Impact on Management of the HEART Risk Score in Chest Pain Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Impact on Management of the HEART Risk Score in Chest Pain Patients (NCT01756846), a randomized na study. The primary outcome is MACE (Major Adverse Cardiac Events).

2. Clinical Question

The comparison is framed as a management strategy question: whether using a structured risk score was associated with a different observed frequency of the composite cardiac outcome than management under usual practice. The registry describes the trial as randomized and crossover, but the sequence of care strategies and the crossover process are not reported in the registry record. The primary result is a comparison of participant counts with a recorded event in each group, alongside an unadjusted risk-difference estimate and its confidence interval. Those summaries describe the posted outcome data; they do not, by themselves, explain how care was delivered in each period or establish why any difference occurred.

3. Trial Design

The registry describes this study as randomized, single-masked and crossover, with phase recorded as NA. Its status is completed. The sponsor is UMC Utrecht. The recorded enrollment is 3666, and the recorded start and primary completion dates are 2013-07 and 2014-10. The record does not explain who was masked, what the crossover sequence was, or how long participants received each strategy.

The two interventions are usual care and use of the HEART risk score. Usual care is described as the daily practice of a cardiologist or attending emergency doctor diagnosing a patient with chest pain and assessing risk using experience and various criteria. The registry does not provide a complete account of those criteria. The HEART care arm description refers to the intervention rather than supplying further operational details, so the precise workflow for score use is not reported in the registry record.

The primary outcome is a count of participants who experienced a major adverse cardiac event (MACE) within 6 weeks after presentation. The composite includes acute myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting or death. The recorded participant counts are 405 of 1827 in Usual Care and 345 of 1821 in HEART Care. The record lists one secondary outcome: cost-effectiveness, covering costs, quality of life and quality-adjusted life years. Results for those measures are not reported in the registry record.

Although the registry labels the design crossover, details needed to understand the role of periods, treatment sequence, possible carryover and the analysis of within-participant data are not reported in the registry record. The outcome summaries are presented by care group; the registry does not explain whether or how the crossover structure was incorporated into the reported comparison.

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: Exclusion criteria were evident ST-segment elevation myocardial infarction, language barriers, recurrent presentation, or unable or unwilling to give informed consent.

Overall Study

Reasons for not completing this period:

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 MACE (Major Adverse Cardiac Events), measured over 6 weeks.

The primary endpoint is the occurrence of major adverse cardiac events within 6 weeks after presentation with chest pain. It is a composite outcome: a participant is counted as having an event if the record includes acute myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting or death during that timeframe. The registry reports the endpoint as a count of participants, rather than as a continuous measurement.

A composite can capture several clinically consequential events in one outcome and provide a single summary for comparing management strategies. Its interpretation depends on the component events: the combined result does not show which component accounts for the observed group counts. The registry describes the composite components but does not provide component-specific results for the primary outcome.

In the posted results, the event counts are 405 among 1827 participants in Usual Care and 345 among 1821 in HEART Care. These counts are the observed endpoint summaries for the two groups. They do not indicate the timing of each event within the 6-week period, and the record does not report a time-to-event analysis for the primary endpoint. The purpose of the stated timeframe is to define which events qualify for this outcome after presentation; it should not be interpreted as a longer-term assessment.

The endpoint is relevant to the study’s stated question about patient outcomes under the two management approaches. It does not measure costs or quality of life, which are addressed in the listed secondary cost-effectiveness outcome. Results for those secondary measures are not reported in the registry record.

7. Results Posted in the Registry

• HEART Care: 18.9% (345/1821) versus 22.2% (405/1827) on control; risk difference -3.2 percentage points (95% CI -5.8 to -0.6), risk ratio 0.85 (0.75–0.97); unadjusted two-proportion z-test p = 0.016.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary: a participant either had a qualifying MACE within 6 weeks after presentation or did not. The registry reports participant counts in each care group and a risk-difference comparison. The posted unadjusted p-value is 0.016. The registry record does not describe the test or model used to produce the comparison, so the statistical procedure behind that p-value and the interval is not reported in the registry record.

What does a risk difference describe?

In general, a risk difference compares the event proportions in two groups by subtracting one group’s proportion from the other’s. It is an absolute measure: it describes the difference in event frequency on the probability scale rather than expressing one group as a multiple of the other. A negative risk difference for HEART Care relative to Usual Care corresponds to a lower observed event proportion in HEART Care. The posted estimate has that direction. No new risk difference is calculated from the counts in this explanation.

The registry also lists relative measures, including a risk ratio and an odds ratio. In general, a risk ratio compares event probabilities, while an odds ratio compares event odds. These measures answer related but distinct questions and should not be interchanged. Their numerical estimates and confidence limits are recorded in the posted results, but the risk-difference measure is the comparison emphasized in this interpretation. The record does not state which measure was designated as the principal inferential measure in an analysis plan.

How should the p-value be read?

In general, a p-value assesses how unusual results at least as discrepant as those observed would be under a specified null hypothesis and the assumptions of a statistical test. It is not a measure of the probability that a treatment effect is absent, nor does it measure the importance of an observed difference. The posted p-value is unadjusted. The registry record does not identify the test, its assumptions, or whether any model-based adjustment was used for the randomized crossover design. Those details should not be inferred from the p-value alone.

Why do confidence intervals matter?

In general, a confidence interval presents a range of estimates compatible with the observed data under a chosen statistical procedure. Its location indicates the directions and values consistent with that procedure, while its width conveys precision. For this risk difference, the posted interval has negative limits and excludes zero. That is consistent with the direction of the point estimate, but does not eliminate uncertainty about the magnitude. The method used to construct the interval is not reported in the registry record.

What does over-dispersion mean?

In general, over-dispersion occurs when observed variation is greater than a statistical model expects. It can make standard errors too small if a model assumes less variation than the data contain. This is a general concept, not a feature reported for this trial. The registry does not report a model or a dispersion assessment, so there is no basis for concluding that over-dispersion was present or that it was addressed.

How might the crossover design matter?

In general, a crossover design can involve participants receiving different strategies in different periods, so analysis may need to account for repeated observations within a participant, period effects and possible carryover. Those considerations depend on the actual sequence and conduct of the study. The registry labels this trial crossover but does not report the sequence, period structure, washout arrangements, carryover assessment or analysis method. It is therefore not possible to determine from the registry record how those design features were handled. The posted group summaries should not be assumed to incorporate a particular crossover adjustment.

The registry records zero analyses and does not describe an analysis population, missing-data method, covariate adjustment, subgroup analyses or an interim analysis. Those elements are not reported in the registry record. The observed counts and unadjusted comparison remain interpretable as posted summaries, but they do not reveal the full analysis process or establish whether additional analyses were conducted outside the registry entry.

10. Confidence Intervals and Precision

The risk-difference estimate for HEART Care relative to Usual Care is negative, and the posted confidence interval has negative lower and upper limits. Because zero is outside that interval, the posted interval is compatible with a difference in the direction of fewer observed events in HEART Care, under the interval procedure used. The unadjusted p-value is 0.016. These are complementary summaries: the interval conveys a range of estimates compatible with the data under a statistical method, while the p-value summarizes evidence relative to a null hypothesis under a test.

Precision is not the same as certainty. A confidence interval gives an indication of statistical uncertainty, but it does not capture every source of uncertainty, such as limitations in outcome recording, trial conduct or analysis choices. The registry does not report how the interval was constructed, whether the crossover design was incorporated, or how missing outcomes were handled. Those omissions constrain how fully the interval can be assessed.

The posted counts are 405 of 1827 in Usual Care and 345 of 1821 in HEART Care. They provide context for the comparison, but counts alone do not communicate the uncertainty in the estimated contrast. The interval should be read alongside the estimate and event counts, not as a standalone verdict. A confidence interval is not a range containing a fixed percentage of individual participant outcomes, nor is it a guarantee about the true effect.

The registry also posts relative-effect measures, but precision depends on the measure and its interval. The numerical limits for those measures are not repeated. No subgroup-specific precision estimates or component-specific intervals are reported in the registry record. The available interval concerns the primary composite risk difference and does not describe uncertainty for the secondary cost-effectiveness outcomes, for which results are not reported.

11. 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 computed from the observed effect, not the original design assumptions for this trial; the trial’s own original sample-size assumptions are not reported in the registry record. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. Each planning scenario uses the stated fraction of the observed effect as the effect to detect.

For planning at 100% of the observed effect, the figures are 2,469 participants per arm for 80% power and 3,305 participants per arm for 90% power. At 75% of the observed effect, the figures are 4,453 participants per arm for 80% power and 5,961 participants per arm for 90% power. At 50% of the observed effect, the figures are 10,161 participants per arm for 80% power and 13,602 participants per arm for 90% power.

In plain language, the 80% power column gives the planning number per arm under which the calculation assigns an 80% chance of detecting the specified effect at the stated significance level, assuming the planning model holds. The 90% column uses a higher target chance of detection under those same stated assumptions. Smaller effects need more participants to detect, which is why the planning figures rise as the assumed effect becomes a smaller fraction of the observed effect. These are planning illustrations, not observed power.

The figures do not describe how the trial was originally designed, and they should not be read as a reassessment of the study’s actual power. They also do not account for any unreported crossover-specific planning or analysis assumptions. The record does not state the original target enrollment or explain how the trial’s design determined its enrollment.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.222; treatment proportion p₁ = 0.189; average p̄ = 0.206.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5715 = 1.1201.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5710 = 0.4806.
4. n = (1.1201 + 0.4806)² / (-0.0322)² = 2,468.5, rounded up to 2,469 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.221674876847291                          # control proportion
p1 <- 0.189456342668863                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1756846)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 2,469 (80% power), 3,305 (90% power)
 75% of observed effect: n per arm = 4,453 (80% power), 5,961 (90% power)
 50% of observed effect: n per arm = 10,161 (80% power), 13,602 (90% power)
power.prop.test: 2468.5 
Simulated power at n = 2,469 per arm: 0.799 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary outcome, MACE within 6 weeks, and one secondary outcome covering cost-effectiveness, costs, quality of life and quality-adjusted life years. The number of outcome measures recorded is 4, while the listed secondary outcome is one combined cost-effectiveness item. Results for the secondary outcome are not reported in the registry record.

Multiplicity refers, in general, to the increased chance of finding at least one apparently notable result when many outcomes, comparisons or analyses are examined. A statistical plan may address this through prespecified outcome hierarchies or adjustment procedures. The registry record does not report a multiplicity strategy, a hierarchy among outcome measures beyond identifying the primary endpoint, or any adjustment of the posted p-value. The reported p-value is unadjusted. This does not establish whether multiplicity was or was not addressed in analyses outside the registry record.

The registry records zero analyses. It does not describe the analysis population, whether all randomized participants were included, how participants were handled across crossover periods, or whether any per-protocol or other population was used. Those details are not reported in the registry record. The reported group counts should therefore be understood as posted counts, without assuming a particular intention-to-treat or per-protocol approach.

Missing-data methods are also not reported in the registry record. The record does not state whether primary outcome status was available for every participant, how unavailable outcomes were handled, or whether sensitivity analyses were conducted. The recorded group denominators are the values attached to the posted outcome summaries; they do not by themselves explain the completeness of follow-up or the treatment of missing observations.

The study is labeled crossover, but the registry does not report whether period-specific outcomes were collected or how repeated observations and possible carryover were treated. It also does not report interim analyses, subgroup analyses or covariate adjustment. Without these details, the posted comparison can be described, but the full statistical analysis strategy cannot be reconstructed.

14. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: cardiac ischemia (21.9%), significant stenosis (pci, cabg, conservative) (15.9%), death (0.5%).

The safety record lists serious-event figures for both groups. Usual Care has 405 participants recorded as affected by a serious event among 1827 at risk, with 9 deaths. HEART Care has 345 affected among 1821 at risk, with 5 deaths. The record reports zero other events in each group under the separate other-event count. These are the posted safety counts, and they should be read separately from the statistical comparison of the primary endpoint.

The registry lists cardiac ischemia, significant stenosis (PCI, CABG, conservative) and death among the leading serious-event terms, with recorded proportions of 21.9%, 15.9% and 0.5%, respectively. The denominator and method used to calculate those term percentages are not reported in the registry record. The listed terms do not establish that each event was caused by an intervention, and the record does not provide a causal assessment of the events.

The safety summary does not explain how serious events were defined, how events were coded, whether multiple events per participant could be counted, or how overlap with the primary composite was handled. The death counts in the safety record should not be assumed to be separate from, or identical to, deaths contributing to the primary outcome. Such links are not reported in the registry record.

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

The posted results show fewer participants with the MACE composite in HEART Care than in Usual Care: 345 of 1821 compared with 405 of 1827. The estimated risk difference is negative, its confidence interval lies below zero, and the unadjusted p-value is 0.016. These summaries describe the observed comparison and its statistical uncertainty. They do not by themselves explain the mechanism behind the difference or establish what would happen in another setting.

The primary outcome combines acute myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting and death. Because the registry does not report component-specific primary outcome results, the group-level comparison cannot show which component contributed most to the composite. Nor does the 6-week endpoint describe outcomes beyond that period. The posted primary outcome is not a measure of cost, quality of life or quality-adjusted life years.

The study’s stated aim included patient outcomes and costs, but the secondary cost-effectiveness results are not reported in the registry record. The primary endpoint comparison therefore cannot answer the economic part of that question. It also cannot provide a complete account of care implementation: details of HEART score use, crossover sequence, analysis of periods and clinician decision-making are not reported.

The findings should not be interpreted as proof of a particular causal mechanism or as medical advice. The registry presents a randomized crossover study, but does not report enough design and analysis detail to establish how crossover features were incorporated in the posted estimate. Information about missing data, analysis populations, multiplicity and the statistical model is also not reported in the registry record. These limits matter when assessing how broadly and precisely the comparison can be interpreted.

16. Why This Trial Matters Statistically

This trial raises a useful statistical question about evaluating a decision strategy rather than a treatment administered in isolation. The comparison is between usual care and use of a risk score in emergency-room management of chest pain. The primary outcome is a composite of several events within a defined follow-up period. Its interpretation depends on both the overall participant counts and the particular events included in the composite.

The posted comparison illustrates why effect measures and uncertainty should be read together. A risk difference describes an absolute contrast, while relative measures express the comparison on a different scale. The confidence interval gives information about precision, and the unadjusted p-value addresses evidence against a null hypothesis under an unspecified test. None of these summaries alone communicates clinical importance, the contribution of each event component or the economic consequences of a management strategy.

The crossover label also makes design transparency important. In general, crossover studies may require analysis that accounts for repeated measurements, periods and carryover. The registry does not report the sequence or analysis details, so the reader cannot assess how those issues were handled from the posted record. This underscores the value of reporting the design structure and statistical methods alongside outcome counts.

Finally, the registry’s stated aim includes costs and quality-of-life outcomes, but only the primary MACE comparison is accompanied by posted results in the record. The absence of those secondary results limits conclusions about cost-effectiveness. Statistically, the study therefore illustrates the distinction between a result for a primary clinical endpoint and evidence addressing a broader policy or economic question.

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 registry record leaves important design details unspecified. It labels the trial randomized, single-masked and crossover, but does not identify who was masked, describe the crossover sequence, state the duration of each period, or explain how carryover was considered. The record also does not explain whether the posted group comparison accounts for within-participant observations or period effects. These omissions limit assessment of how the design relates to the reported estimate.

Details about allocation procedures, eligibility criteria, settings beyond the emergency-room presentation, and implementation of the HEART risk score are not reported in the registry record. Usual care is described broadly as clinicians’ daily practice using experience and various criteria, but the full criteria are not provided in the record. This makes it difficult to characterize precisely what the intervention changed in practice.

The statistical methods are also incompletely described. The test behind the unadjusted p-value, the method used to construct the confidence interval, analysis populations, handling of missing outcomes, covariate adjustment and multiplicity procedures are not reported in the registry record. The record reports zero analyses, which leaves no documented analysis detail to clarify these issues.

The primary endpoint combines four event types, but component-specific primary outcome counts and timing are not reported. The listed secondary cost-effectiveness outcome has no posted results in the registry record. Safety-term percentage denominators and the relationship between safety events and primary endpoint events are likewise not reported. These limitations restrict interpretation of the composite result, safety summaries and the study’s broader cost-effectiveness aim.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Impact on Management of the HEART Risk Score in Chest Pain Patients — NCT01756846.
• Registry record last updated 2019-01-25; status last verified 2018-08.
• Results first posted 2019-01-25.
• 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

NCT01756846, titled Impact on Management of the HEART Risk Score in Chest Pain Patients, is recorded as a completed randomized, single-masked crossover study sponsored by UMC Utrecht. The registry lists an enrollment of 3666, a start date of 2013-07 and a primary completion date of 2014-10.

The comparison is between usual care and use of the HEART risk score for patients presenting with chest pain. The primary endpoint is MACE within 6 weeks after presentation. The posted counts are 405 of 1827 in Usual Care and 345 of 1821 in HEART Care. The risk-difference estimate is negative, the posted confidence interval lies below zero, and the unadjusted p-value is 0.016.

The record lists cost-effectiveness, including costs, quality of life and quality-adjusted life years, as a secondary outcome, but those results are not reported in the registry record. Details of the crossover sequence, statistical analysis, missing-data handling and analysis populations are also not reported in the registry record.