledge on participants’ experiences and on assessment. These design features support a fair comparison, although they do not remove uncertainty from sampling variation or missing measurements.
What does a least-squares mean represent?
The registry reports least-squares means for the primary outcome. In general, a least-squares mean is a model-based group mean, often adjusted for variables in the statistical model. It can differ from a simple arithmetic mean. The model and adjustment variables used for the sponsor’s primary analysis are not reported in the registry record, so the posted least-squares means should be quoted as reported rather than interpreted as an unadjusted mean.
The standard errors reported alongside those means describe the estimated sampling uncertainty of each mean. In general, a standard error is the estimated variability of a statistic across repeated samples; it is not the spread of individual participant outcomes. The registry does not report standard deviations for the primary endpoint. The recalculated pairwise comparisons use an approximate standard deviation inferred from the posted standard errors and sample sizes, so they are not identical to a fully specified model-based comparison.
How should the pairwise estimates be read?
The recalculated mean difference expresses one group’s average change relative to the losartan group. For example, the primary comparison of aliskiren with losartan is reported as 0.7 g/m^2. The sign reflects the order of the comparison used in the posted calculation. A value near zero indicates that the group averages are close; it does not establish that the treatments are equivalent.
The 95% confidence interval describes uncertainty around the estimated difference under the assumptions of the calculation. In general, a confidence interval gives a range of values compatible with the data and method; it is not a guarantee that the true effect lies in the interval. When the interval includes zero, the data do not distinguish the estimated difference from no difference at the conventional two-sided 0.05 level. The reported p values are unadjusted and should not be interpreted as probabilities that a treatment has no effect.
Why do the recalculated comparisons need caution?
The primary arm summaries are least-squares means with standard errors. The pairwise estimates and intervals are recalculated from those posted summaries rather than taken from a reported sponsor analysis. This makes the calculations useful for describing the scale and uncertainty of the observed differences, but they do not reproduce an unreported analysis model. The registry record does not report the covariates, covariance structure, or other model details that would be needed to verify a model-based comparison.
General statistical caution also applies when the outcome is measured repeatedly or when participants have missing follow-up data. The registry describes an efficacy population that required treatment for at least 28 weeks and evaluable MRI assessments at baseline and the end of the study. Restricting an analysis to participants meeting such criteria may affect how representative the analyzed group is of all randomized participants. The registry record does not report the number excluded from this population or the reasons for missing MRI assessments.
Why can over-dispersion matter?
In general, over-dispersion means that observed variability is greater than a statistical model expects. It can make standard errors that rely on an overly restrictive variance assumption too small, which can make confidence intervals look narrower than warranted. The primary endpoint is continuous and the posted summaries do not report an over-dispersion assessment. The concept is relevant as a general modeling consideration, but there is no basis in the registry record to say that over-dispersion occurred in this trial.
How should secondary comparisons be treated?
The posted secondary outcomes include continuous MRI measures and their changes from baseline. The numerical contrasts described in the secondary results are unadjusted recalculations from arm-level summaries. In general, evaluating many outcomes or pairwise comparisons increases the chance that some results appear notable by chance. A multiplicity-adjustment method for the reported secondary results is not reported in the registry record. Accordingly, secondary findings are best regarded as descriptive or exploratory unless a prespecified analysis plan establishes otherwise.
The registry record does not report the original sample-size justification, the sponsor’s full statistical analysis plan, or interim analysis procedures. No inference about those methods should be drawn from the recalculated comparisons or planning illustrations.
11. Confidence Intervals and Precision
The primary comparisons are not estimated with high precision. For aliskiren compared with losartan, the recalculated mean difference was 0.7 g/m^2 and the 95% confidence interval ranged from -1.975 to 3.375. For the combination compared with losartan, the estimated difference was -0.1 g/m^2 and the interval ranged from -2.706 to 2.506. Both intervals include zero and extend in both directions from the point estimate.
In general, the width of a confidence interval reflects the amount of uncertainty in an estimate under the analysis assumptions. These intervals indicate that the posted results are compatible with more than a very narrow set of possible differences. They do not provide strong precision for distinguishing small differences between groups. The registry record does not identify a clinically important difference for this endpoint, so the intervals cannot be classified against a stated clinical threshold.
The primary means are reported with standard errors, while the arm-level confidence limits are not reported. The intervals for the group comparisons are recalculated from the posted summary statistics. They should therefore be understood as approximate, unadjusted intervals, not as intervals from a fully documented sponsor model. The registry record does not provide the model specification needed to assess how an adjusted analysis might affect the estimates or their uncertainty.
Precision is also shaped by the number of participants with evaluable endpoint data, not just the overall enrollment. The primary efficacy analysis included 132 participants in the aliskiren group, 123 in the losartan group, and 136 in the combination group. The registry record does not report how many randomized participants lacked endpoint data or how missing measurements were handled in the sponsor’s analysis. This limits assessment of both the precision and the potential influence of missing data.
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.
| Effect to detect | Participants per arm, 80% power | Participants per arm, 90% power |
|---|---|---|
| 100% of the observed effect | 3,802 | 5,089 |
| 75% of the observed effect | 6,758 | 9,047 |
| 50% of the observed effect | 15,205 | 20,354 |
The sample-size calculations are planning illustrations based on the observed effect, not the trial’s original design calculations. For these continuous-outcome comparisons, the figures are participants per arm, not a total across both groups. The stated 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 set to the stated fraction of the observed effect.
The 80% power column gives the number of participants per arm that the planning calculation estimates would be needed for an 80% chance of detecting the selected effect under those assumptions, if that effect were the true difference. The 90% power column uses a higher target chance of detection and therefore generally requires more participants per arm. These are planning concepts, not guarantees about what a future study would find. This is not observed power.
Rows for 100%, 75%, and 50% of the observed effect ask how the required sample size changes when the target difference is set at the full observed estimate or at a smaller fraction of it. Smaller effects need more participants because they are harder to distinguish from random variation. When the observed estimate is close to zero, using it as the target effect can yield extremely large planning figures. For example, the primary combination comparison has a near-zero observed difference and correspondingly very large participant requirements in the illustration; this reflects the calculation’s target, not a claim about a feasible study.
The registry record does not report the trial’s original sample-size justification or its planned assumptions. The illustrations should not be used to infer what the investigators expected before the study began.
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 z1−α/2 = 1.960) and the desired power (z1−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
- Observed difference Δ = 0.700; pooled standard deviation σ = 10.893.
- n = 2 × (1.96 + 0.842)2 × 10.8932 / 0.7002 = 3,801.0, rounded up to 3,802 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 <- 0.7 # observed difference in means
sigma <- 10.8925387669961 # 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(219141)
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 = 3,802 (80% power), 5,089 (90% power)
75% of observed effect: n per arm = 6,758 (80% power), 9,047 (90% power)
50% of observed effect: n per arm = 15,205 (80% power), 20,354 (90% power)
power.t.test: 3802
Simulated power at n = 3,802 per arm: 0.802 (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 record lists one primary endpoint and multiple secondary outcomes. It does not report a statistical plan describing how the family of comparisons was controlled for multiplicity. In general, testing multiple outcomes can increase the chance of at least one apparently notable finding arising through random variation. The posted secondary comparisons are unadjusted, so their p values should not be read as though they account for the full set of outcomes or comparisons.
The registry record reports no analyses in its analysis listing. The pairwise contrasts discussed for the primary and secondary outcomes are recalculations from posted group summaries, not reported sponsor analyses. No sample-size justification, interim analysis procedure, or detailed analysis plan is reported in the registry record. Consequently, it is not possible to establish from the record whether the analyses followed a prespecified hierarchy, whether any interim monitoring affected the analysis, or which covariates were used in the sponsor’s model.
The primary endpoint population required a baseline measurement, at least one post-baseline efficacy measurement, at least 28 weeks of treatment, and evaluable MRI assessments at baseline and study end. This is a stated analysis-population definition, but the number of randomized participants who did not meet it and the reasons are not reported in the registry record. The method used to handle missing outcome data is also not reported in the registry record.
These gaps matter because analysis populations and missing-data methods can influence both the estimated treatment effect and its uncertainty. The enrollment figure alone does not establish how many participants contributed to each endpoint. The arm-level analysis counts are reported, but the registry record does not provide a complete account of participant flow, missingness, or the sensitivity analyses used to assess their impact. This limits evaluation of the robustness of the posted results.
15. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Aliskiren 300 mg | 10 | 154 | 6.5% |
| Losartan 100 mg | 13 | 152 | 8.6% |
| Aliskiren/Losartan 300/100 mg | 10 | 154 | 6.5% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Aliskiren 300 mg | 31 of 154 |
| Losartan 100 mg | 31 of 152 |
| Aliskiren/Losartan 300/100 mg | 29 of 154 |
Most frequent serious adverse event terms
| Event term | Organ system | Aliskiren 300 mg | Losartan 100 mg | Aliskiren/Losartan 300/100 mg |
|---|---|---|---|---|
| Atrial fibrillation | Cardiac disorders | 2 of 154 | 2 of 152 | 1 of 154 |
| Acute myocardial infarction | Cardiac disorders | 1 of 154 | 0 of 152 | 1 of 154 |
| Angina pectoris | Cardiac disorders | 1 of 154 | 1 of 152 | 0 of 154 |
| Leukocytosis | Blood and lymphatic system disorders | 1 of 154 | 0 of 152 | 0 of 154 |
| Thrombocythaemia | Blood and lymphatic system disorders | 1 of 154 | 0 of 152 | 0 of 154 |
| Coronary artery stenosis | Cardiac disorders | 0 of 154 | 1 of 152 | 0 of 154 |
| Myocardial infarction | Cardiac disorders | 1 of 154 | 0 of 152 | 0 of 154 |
| Palpitations | Cardiac disorders | 1 of 154 | 0 of 152 | 0 of 154 |
| Sick sinus syndrome | Cardiac disorders | 1 of 154 | 0 of 152 | 0 of 154 |
| Vestibular disorder | Ear and labyrinth disorders | 0 of 154 | 0 of 152 | 1 of 154 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Aliskiren 300 mg | Losartan 100 mg | Aliskiren/Losartan 300/100 mg |
|---|---|---|---|---|
| Nasopharyngitis | Infections and infestations | 11 of 154 | 13 of 152 | 11 of 154 |
| Headache | Nervous system disorders | 14 of 154 | 8 of 152 | 10 of 154 |
| Diarrhoea | Gastrointestinal disorders | 6 of 154 | 9 of 152 | 7 of 154 |
| Dizziness | Nervous system disorders | 5 of 154 | 3 of 152 | 8 of 154 |
Serious events with the highest arm-level rate: atrial fibrillation (1.3%), angina pectoris (0.7%), coronary artery stenosis (0.7%), conjunctivitis (0.7%), non-cardiac chest pain (0.7%).
The registry reports serious adverse events among 154 participants at risk in the aliskiren group, 152 in the losartan group, and 154 in the combination group. The counts with at least one serious adverse event were 10, 13, and 10, respectively. These are counts within the listed safety groups; they are not a comparison adjusted for differences in follow-up or participant characteristics.
The most frequently listed serious adverse event terms were atrial fibrillation at 1.3%, followed by angina pectoris, coronary artery stenosis, conjunctivitis, non-cardiac chest pain, and erysipelas, each at 0.7%. These are registry-reported terms and percentages. The record does not provide enough detail to interpret each event’s timing, duration, severity beyond the serious classification, or relationship to treatment.
Deaths are not reported in the registry record. Serious adverse-event counts describe one part of the safety information and do not, by themselves, establish a comparative safety profile. The counts should be read alongside the trial’s duration, population, and reporting limitations.
16. What the Result Does, and Does Not, Mean
The primary endpoint results describe average change in MRI-measured left ventricular mass index among participants included in the efficacy analysis. The posted least-squares means decreased in each group over the study period. The recalculated comparisons between aliskiren and losartan, and between the combination and losartan, are close to zero and have confidence intervals that include zero. The data therefore do not establish a clear difference between either comparison on this endpoint.
This is not the same as demonstrating that the treatments are equivalent. Equivalence requires a prespecified margin and an analysis designed to determine whether the plausible treatment difference lies within that margin. The registry record does not report such a margin or an equivalence analysis. Nor do the intervals establish that there is no effect; they represent uncertainty across a range of possible differences.
The primary outcome is an imaging-based measure of cardiac structure. The results do not directly answer whether treatment changes symptoms, cardiovascular events, quality of life, or other outcomes not reported as results in the registry record. The registry’s description also notes that increased left ventricular mass can have different explanations. A change in the measure alone does not identify its cause or establish the broader clinical meaning of that change.
The study was conducted in overweight patients with essential hypertension, and the primary analysis required sustained treatment and evaluable MRI assessments at both time points. Interpretation should be limited to that study population and analysis context. The reported arm-level results and recalculated contrasts do not justify advice about treatment for an individual patient or conclusions beyond the outcomes and population described in the registry record.
17. Why This Trial Matters Statistically
This trial illustrates why within-group improvement and between-group evidence are different questions. All three groups had negative average changes in left ventricular mass index, but the treatment comparison depends on how much the groups differ from one another, not simply on whether each group’s average moved downward. The recalculated differences are small relative to their uncertainty, so the observed within-group changes do not by themselves show that one treatment strategy produced greater regression than another.
It also highlights the importance of matching claims to the precision and source of the estimates. The registry reports least-squares means and standard errors for the primary endpoint, but no sponsor-reported pairwise analyses are listed. The comparison intervals are recalculated from those summaries. They are informative as approximate descriptions, but they do not substitute for a fully reported analysis model.
The study’s primary endpoint is a structural MRI measure, while its secondary outcomes include other cardiac imaging measures. Such outcomes can provide a detailed description of cardiac structure and function, but their interpretation depends on clear definitions, a planned analysis approach, and attention to multiplicity. Unadjusted secondary findings require particular restraint when many measures are examined.
Finally, the reported efficacy population and the arm-specific analysis counts show why enrollment and analyzed sample size are not interchangeable. Missing-data handling, population exclusions, and original planning assumptions are not reported in the registry record. Those omissions limit how completely readers can assess the analysis, even when the endpoint estimates themselves are available.
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 specific to this trial constrain interpretation. First, the primary endpoint results are reported as least-squares means and standard errors, but the registry record does not report the underlying model, adjustment variables, or sponsor-reported pairwise comparisons. The differences and confidence intervals discussed are recalculated, unadjusted estimates from the posted summaries. They may not reproduce the sponsor’s intended model-based analysis.
Second, the primary efficacy population required at least 28 weeks of treatment and evaluable MRI assessments at baseline and the end of the study. The registry record does not report participant flow into this population, the number or reasons for missing endpoint assessments, or the method used to address missing data. The available counts therefore do not show how missingness may have affected the primary estimate.
Third, the registry record does not report the original sample-size justification, statistical analysis plan, interim analysis procedures, or a multiplicity plan. This prevents assessment of whether the observed precision met the investigators’ original expectations and whether secondary comparisons were confirmatory. The posted recalculations should not be mistaken for an account of the full planned analysis.
Finally, the study lasted 36 weeks and the primary endpoint was an MRI-based structural measure. The registry record does not report results for clinical events or patient-reported outcomes in the information summarized for this trial. Serious adverse-event counts are available, but deaths are not reported in the registry record. These features limit conclusions about outcomes beyond the imaging measures and reported safety counts.
19. Related Tutorials
20. Related Statistical Calculators
21. Sources
- ClinicalTrials.gov: Aliskiren in Combination With Losartan Compared to Losartan on the Regression of Left Ventricular Hypertrophy in Overweight Patients With Essential Hypertension — NCT00219141.
- Registry record last updated 2011-05-26; status last verified 2011-05.
- Results first posted 2011-05-10.
- 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.
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22. Record Summary
NCT00219141 was a completed, randomized, double-blind, multi-center, parallel-group Phase 3 study sponsored by Novartis Pharmaceuticals. The registry lists enrollment of 460 and describes a 36-week comparison of aliskiren, losartan, and their combination in overweight patients with essential hypertension and left ventricular hypertrophy.
The primary endpoint was change in MRI-measured left ventricular mass index from baseline to Week 36. Posted group means decreased in all three arms, while recalculated unadjusted comparisons with losartan were close to zero and had confidence intervals spanning zero. These estimates do not establish a clear between-group difference, but they also do not demonstrate equivalence.
The registry reports multiple secondary MRI outcomes and serious adverse-event counts. The original sample-size rationale, full statistical plan, multiplicity approach, missing-data method, and deaths are not reported in the registry record.