The Effects of Systolic Blood Pressure Lowering on Diastolic Function Using Valsartan + Amlodipine in Patients With Hypertension and Diastolic Dysfunction: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Effects of Systolic Blood Pressure Lowering on Diastolic Function Using Valsartan + Amlodipine in Patients With Hypertension and Diastolic Dysfunction (NCT00523549), a randomized phase 4 study. The primary outcome is Change in Lateral Mitral Annular Myocardial Relaxation Velocity.

2. Clinical Question

The trial focused on whether aiming for the lower systolic blood pressure target was associated with a different change in this echocardiographic measure. The comparison concerns the treatment strategies and target levels, not a comparison of valsartan plus amlodipine against no treatment or against a different drug regimen. Both groups received the same named medications; their assigned systolic blood pressure targets differed.

The registry record identifies change in left atrial size and change in the ratio of peak E wave velocity to lateral mitral annular myocardial relaxation velocity among the secondary outcomes. Other listed secondary measures concern vascular stiffness and blood pressure. Their names indicate additional dimensions of cardiac structure, function, or blood pressure response, but the primary question remains the between-group contrast in change in E' at Week 24.

3. Trial Design

This was a multicenter, prospective, randomized, open-label study with blinded outcome evaluation. The registry record classifies it as phase 4, with randomized allocation and a parallel-group model. Masking is recorded as none; the study title specifies blinded outcome evaluation. These descriptions distinguish the open-label treatment conduct from the evaluation of outcomes.

The registry record reports enrollment of 229 and a completed status. The study start is listed as 2006-11, and primary completion as 2008-01. The posted primary outcome summaries list 98 participants in each regimen. Those outcome summary counts are not the same information as the overall enrollment figure; the registry record does not explain the difference in these counts.

The intensive regimen used valsartan plus amlodipine toward a systolic blood pressure target of <130 mmHg. The standard regimen used the same medications toward a target of <140 mmHg. The registry record names the Joint National Commission on the Treatment of Hypertension 7 recommended target as the basis for the standard target. The intervention contrast is therefore the assigned target strategy while using the named drug combination.

The primary outcome timeframe was baseline to 24 weeks after treatment. The primary measure was change in lateral mitral annular myocardial relaxation velocity, and the identified analysis population was intent-to-treat. Details such as the randomization procedure, allocation concealment, treatment titration schedule, visit schedule beyond the primary timeframe, and site count are not reported in the registry record.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Change in Lateral Mitral Annular Myocardial Relaxation Velocity, measured over Baseline to 24 weeks after treatment.

The primary endpoint is change from baseline in lateral mitral annular myocardial relaxation velocity, also identified as E', at Week 24. It is a continuous echocardiographic measure reported in cm/s. A change endpoint compares the measure at follow-up with its baseline value, so the outcome describes movement over the specified study period rather than the Week 24 level alone.

E' is used in the study as a measure related to myocardial relaxation. The trial's stated purpose was to assess whether targeting different systolic blood pressure levels with valsartan plus amlodipine affected intrinsic diastolic properties of the myocardium in patients with hypertension and echocardiographic evidence of diastolic dysfunction. Thus, the endpoint addresses a cardiac functional measure rather than serving as a direct measure of blood pressure itself.

The registry reports group means and standard deviations for change, together with a between-group mean difference and a confidence interval. The endpoint is not a clinical event count, and its interpretation depends on the scale and clinical context of E'. A threshold for a clinically important change is not reported in the registry record. Nor do the posted primary results give the achieved systolic blood pressure values corresponding to the assigned targets.

7. Results Posted in the Registry

• Intensive Treatment Regimen: mean 1.54 versus 1.48 on control; difference 0.07 (95% CI -0.35 to 0.49), standardized effect d = 0.05; z-test p = 0.751.

8. Secondary Efficacy Endpoints

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

Change in Left Atrial Size

• 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:
  • Intensive Treatment Regimen: mean -0.13 versus -0.10 on control; difference -0.02 (95% CI -0.11 to 0.06), standardized effect d = -0.08; z-test p = 0.587.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Intensive Treatment Regimen and the control. The interval gives the range of effects that remain compatible with the data.

Change in Ratio of Peak E Wave Velocity/Lateral Mitral Annular Myocardial Relaxation Velocity

• 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:
  • Intensive Treatment Regimen: mean -0.95 versus -0.68 on control; difference -0.27 (95% CI -0.87 to 0.32), standardized effect d = -0.13; z-test p = 0.372.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Intensive Treatment Regimen and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes extend the primary question to measures of cardiac structure and function, vascular stiffness, and sitting blood pressure. Numerical group summaries and recalculated comparisons are posted for change in left atrial size and change in the ratio of peak E wave velocity to lateral mitral annular myocardial relaxation velocity. These measures broadly relate to the primary endpoint's focus on cardiac function, but they are distinct outcomes and do not replace the primary E' comparison.

The two posted secondary comparisons have confidence intervals that include zero. Their estimates therefore do not give a precise indication of a between-group difference in either direction. In broad terms, this pattern is consistent with the primary result: the posted summaries do not identify a clear separation between the target groups on these measured changes. It does not establish that the regimens are equivalent, nor does it demonstrate that all secondary outcomes had the same pattern.

The registry lists additional secondary outcomes involving vascular stiffness and mean sitting systolic and diastolic blood pressure, as well as estimated central aortic pressure. Numerical results for those listed measures are not reported in the registry record. It is consequently not possible to assess whether they support, qualify, or differ from the posted cardiac-measure results.

Unadjusted secondary results carry less weight than a prespecified primary analysis because testing multiple outcomes increases the chance of at least one apparently unusual result arising by chance. The registry record does not report a multiplicity procedure or a hierarchy for secondary testing. The secondary findings are best treated as supportive or exploratory descriptions, not as independent proof of a broad treatment effect. Their interpretation also depends on the unreported analysis and missing-data details.

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

• Change in Left Atrial Size
• Change in Ratio of Peak E Wave Velocity/Lateral Mitral Annular Myocardial Relaxation Velocity
• Percent Change From Baseline in Vascular Stiffness
• Change in Mean Sitting Systolic Blood Pressure (msSBP)
• Change in Mean Sitting Diastolic Blood Pressure (msDBP)
• Change in Estimated Central Aortic Pressure

9. Statistical Interpretation

10. Statistical Methods Explained

A randomized parallel-group design assigns participants to one of the treatment strategies and compares outcomes between groups. Here, the strategies shared the named drugs and differed in their systolic blood pressure targets. Random assignment can support a causal comparison when implemented as intended, but details of the allocation procedure and the analysis plan are not reported in the registry record. The study was open-label, with outcome evaluation described as blinded.

What does a mean change represent?

A mean is the arithmetic average of a continuous outcome. For a change endpoint, each participant's follow-up measure is considered relative to baseline, and the group mean summarizes those changes. Positive and negative changes are interpreted according to the measure's scale and definition. In this trial, the posted mean changes are for lateral mitral annular myocardial relaxation velocity from baseline to Week 24. The registry record reports the outcome in cm/s and identifies the summary as a mean with standard deviation.

A standard deviation describes the spread of individual values around a group mean. It is not the same as the uncertainty in the mean itself. A group's standard deviation can be substantial even when the mean is estimated more precisely, because the mean uses information across participants. The primary summaries report standard deviations of 1.395 cm/s and 1.599 cm/s for the intensive and standard regimens, respectively.

How is the group contrast read?

The mean difference compares the intensive regimen with the standard regimen. The posted estimate is 0.068 cm/s, calculated as intensive minus standard. A value of zero would represent equal group means on this scale. A positive estimate means the intensive group's mean change is numerically higher; a negative estimate would mean it is numerically lower. The estimate is a difference in average changes, not a percentage change or a comparison of individual responses.

The confidence interval expresses uncertainty around the estimated mean difference under the calculation used. The primary interval extends from -0.352 to 0.488 cm/s. It includes zero, so the values compatible with the interval include no difference as well as differences in either direction. The interval does not establish that every value in its range is equally plausible, nor does it set a clinical importance threshold.

What does the p-value add?

The unadjusted p-value is 0.751. In general, a p-value measures how unusual an observed result, or one more extreme, would be under a specified null hypothesis and analysis model. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. The registry record does not report a sponsor inferential analysis or specify the model underlying a p-value; the posted p-value is an unadjusted recalculation from the summary statistics.

Unadjusted means the comparison has not been adjusted for other variables or for multiple testing. No covariate adjustment is reported. The registry record also does not report whether the original analysis used a different test, handled repeated measurements in a model, or included other prespecified adjustments. The recalculated comparison is useful as a transparent summary-statistic comparison, but it should not be mistaken for a fully documented trial analysis.

Why can variability and over-dispersion matter?

For a continuous outcome, substantial variability makes it harder to estimate a mean difference precisely, especially when the effect of interest is small relative to the spread of participant outcomes. A confidence interval reflects this uncertainty. General statistical principle: if outcome variation is greater than an analysis assumes, standard errors can be too small and confidence intervals too narrow. This issue is often called over-dispersion in settings where a model's assumed variability is lower than the observed variability. The registry record does not report an over-dispersion assessment or a model for the primary outcome; the posted summaries are means and standard deviations.

What is known about the analysis population?

The primary outcome population is identified as intent-to-treat. In general, this label indicates analysis according to randomized assignment, regardless of subsequent treatment adherence, although the precise implementation depends on the protocol and handling of missing outcomes. The registry record does not explain which participants were included in the posted outcome summaries, how missing values were handled, or whether the intent-to-treat label was implemented with imputation or another method. Those details are important for interpreting a change endpoint and cannot be inferred from the group summaries alone.

11. Confidence Intervals and Precision

The primary estimated mean difference is 0.068 cm/s, with a 95% confidence interval from -0.352 to 0.488 cm/s. The interval is the central summary of precision: it indicates that the estimated between-group contrast is uncertain across a range that includes zero. The lower end is negative and the upper end positive, so the data do not precisely determine which regimen had the larger mean change.

In general, a confidence interval gives a range of estimates compatible with the data and the method used to calculate it. It is not a guarantee that the true effect lies in the interval, and it does not mean that all values in the range have equal probability. Its width reflects sampling variability as well as the calculation method. The registry record does not report a clinical threshold for interpreting the magnitude of the interval, so it cannot be classified as excluding all clinically important effects.

The primary group standard deviations, 1.395 cm/s and 1.599 cm/s, describe variation in individual changes and provide context for the uncertainty in the group contrast. The posted group summaries list 98 participants in each regimen. These summaries and the interval concern the primary outcome; they do not provide confidence intervals for every individual participant's response or establish the precision of other outcomes.

The unadjusted p-value of 0.751 is consistent with the interval including zero, but the confidence interval is more informative about the range and direction of estimates compatible with the data. Since the registry record does not report a clinically meaningful difference threshold, a judgment about whether the interval is sufficiently narrow for a clinical decision cannot be made from this endpoint information alone.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total participants. They are illustrations based on the observed effect, not the trial's own original design assumptions. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect.

For the primary outcome, the planning figures for 100% of the observed effect are 7,639 participants per arm for 80% power and 10,226 participants per arm for 90% power. For 75% of the observed effect, the figures are 13,580 participants per arm for 80% power and 18,180 participants per arm for 90% power. For 50% of the observed effect, they are 30,555 participants per arm for 80% power and 40,904 participants per arm for 90% power.

In general, power is the chance that a planned study will detect an effect of a specified size under the assumptions used, if that effect is present. The 80% and 90% columns describe different planning targets: the higher target requires more participants under otherwise similar assumptions. Smaller effects need more participants because they are harder to distinguish from random variation. These figures are planning illustrations, not observed power; observed power is not a useful substitute for interpreting the estimated effect and its confidence interval.

The registry record does not report the original sample-size justification or its design assumptions. The planning calculation uses the observed primary effect as its reference, so it should not be read as evidence that the trial was designed to detect that effect or that its enrollment was selected using these calculations. All listed figures for this continuous outcome are per arm.

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 = 0.068; pooled standard deviation σ = 1.500.
2. n = 2 × (1.96 + 0.842)² × 1.500² / 0.068² = 7,638.6, rounded up to 7,639 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 <- 0.0680000000000001                      # observed difference in means
sigma <- 1.50001856821841                     # 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(523549)
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 = 7,639 (80% power), 10,226 (90% power)
 75% of observed effect: n per arm = 13,580 (80% power), 18,180 (90% power)
 50% of observed effect: n per arm = 30,555 (80% power), 40,904 (90% power)
power.t.test: 7639.5 
Simulated power at n = 7,639 per arm: 0.796 (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 identifies one primary outcome and lists secondary outcomes, but does not report a multiplicity adjustment, a testing hierarchy, or a detailed statistical analysis plan. No reported analyses are listed. The posted p-values are unadjusted recalculations from summary statistics, so they do not account for testing more than one outcome. Without a stated plan, it is not possible to determine how the trial team intended to control the chance of false-positive findings across outcomes or time points.

The primary outcome population is identified as intent-to-treat. The registry record does not describe the actual analysis population in enough detail to verify how that label was applied. It does not report the number of missing primary outcomes, reasons for missingness, the handling of missing values, or any sensitivity analyses. These omissions matter because an analysis of change from baseline requires outcome information at the relevant time points or a stated approach for incomplete observations.

The record also does not report whether the primary comparison was adjusted for baseline values or other covariates, which inferential model was prespecified, or whether an interim analysis was planned or conducted. The original sample-size justification is not reported. The record gives an overall enrollment figure and group summary counts for the primary outcome, but does not explain how participants moved from enrollment to those outcome summaries.

These details affect how closely the recalculated unadjusted comparison matches the intended trial analysis. They do not change the arithmetic of the posted summary comparison, but they limit assessment of the prespecified inferential approach, missing-data bias, and the strength of claims across multiple outcomes.

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: atrial fibrillation (0.9%), goitre (0.9%), appendicitis perforated (0.9%), intestinal obstruction (0.9%), pancreatitis (0.9%).

The registry reports serious adverse events for groups with 114 participants at risk in each regimen. Three participants are listed as affected in the intensive regimen and three in the standard regimen. The most frequent serious terms listed are atrial fibrillation, goitre, appendicitis perforated, intestinal obstruction, pancreatitis, and cholecystitis acute, each reported as 0.9%. The record does not assign these listed terms to a specific treatment group.

The other adverse event counts are 49 in the intensive regimen and 41 in the standard regimen, with 114 at risk in each group. The registry record does not provide additional detail about event severity, duration, recurrence, or causal attribution. Death counts are not reported in the registry record.

These figures describe events recorded in the trial; they do not establish that a treatment caused an event or that the groups differ in safety. The safety denominators are distinct from the primary outcome summary counts, and the record does not explain the relationship between them. Comparisons should be interpreted cautiously because the registry does not report a detailed safety analysis or uncertainty estimates for these counts.

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

The posted primary result is an estimated difference between two randomized blood pressure target strategies using valsartan plus amlodipine. It concerns mean change in lateral mitral annular myocardial relaxation velocity from baseline to Week 24. The estimate is 0.068 cm/s, with a 95% confidence interval from -0.352 to 0.488 and an unadjusted p-value of 0.751. These statistics describe the observed comparison and its uncertainty; they do not prove that the strategies are identical.

The result does not establish whether targeting systolic blood pressure below 130 mmHg is better or worse for clinical outcomes. The endpoint is an echocardiographic functional measure, not a direct report of symptoms, cardiovascular events, or survival. The posted primary results also do not establish the achieved blood pressure in each group. A target is an assigned treatment goal, not evidence that participants reached it.

The confidence interval spans values on either side of zero. Without a reported threshold for a clinically meaningful E' difference, the clinical importance of the range cannot be determined from these results alone. The point estimate is not a complete description of the evidence; its uncertainty, the study design, and the limits of the posted analysis all matter.

The trial record provides evidence about this comparison in the stated population and timeframe, but it does not settle questions about other patient groups, different treatments, longer follow-up, or outcomes not reported. The registry record's lack of detail on missing data, multiplicity, and the original statistical plan further limits the conclusions that can be drawn. The appropriate reading is a relatively imprecise, unadjusted estimate for the primary measure, not a broad verdict about treatment benefit or harm.

17. Why This Trial Matters Statistically

This trial illustrates the difference between a treatment target and a measured outcome. The assigned targets were <130 mmHg and <140 mmHg, while the primary comparison concerned change in a cardiac relaxation measure. A statistical result for that measure cannot automatically be translated into a conclusion about achieved blood pressure or clinical outcomes.

It also shows why an estimate should be read together with its uncertainty. The primary mean difference is close to zero, but its confidence interval includes values in both directions. The p-value alone cannot establish equivalence or explain which effect sizes remain compatible with the data. Precision and clinical context are essential to interpretation.

The study's open-label treatment conduct and blinded outcome evaluation are distinct design features. Recognizing that distinction is important when considering potential sources of bias: outcome evaluation was described as blinded, while the treatment assignment was not masked. The registry record does not give enough detail to assess how these features were implemented.

Finally, the record distinguishes posted descriptive summaries from a fully documented analysis. The primary population is identified, but the statistical plan, missing-data approach, multiplicity strategy, and original sample-size justification are not reported. Recalculations from group summaries can clarify the numerical contrast, yet they cannot substitute for those protocol and analysis details. This is a useful example of interpreting an available estimate without claiming more than the record supports.

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 information available for this trial. The study was open-label, although outcome evaluation was described as blinded. The registry record does not explain which people were blinded, how blinding was maintained, or whether treatment awareness could have influenced conduct beyond outcome evaluation.

The posted primary summaries list 98 participants in each regimen, while overall enrollment is reported as 229. The registry record does not explain this difference or describe participant flow into the primary outcome summaries. It also does not report missing-outcome counts, reasons for missingness, or the method used to handle missing data, despite identifying the primary population as intent-to-treat.

Only two listed secondary measures have numerical group summaries and comparisons in the posted results. Numerical results for the other listed secondary measures are not reported in the registry record. A multiplicity strategy is also not reported, making it difficult to assess the inferential standing of multiple outcome comparisons.

The primary comparison is an unadjusted recalculation from summary statistics. The registry record does not report the planned model, baseline adjustment, original sample-size justification, or interim analysis details. It also does not provide a clinical-importance threshold for the primary endpoint or achieved blood pressure values by group. These limitations constrain interpretation of both the magnitude and practical meaning of the observed difference.

The safety record gives event counts and denominators but not detailed causal assessments or uncertainty estimates. Death counts are not reported in the registry record. These gaps prevent a comprehensive comparison of safety from the posted event summaries alone.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: The Effects of Systolic Blood Pressure Lowering on Diastolic Function Using Valsartan + Amlodipine in Patients With Hypertension and Diastolic Dysfunction — NCT00523549.
• Registry record last updated 2012-04-23; status last verified 2012-04.
• Results first posted 2011-03-10.
• 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.

22. Record Summary

NCT00523549 is a completed phase 4, randomized, parallel-group, multicenter study of valsartan plus amlodipine in patients with hypertension and diastolic dysfunction. The treatment groups differed in their systolic blood pressure targets: <130 mmHg for the intensive regimen and <140 mmHg for the standard regimen. The study was open-label, with blinded outcome evaluation described in the title.

The primary outcome was change in lateral mitral annular myocardial relaxation velocity from baseline to Week 24, in an intent-to-treat population. The reported mean difference was 0.068 cm/s, with a 95% confidence interval from -0.352 to 0.488 and an unadjusted p-value of 0.751. The interval includes zero and leaves uncertainty about the direction and magnitude of the difference.

The registry record reports enrollment of 229 and primary outcome summaries listing 98 participants in each regimen. Numerical secondary comparisons are posted for two measures; other listed secondary results and key analysis details are not reported in the registry record.