Phase II Study of Heart Polypill Safety and Efficacy in Primary Prevention of Cardiovascular Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase II Study of Heart Polypill Safety and Efficacy in Primary Prevention of Cardiovascular Disease (NCT00603590), a randomized phase 2 study. The primary outcome is Systolic Blood Pressure.

2. Clinical Question

3. Trial Design

NCT00603590 is a completed Phase II randomized controlled trial sponsored by Tehran University of Medical Sciences. The registry records a parallel-group design and an enrollment of 475. Its masking field says quadruple masking, whereas the narrative description says double-blind. The precise meaning of those masking labels, including which trial roles were unaware of assignment, is not reported in the registry record.

Participants were assigned to the fixed-dose polypill or an identical placebo. The active tablet combined aspirin 81mg, hydrochlorothiazide 12.5mg, enalapril 2.5mg and atorvastatin 20mg. The population was described as people not currently considered eligible for antihypertensive or lipid-lowering treatment. The summary gives age ranges of 50 to 80 for men and 55 to 80 for women; further eligibility details are not reported in the registry record.

The primary outcome was systolic blood pressure at one year. The registry says the reported results are based on 12 month observation and labels the population intention to treat. It also says an analysis for a final paper will use last observation carried forward. Whether that imputation was used for the posted results is not reported in the registry record.

The registry lists diastolic blood pressure and LDL cholesterol as secondary outcomes, also at one year. The posted arm counts vary by outcome, and the reasons for those differences are not reported in the registry record. The original sample-size justification, allocation procedures, adherence details and prespecified analysis plan 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.

Before assignment: 872 subjects entered the run in phase, 258 were excluded. Most exclusions were due to laboratory test results. 614 completed the run-in phase of the study, 65 were excluded. Most were excluded because they did not attend the clinic. Of 549 subjects remaining, 74 were not randomized. 475 subjects who were randomized.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intention to treat Results shown here are based on 12 month observation. Analysis for final paper will be last observation carried forward

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 Systolic Blood Pressure, measured over One year.

The primary endpoint is systolic blood pressure, measured in mm Hg. The registry defines it as the mean of two seated measurements and gives a one-year timeframe. The posted arm results are group means with standard deviations. This makes the comparison a difference between average continuous measurements rather than a comparison of event counts or the proportion of participants crossing a threshold.

Using the mean of two seated readings is part of the endpoint definition in this trial. In general, averaging repeated measurements can reduce the influence of short-term variation or measurement noise compared with relying on a single reading. That statistical rationale is general; the registry does not report why this particular endpoint or measurement procedure was selected.

The primary endpoint allows a quantitative comparison between randomized groups at the stated follow-up. The posted data estimate an average difference, with uncertainty expressed by a confidence interval. This outcome does not itself measure cardiovascular events, mortality, or longer-term health outcomes. The registry lists those endpoints only indirectly in its background rationale, not as the primary outcome.

The description identifies the results as intention to treat and based on 12 month observation. However, the exact handling of participants without a recorded one-year measurement is not reported in the registry record. The proposed last-observation-carried-forward approach for a final paper should not be assumed to describe the analysis behind these posted results.

7. Results Posted in the Registry

• Polypill: mean 121.70 versus 129.70 on control; difference -8.00 (95% CI -11.69 to -4.31), standardized effect d = -0.45; z-test p = <0.001.

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.

Diastolic Blood Pressure

• 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:
  • Polypill: mean 77.60 versus 81.30 on control; difference -3.70 (95% CI -5.98 to -1.42), standardized effect d = -0.34; z-test p = 0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Polypill than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

LDL Cholesterol

• 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:
  • Polypill: mean 87.80 versus 112.00 on control; difference -24.20 (95% CI -29.93 to -18.47), standardized effect d = -0.90; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Polypill than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes are diastolic blood pressure and LDL cholesterol at one year. Across these endpoints, the posted group averages are lower in the polypill arm than in the placebo arm, matching the direction of the primary systolic blood pressure comparison. This directional consistency provides context for the primary finding, but each outcome remains a distinct measurement with its own variability and participant counts.

The registry reports unadjusted comparisons for the secondary outcomes and lists no separate analysis records. No adjustment for testing multiple outcomes is reported. When several outcomes are examined, the chance of finding at least one apparently unusual result can increase if each is assessed independently. In general, multiplicity procedures can address that issue, but the record does not say that such a procedure was prespecified or used.

Secondary results therefore carry less inferential weight than a prespecified primary endpoint, particularly when the analysis plan and multiplicity handling are not reported. Their direction can be considered alongside the primary endpoint, but they should not be treated as independent confirmation or as evidence about outcomes the trial did not measure. The record does not report whether these secondary outcomes were specified in advance beyond listing them as secondary outcomes.

Participant counts differ across the outcomes. The reasons for those differences are not reported in the registry record, so the pattern should not be interpreted as evidence of a particular missing-data mechanism. The secondary endpoints add information about the measured one-year outcomes, while leaving uncertainty about data completeness, analysis choices and broader clinical outcomes.

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

• Diastolic Blood Pressure
• LDL Cholesterol

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous, so the central comparison is between two group means. Each arm's mean describes its average systolic blood pressure at the stated follow-up, while the standard deviation describes the spread of individual measurements around that group average. A standard deviation is not the same as the uncertainty in the mean: the latter depends on both variability and the number of participants contributing data.

What does the mean difference represent?

The mean difference is calculated as the polypill-group mean minus the control-group mean. A negative value therefore indicates a lower observed group average in the polypill arm. For systolic blood pressure, the posted means are 121.7 mm Hg and 129.7 mm Hg, respectively, and the posted difference is -8.0 mm Hg. This contrast describes the group averages; it does not mean every participant had a lower measurement, nor does it describe the distribution of individual responses.

The registry's comparative results include confidence intervals and p-values. The listed comparisons are unadjusted; no covariate-adjusted analysis is reported. In general, an unadjusted comparison uses the reported group summaries without accounting for other participant characteristics in a statistical model. Random allocation is intended to make groups comparable on average, but it does not remove the importance of transparent reporting about the analysis and incomplete data.

How should the confidence interval and p-value be read?

In general, a confidence interval expresses the precision of an estimate under the assumptions of the method used. A narrower interval indicates greater precision than a wider interval, while an interval spanning a broad range leaves more uncertainty about the size of the difference. A conventional 95% confidence interval is generated by a procedure that, under its assumptions, would cover the target quantity in 95% of repeated applications. It is not a probability statement that the particular fixed effect lies within this particular interval.

A p-value evaluates how compatible the observed data are with a specified null model, typically one with no group difference. It is not an effect size, does not measure clinical importance and does not account for every possible source of bias. The primary p-value is reported as <0.001. The registry does not report the full test specification or whether any adjustment beyond the stated comparison was used.

What do the spread and participant counts add?

The standard deviations for systolic blood pressure are 16.8 in the polypill group and 18.3 in the control group. Together with the participant counts, they convey the variability and amount of information contributing to the group summaries. In general, more observations can improve precision when the other features of the data and analysis are comparable; larger variability can make a mean difference less precise. These principles do not resolve uncertainty about participants with unobserved measurements or the reason outcome-specific counts differ.

The registry labels the primary results intention to treat and says they are based on 12 month observation. In general, intention-to-treat analysis compares groups according to randomized assignment, regardless of treatment received. The exact implementation matters, especially if outcomes are missing or participants do not follow assigned treatment. The registry says an analysis for a final paper will use last observation carried forward. That describes a planned approach for the final paper; the registry does not establish that it was used for the posted estimates.

Why does over-dispersion matter in other kinds of outcomes?

General explanation: over-dispersion arises when count or binary outcome data vary more than a statistical model assumes. If it is ignored, standard errors and confidence intervals can be too small, making results appear more precise than they are. It is not the main issue for interpreting the posted continuous mean comparisons, and the registry does not report an over-dispersion analysis.

The registry includes planning illustrations based on observed effects. These are distinct from the original trial design assumptions, which are not reported in the registry record. Planning calculations ask how many participants might be needed under specified assumptions; they do not establish how the trial was originally designed or how likely its observed estimate was to be significant. They are not observed power.

The record lists no separate reported analysis entries. It also does not report a prespecified model, baseline adjustment, handling of multiple comparisons, or detailed missing-data procedure for the posted results. These omissions limit how completely the calculation can be reconstructed or evaluated. The comparative summaries remain interpretable as group-level estimates, but the unreported details should not be filled in by assumption.

11. Confidence Intervals and Precision

The primary mean difference is -8.0 mm Hg, and its 95% confidence interval extends from -11.69 to -4.312. The interval gives a range of estimates compatible with the observed data and the method's assumptions. Its width is relevant because the point estimate alone does not convey how precisely the group contrast has been estimated.

Both limits are below zero, and the primary p-value is <0.001. These features indicate that the posted data are inconsistent with a null model of no difference under the unadjusted comparison. They do not establish that the estimate is free of bias, identify the effect for every participant, or establish the importance of the difference for outcomes not measured in the trial.

Precision is also shaped by the observed variability and the number of measurements contributing to each arm. The posted primary outcome counts are 165 and 183, compared with total enrollment of 475. The reasons that the outcome counts do not account for all enrolled participants are not reported in the registry record. Without details on missingness and its handling, the confidence interval alone cannot capture all uncertainty related to the observed data.

In general, confidence intervals are most informative when read alongside the estimate, study design and analysis details. The registry does not report an adjusted analysis or a full statistical plan, so the interval should be understood as uncertainty around the posted unadjusted comparison rather than as a complete account of every source of uncertainty.

12. Planning a Similar Trial: Sample Size

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

The planning figures are participants per arm, not total events. They are illustrations based on the observed effect, rather than the trial's original design assumptions; the original sample-size justification is not reported in the registry record. The calculations assume a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. Each planning row uses the stated fraction of the observed effect as the effect to detect.

For the primary endpoint, planning for 100% of the observed effect gives 77 participants per arm for 80% power and 102 participants per arm for 90% power. Planning for 75% of the observed effect gives 136 participants per arm for 80% power and 181 participants per arm for 90% power. Planning for 50% of the observed effect gives 305 participants per arm for 80% power and 408 participants per arm for 90% power.

In plain language, 80% power means that, if the assumed effect and other calculation assumptions were true, the design would have an 80% chance of detecting that effect by the specified test procedure. The 90% column describes a higher target chance under those same assumptions. Smaller effects need more participants to be detected with the same power, which is why the planning figures increase as the assumed fraction of the observed effect gets smaller.

These are planning illustrations, not observed power. They do not describe the probability that this completed trial's result is correct, nor do they show that the original trial was planned around these assumptions. The same type of illustration is available for the secondary outcomes, but those figures should be interpreted with the corresponding endpoint's observed effect and variability in mind.

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 = -8.000; pooled standard deviation σ = 17.605.
2. n = 2 × (1.96 + 0.842)² × 17.605² / -8.000² = 76.0, rounded up to 77 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 <- -7.99999999999999                      # observed difference in means
sigma <- 17.6049569346398                     # 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(603590)
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 = 77 (80% power), 102 (90% power)
 75% of observed effect: n per arm = 136 (80% power), 181 (90% power)
 50% of observed effect: n per arm = 305 (80% power), 408 (90% power)
power.t.test: 77 
Simulated power at n = 77 per arm: 0.801 (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 one primary endpoint and two secondary endpoints. It does not report a multiplicity adjustment, a hierarchy for testing outcomes, or a detailed prespecified statistical analysis plan. In general, when multiple outcomes are tested, interpreting each unadjusted p-value as though it were the only planned test can overstate the strength of evidence. The posted secondary findings should therefore be treated as supportive descriptive context rather than as definitive independent tests.

The primary results are labeled intention to treat and based on 12 month observation. The registry also states that an analysis for a final paper will use last observation carried forward. It is not reported whether this method was applied to the posted estimates, how many observations were missing, or how missing measurements were handled in the reported comparisons. Last observation carried forward is an imputation approach; in general, it fills a missing later measurement using an earlier observed value and relies on assumptions about what the unobserved outcome would have been.

The posted primary arm counts are 165 and 183. Secondary outcome counts are 165 and 183 for diastolic blood pressure, and 160 and 175 for LDL cholesterol. Enrollment was 475. The reasons these counts vary and do not include all enrolled participants are not reported in the registry record. It would be inappropriate to infer that participants withdrew, were excluded, or had missing measurements for any specific reason.

The record does not give details about adherence, treatment discontinuation, protocol deviations, baseline adjustment, or sensitivity analyses. Those omissions do not alter the numerical summaries, but they limit evaluation of how robust the results are to analytic choices and incomplete data. The registry has no separate reported analysis entries.

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

The posted data show a lower mean systolic blood pressure in the polypill group than in the placebo group at one year, with an unadjusted estimated difference of -8.0 mm Hg and a 95% confidence interval from -11.69 to -4.312. The result is a comparison of randomized groups on the endpoint reported in the registry. It is not a direct comparison of cardiovascular events, mortality or long-term outcomes.

The trial's rationale concerned primary prevention, but the posted primary result is a blood-pressure measurement. The record also reports diastolic blood pressure and LDL cholesterol as secondary outcomes. Changes in these measurements do not, by themselves, establish what happened to cardiovascular disease incidence or other outcomes that were not reported as trial endpoints.

Random allocation and a placebo comparator are design features intended to support a fair comparison between assigned groups. Interpretation still depends on implementation, completeness of outcome data and analysis choices. The registry does not report the detailed missing-data procedure used for the posted results, a complete analysis plan, or adjusted comparisons. The trial's Phase II and pilot descriptions also frame the evidence as focused rather than comprehensive.

The results should not be generalized beyond the population and follow-up described without additional evidence. Eligibility was described in broad terms, and the registry summary gives age ranges but not the full criteria. The primary outcome is based on 12 month observation; the registry does not report longer follow-up for the primary result. These limits mean that the posted comparison answers a narrower statistical question than whether the intervention changes long-term health outcomes across broader populations.

In general, statistical evidence about a group-average difference is distinct from a judgment about clinical value. That judgment would require context beyond the estimate and confidence interval, including outcomes and considerations not reported in this record. The result should be read as a precise estimate of the posted endpoint within the documented limitations, not as a conclusion about every possible benefit or harm.

16. Why This Trial Matters Statistically

This trial is statistically informative because it reports a randomized, placebo-controlled comparison of a combination intervention in a primary-prevention setting, with continuous outcomes measured at one year. The primary endpoint is defined as the mean of two seated systolic blood pressure measurements, and the record gives group means, standard deviations, participant counts, a mean difference, a confidence interval and a p-value. Those details allow readers to distinguish the size of the observed contrast from its statistical precision.

The record also illustrates why a statistically clear comparison is not the same as a complete clinical conclusion. The primary outcome is a physiological measurement, not a cardiovascular event endpoint. The intervention combines several agents, so the group comparison pertains to the assigned combination and does not separate the contribution of its components. The study's Phase II and pilot labels further indicate that the reported question is limited in scope.

Statistically, the presence of secondary outcomes raises questions about multiplicity, while outcome-specific participant counts raise questions about data completeness. The registry does not report a detailed analysis plan, multiplicity procedure or exact missing-data handling for the posted results. These are important reporting details because they shape how confidently estimates can be interpreted and compared.

The trial matters as an example of reading results at the level actually measured: a randomized group contrast in one-year blood pressure, with an uncertainty interval, rather than an extrapolation to unreported outcomes. It also shows why planning illustrations based on an observed effect must be kept separate from original design assumptions and from the power of the completed study.

17. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The record leaves several trial-specific uncertainties. Enrollment was 475, while the posted primary outcome counts are 165 and 183, and the LDL cholesterol counts are 160 and 175. The causes of these differences are not reported. Without information on missing observations and their handling, it is not possible to assess whether the reported outcome summaries represent all randomized participants or how incomplete data may affect the estimates.

The registry labels the primary results intention to treat, but does not give enough detail to reconstruct the analysis. It mentions last observation carried forward for a final paper, without stating whether that method was applied to the posted data. The original sample-size justification and detailed analysis plan are not reported. No covariate adjustment, sensitivity analysis or multiplicity procedure is described.

The record's narrative calls the trial double-blind, while its masking classification is quadruple. The specific masked roles are not reported. This difference in descriptions limits understanding of the masking procedures but does not, by itself, establish how the trial was conducted.

The primary outcome is reported at one year, and the posted result does not measure cardiovascular events or mortality. The record includes a serious cardiovascular event term at 0.4%, with one serious event listed in the control group and none in the polypill group. It reports two other adverse events in the polypill group and none in the control group. Denominators for adverse-event risk and death counts are not reported, so these entries do not support a complete comparison of safety rates.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Phase II Study of Heart Polypill Safety and Efficacy in Primary Prevention of Cardiovascular Disease — NCT00603590.
• Registry record last updated 2009-10-02; status last verified 2009-09.
• Results first posted 2009-06-23.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

21. Record Summary

NCT00603590 is a completed randomized Phase II parallel-group trial sponsored by Tehran University of Medical Sciences. It enrolled 475 participants and compared a fixed-dose polypill with an identical placebo. The active tablet contained aspirin 81mg, hydrochlorothiazide 12.5mg, enalapril 2.5mg and atorvastatin 20mg.

The primary outcome was mean systolic blood pressure at one year, defined as the mean of two seated measurements. The posted comparison favored a lower group average in the polypill arm, with a mean difference of -8.0 mm Hg and a 95% confidence interval from -11.69 to -4.312. Diastolic blood pressure and LDL cholesterol were listed as secondary outcomes.

The registry identifies the primary results as intention to treat and based on 12 month observation. Detailed missing-data handling, the original sample-size justification, a full statistical analysis plan and multiplicity procedures are not reported in the registry record. The trial narrative describes double-blinding, while the masking classification says quadruple.