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 Drug-drug Interaction Study of Aggrenox and Omeprazole in Normal Volunteers (NCT01303445), a randomized phase 1 study. The primary outcome is Plasma Dipyridamole Maximum Concentration (Cmax).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01303445 |
| Phase | Phase 1 |
| Condition | Healthy |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | None (open label) |
| Enrollment | 60 |
| Arms in the primary outcome | 4 |
| Lead sponsor | Boehringer Ingelheim |
| Results posted | Yes |
2. Clinical Question
The study asked whether taking omeprazole 80 mg once daily at steady state changed the pharmacokinetics of dipyridamole or the pharmacodynamics of aspirin-induced platelet aggregation inhibition when Aggrenox was taken every 12 hours at steady state. The registry record describes healthy male and female volunteers and an open-label, randomized crossover design.
Population
Healthy male and female volunteers. The primary outcome population comprised treated participants with relevant pharmacokinetic data and without a relevant protocol violation. The registry record does not report demographic details such as age or the number of male and female participants.
Intervention
Aggrenox every 12 hours with omeprazole 80 mg once daily at steady state. The registry record also lists Aggrenox-alone and omeprazole-alone treatment conditions.
Comparator
Aggrenox alone, with the two combination-treatment groups described in relation to whether Aggrenox alone or omeprazole alone came first. The registry record does not give the full sequence schedule or treatment-period details.
Primary question
How did the maximum measured plasma concentration of dipyridamole compare between Aggrenox alone and Aggrenox with omeprazole? The study also assessed platelet aggregation inhibition and peak-to-trough fluctuation.
3. Trial Design
This was a Phase 1, randomized, open-label crossover study, with a recorded enrollment of 60 and a completed status. The registry record gives a start of 2011-03 and a primary completion of 2011-04. It identifies the sponsor as Boehringer Ingelheim and the study population as healthy volunteers.
The treatment descriptions include Aggrenox alone, Aggrenox with omeprazole following Aggrenox alone, Aggrenox with omeprazole following omeprazole alone, and omeprazole alone. These descriptions indicate that treatment order was relevant to the combination groups, but the full sequence allocation, washout duration, and period schedule are not reported in the registry record. The randomized crossover structure means treatment comparisons were made in a study that included different treatment conditions and sequences; the registry record does not provide enough detail to reconstruct each participant’s sequence.
The primary outcome was plasma dipyridamole maximum concentration (Cmax) over 7 days. Its analysis population was described as treated subjects with pharmacokinetic data and without a relevant protocol violation. The record states that no dipyridamole data were expected for omeprazole alone. It also lists secondary outcomes for dipyridamole minimum concentration, platelet aggregation inhibition at 12 hours after dose, and percentage peak-to-trough fluctuation. The primary completion date and completed status describe the study record, not the completeness of every outcome or analysis.
The record does not report the planned sample-size justification, full statistical analysis plan, treatment-period specifics, or whether any interim analyses were planned or conducted. The number enrolled is not the same as the number contributing to each posted outcome: the primary endpoint groups have 54 or 55 participants, and the secondary endpoint groups have outcome-specific counts.
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.
First Intervention (7 Days)
| Stage | ABCD Sequence | CDAB Sequence |
|---|---|---|
| STARTED | 30 | 30 |
| COMPLETED | 29 | 30 |
| NOT COMPLETED | 1 | 0 |
Reasons for not completing this period:
| Reason | ABCD Sequence | CDAB Sequence |
|---|---|---|
| Withdrawal by Subject | 1 | 0 |
Second Intervention (7 Days)
| Stage | ABCD Sequence | CDAB Sequence |
|---|---|---|
| STARTED | 29 | 30 |
| COMPLETED | 28 | 28 |
| NOT COMPLETED | 1 | 2 |
Reasons for not completing this period:
| Reason | ABCD Sequence | CDAB Sequence |
|---|---|---|
| Adverse Event | 0 | 2 |
| Withdrawal by Subject | 1 | 0 |
Washout (14 Days)
| Stage | ABCD Sequence | CDAB Sequence |
|---|---|---|
| STARTED | 28 | 28 |
| COMPLETED | 27 | 26 |
| NOT COMPLETED | 1 | 2 |
Reasons for not completing this period:
| Reason | ABCD Sequence | CDAB Sequence |
|---|---|---|
| Protocol Violation | 1 | 0 |
| Lost to Follow-up | 0 | 2 |
Third Intervention (7 Days)
| Stage | ABCD Sequence | CDAB Sequence |
|---|---|---|
| STARTED | 27 | 26 |
| COMPLETED | 27 | 26 |
| NOT COMPLETED | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: The pharmacokinetic data set (PK set) and the pharmacodynamic data set (PD set) include all treated subjects with data that do not have a relevant protocol violation (relevant to PK or PD). No data collected for Omeprazole arm since no plasma dipyridamole was expected for this treatment.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
| Characteristic | Unit | Entire Study Population |
|---|---|---|
| Participants analysed | 60 | |
| Age, Continuous | years | 35.3 (20 to 50) |
| Sex: Female, Male: Female | Participants | 18 |
| Sex: Female, Male: Male | Participants | 42 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 48 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 12 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 |
| Race/Ethnicity, Customized: White | participants | 57 |
| Race/Ethnicity, Customized: Black / African American | participants | 3 |
| Weight | kilograms | 75.69 (55.2 to 101.7) |
| Body Mass Index (BMI) | kilograms per square meter | 26.81 (20.45 to 31.94) |
6. Primary Endpoint
The registry lists the primary outcome as Plasma Dipyridamole Maximum Concentration (Cmax), measured over 7 days.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | Geometric Coefficient of Variation |
| Unit | nanogram/milliliter |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was plasma dipyridamole maximum concentration, or Cmax, measured in nanograms per milliliter over 7 days. Cmax is the highest measured plasma concentration during the specified assessment period. It is a pharmacokinetic measure: it describes drug exposure in blood rather than a clinical health outcome.
The registry reports geometric means and geometric coefficients of variation for the groups with Aggrenox treatment. The geometric mean is a way of summarizing positive measurements when values are better represented on a multiplicative scale. The geometric coefficient of variation describes relative variability around a geometric mean; it is not the same quantity as a standard deviation on the original measurement scale.
Dipyridamole is one of the components named in the study description. Comparing Cmax between Aggrenox alone and Aggrenox with omeprazole addresses whether the recorded peak exposure differed between those treatment conditions. The registry record states that plasma dipyridamole was not expected for the omeprazole-alone condition, so that condition has no posted primary Cmax value.
Cmax is useful for describing peak exposure, but it does not by itself describe the full concentration-time profile or establish a clinical effect. The registry also identifies dipyridamole minimum concentration, platelet aggregation inhibition, and peak-to-trough fluctuation as secondary outcomes, which provide other kinds of pharmacokinetic or pharmacodynamic information.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
For the primary endpoint, the registry reports geometric mean Cmax values of 2750 for Aggrenox alone and 2550 for each of the two Aggrenox-plus-omeprazole groups. The geometric coefficient of variation was 30.4 for Aggrenox alone, 27.5 for the combination following Aggrenox alone, and 29.1 for the combination following omeprazole alone. The posted group sizes were 55, 54, and 54, respectively. No primary Cmax value was expected or reported for omeprazole alone.
The sponsor-reported comparisons express the combination conditions as percent mean ratios relative to Aggrenox alone. For Aggrenox plus omeprazole following omeprazole alone, the ratio was 92.03, with a 90% confidence interval from 86.95 to 97.40. For the combination following Aggrenox alone, it was 92.30, with a 90% confidence interval from 87.76 to 97.08. These intervals communicate uncertainty around the reported ratios; they do not establish equivalence or non-inferiority without the relevant prespecified margin and analysis details. Those details are not reported in the registry record.
The secondary outcomes add related but distinct information. The registry reports platelet aggregation inhibition and peak-to-trough fluctuation, and the posted summary-based recalculations give unadjusted comparisons with confidence intervals that include zero for both combination comparisons on each endpoint. Such intervals are compatible with a range of differences, including no difference, and also with some differences in either direction. The registry’s own platelet inhibition analyses are reported as percent mean ratios with 90% confidence intervals. No sponsor-reported analysis is listed for peak-to-trough fluctuation.
The endpoint estimates should be read as results from this healthy-volunteer study, not as direct evidence about clinical outcomes. The posted data describe measured drug concentration and platelet aggregation under the trial conditions. The registry record does not report a clinical outcome endpoint or a conclusion about clinical benefit or harm. Nor does it report enough methodological detail to determine the prespecified decision criteria for interpreting the ratios.
The primary analysis group sizes are below the enrollment count, and outcome-specific participation varies. The record describes the primary population as treated participants with relevant data and no relevant protocol violation, but it does not report a full accounting of exclusions or missing measurements. Consequently, the estimates are best understood in the context of the analyzed populations and the uncertainties represented by their intervals, rather than as exact descriptions of all enrolled participants.
9. Statistical Methods Explained
The study used a randomized crossover design and was open label. In general, crossover studies compare treatment conditions within a study in which participants may receive different conditions in a sequence. This can make within-person comparisons informative, but the analysis depends on the treatment periods, sequence, washout, and handling of period or carryover effects. The complete details of those elements are not reported in the registry record, so the reported results cannot be used to reconstruct the full crossover analysis.
What do the reported concentration summaries mean?
The primary endpoint is summarized with geometric means and geometric coefficients of variation. In general, a geometric mean summarizes positive measurements after working on a logarithmic scale and returning to the original scale. It is useful when variation is proportional to the size of the measurement rather than additive. The geometric coefficient of variation expresses relative dispersion on a percentage-like scale. It should not be interpreted as a standard deviation in nanograms per milliliter.
The registry reports the primary comparisons as percent mean ratios and gives 90% confidence intervals. A ratio compares the reported mean in one condition with the mean in another condition on a relative scale. A confidence interval describes the range of values compatible with the estimate and the analysis assumptions at the stated confidence level. It is not a guarantee that the true value lies in the interval. The record labels these analyses as non-inferiority or equivalence analyses, but the method, prespecified margin, and decision rule are not reported in the registry record. A ratio and interval alone therefore do not establish whether a formal criterion was met.
What are the secondary recalculations?
For platelet aggregation inhibition and peak-to-trough fluctuation, the additional comparisons are simple, unadjusted recalculations from the posted summary statistics. They report mean differences and confidence intervals. A mean difference is an absolute-scale contrast between group means. An interval that crosses zero includes no difference as one value compatible with the calculation, but does not prove that the groups are identical.
These recalculations are not a reproduction of the sponsor’s full crossover analysis. The registry does not provide individual participant measurements or the within-person correlation needed to reconstruct paired comparisons from the posted summaries. The recalculations should therefore be treated as descriptive, unadjusted comparisons, rather than as substitutes for the sponsor’s analysis. Their p-values are unadjusted, and no multiplicity adjustment is reflected in them.
Why does over-dispersion matter?
In general, over-dispersion means that observed variability is greater than a statistical model expects. When variability is underrepresented, uncertainty intervals may be too narrow and tests may overstate the precision of estimates. The record does not report whether over-dispersion was assessed or how it was handled in the sponsor’s analysis. The posted primary endpoint uses a geometric coefficient of variation, while the secondary continuous outcomes are summarized using means and standard deviations; these are different summaries and should not be conflated.
How should the planning illustrations be read?
The planning illustrations are based on observed secondary endpoint effects and are not the trial’s original design calculations. They use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They show participants per arm for 80% or 90% power under assumptions that the effect to detect is 100%, 75%, or 50% of the observed effect. For example, the posted illustrations include planning for 75% of the observed effect; these figures are hypothetical planning inputs, not the number enrolled or an estimate of observed power. The trial’s own sample-size justification is not reported in the registry record.
In general, such calculations depend on the assumed effect, variability, allocation, test, and design. Because the registry describes a crossover study while the illustrations use equal allocation between two arms, the illustrations should not be read as a reconstruction of the original crossover design. They also do not demonstrate that the study had or lacked adequate power for its primary endpoint.
10. Analyses Reported by the Sponsor
| Method | Estimate | 95% CI | P-value |
|---|---|---|---|
| not stated | Percent Mean Ratio 92.03 | 86.95 to 97.40 | not reported |
| not stated | Percent Mean Ratio 92.30 | 87.76 to 97.08 | not reported |
The sponsor-reported primary analyses are percent mean ratios with 90% confidence intervals: 92.03 (86.95 to 97.40) for the combination following omeprazole alone, and 92.30 (87.76 to 97.08) for the combination following Aggrenox alone, each compared with Aggrenox alone. The registry labels these analyses as non-inferiority or equivalence analyses. Their method and the margin used for such a conclusion are not reported in the registry record, so the ratios and intervals can be described, but the registry record does not support independently confirming a formal non-inferiority or equivalence determination.
The recalculated comparisons apply to secondary continuous outcomes, not to the primary Cmax endpoint. They are simple, unadjusted calculations from posted summary statistics, and they do not reproduce a full sponsor crossover analysis. No discrepancy is flagged between the sponsor’s reported primary results and the posted record. The sponsor’s own analysis is therefore the relevant reported analysis for the primary endpoint; the recalculations are supplementary descriptions of the secondary summaries, not replacements for it.
The registry does not report the full statistical methods behind the sponsor’s analyses, including details needed to assess how the crossover structure was incorporated. It also does not report a prespecified non-inferiority or equivalence margin. These omissions limit how far a reader can go from the reported ratios to a formal decision about the study’s stated analysis type.
11. Multiplicity, Missing Data and Analysis Populations
The registry record lists multiple outcomes and analyses, including a primary concentration endpoint and secondary pharmacokinetic and pharmacodynamic outcomes. It does not report a multiplicity strategy, such as a prespecified hierarchy, family-wise adjustment, or another method for controlling the interpretation of repeated comparisons. This matters because the chance of at least one apparently notable result can increase when multiple hypotheses are tested. Unadjusted secondary p-values should therefore be read as exploratory unless a broader analysis plan establishes otherwise.
The record describes the primary pharmacokinetic population as treated subjects with data and without a relevant protocol violation, and separately refers to a pharmacodynamic data set with a similar eligibility description. It does not report the number excluded for protocol violations, the reasons for missing measurements, or how missing data were handled in each analysis. The number enrolled was 60, whereas primary endpoint group sizes were 55, 54, and 54. The secondary outcome group sizes also vary. These differences show that analysis counts are outcome-specific, but the registry record does not provide a complete participant flow or missing-data account.
For a crossover study, sequence, period, washout, and within-person dependence can affect interpretation. The registry record does not report the full statistical model or sufficient details to determine how these features were handled. The summary-based secondary recalculations are unadjusted and cannot recover within-person associations from group summaries. This limits their use for assessing the precision of a crossover treatment contrast.
The record also does not report the primary sample-size justification, the non-inferiority or equivalence margin, or whether interim analyses were planned or conducted. These are not details that can be inferred from the posted estimates. Without them, the formal design and decision framework for the primary analysis cannot be fully assessed.
12. 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 |
|---|---|---|---|
| Aggrenox Alone BID | 0 | 56 | 0.0% |
| Aggrenox BID Plus Omeprazole QD Following Aggrenox Alone | 0 | 55 | 0.0% |
| Omeprazole Alone QD | 0 | 57 | 0.0% |
| Aggrenox BID Plus Omeprazole QD Following Omeprazole Alone | 0 | 57 | 0.0% |
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 |
|---|---|
| Aggrenox Alone BID | 41 of 56 |
| Aggrenox BID Plus Omeprazole QD Following Aggrenox Alone | 15 of 55 |
| Omeprazole Alone QD | 17 of 57 |
| Aggrenox BID Plus Omeprazole QD Following Omeprazole Alone | 48 of 57 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Aggrenox Alone BID | Aggrenox BID Plus Omeprazole QD Following Aggrenox Alone | Omeprazole Alone QD | Aggrenox BID Plus Omeprazole QD Following Omeprazole Alone |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | 39 of 56 | 6 of 55 | 7 of 57 | 41 of 57 |
| Myalgia | Musculoskeletal and connective tissue disorders | 18 of 56 | 4 of 55 | 2 of 57 | 20 of 57 |
| Nausea | Gastrointestinal disorders | 19 of 56 | 0 of 55 | 4 of 57 | 14 of 57 |
| Vomiting | Gastrointestinal disorders | 12 of 56 | 2 of 55 | 2 of 57 | 14 of 57 |
| Dizziness | Nervous system disorders | 7 of 56 | 3 of 55 | 2 of 57 | 10 of 57 |
| Diarrhoea | Gastrointestinal disorders | 6 of 56 | 4 of 55 | 2 of 57 | 6 of 57 |
| Chest discomfort | General disorders | 6 of 56 | 1 of 55 | 1 of 57 | 4 of 57 |
| Epistaxis | Respiratory, thoracic and mediastinal disorders | 7 of 56 | 1 of 55 | 0 of 57 | 1 of 57 |
| Contusion | Injury, poisoning and procedural complications | 3 of 56 | 2 of 55 | 1 of 57 | 2 of 57 |
| Palpitations | Cardiac disorders | 3 of 56 | 0 of 55 | 2 of 57 | 2 of 57 |
The registry reports zero serious adverse events in each of the four safety groups. The corresponding numbers at risk were 56 for Aggrenox alone, 55 for Aggrenox with omeprazole following Aggrenox alone, 57 for omeprazole alone, and 57 for Aggrenox with omeprazole following omeprazole alone. No top serious adverse event terms are listed. Death counts are not reported in the registry record.
The record separately reports other, non-serious adverse events affecting 41, 15, 17, and 48 participants in those groups, respectively. These counts are distinct from serious adverse events and should not be read as serious-event totals. The registry excerpt does not provide event types, severity breakdowns for those other events, or a participant-level account of repeated events.
These figures describe what was recorded in the registry for the listed groups. They do not establish the absence of risk, particularly in a study with a limited number of participants and a short primary outcome timeframe of 7 days. The safety counts also do not by themselves establish a comparative safety effect between treatment conditions.
13. What the Result Does, and Does Not, Mean
The posted results describe measured plasma dipyridamole exposure and platelet aggregation outcomes under the study’s treatment conditions in healthy volunteers. The primary endpoint comparisons are reported as percent mean ratios with 90% confidence intervals. Those estimates give a relative comparison and a range reflecting statistical uncertainty under the sponsor’s analysis, but the registry does not report the margin or full method needed to interpret them as a formal equivalence or non-inferiority conclusion.
The results do not establish what would happen in a patient population or whether treatment conditions differ in clinical outcomes. The study record identifies healthy volunteers, and the primary endpoint is a plasma concentration measure rather than a clinical event. Pharmacokinetic and pharmacodynamic endpoints may be informative about exposure and measured biological response, but they are not themselves proof of clinical benefit or harm.
The secondary outcomes should also be interpreted within their limits. Summary-based recalculations are unadjusted and do not reproduce a full crossover analysis. Their intervals include zero, which leaves a range of possible differences compatible with the calculations; it does not demonstrate that there is no difference. The absence of reported multiplicity details further cautions against treating isolated secondary findings as definitive.
Finally, the registry record does not provide all information needed to evaluate the design and analysis, including the complete treatment schedule, missing-data handling, sample-size justification, or prespecified margins. The most defensible reading is therefore descriptive: the record reports estimates for the measured endpoints and their uncertainty, while important protocol and analysis details remain not reported in the registry record.
14. Why This Trial Matters Statistically
This study is statistically instructive because it combines a crossover design with pharmacokinetic and pharmacodynamic outcomes. A crossover design can make within-person contrasts relevant, but interpreting those contrasts requires information about sequence, period, washout, and the model used to account for repeated measurements. The registry record describes the design but does not provide those details in full.
The primary endpoint also illustrates the distinction between a point estimate and a formal non-inferiority or equivalence conclusion. The registry reports percent mean ratios and 90% confidence intervals, and labels the analyses as non-inferiority or equivalence. Without the prespecified margin and analysis method, the estimates can be described but the decision criterion cannot be independently assessed from the registry record.
The secondary results show why multiple outcome types should not be collapsed into one conclusion. Geometric summaries of concentration, mean summaries of platelet inhibition, and mean summaries of peak-to-trough fluctuation describe different features of the measurements. Unadjusted recalculations and planning illustrations add context, but they are not substitutes for the sponsor’s analysis or for the trial’s original design assumptions.
Finally, the differing outcome-specific group sizes illustrate why enrollment and analysis counts should be distinguished. The record describes eligible analysis populations but does not give a complete account of missingness and exclusions. Together, these features make the study useful for understanding how reporting details shape interpretation, even when the available estimates are clearly stated.
15. 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 trial-specific limitations affect interpretation. The registry record gives the randomized, open-label crossover design but does not report the complete treatment sequence, period schedule, or washout details. Those elements matter when assessing whether treatment-period effects or carryover could influence a crossover comparison. The full sponsor analysis method is also not reported.
The primary outcome population is described by treatment and protocol-violation criteria, but a full participant flow and reasons for missing outcome data are not reported in the registry record. The primary groups include 55, 54, and 54 participants, while the total enrollment was 60. Counts differ across secondary outcomes as well. The record does not explain all of these differences or specify the missing-data methods.
The registry labels the primary comparisons as non-inferiority or equivalence analyses but does not report the margin or enough method detail to assess the formal decision rule. It also does not report the trial’s sample-size justification or any multiplicity strategy. The supplementary recalculations for secondary endpoints are unadjusted summary-based comparisons and do not reconstruct within-person crossover contrasts.
The study enrolled healthy volunteers and its principal endpoint is a pharmacokinetic measurement. This limits the scope of what can be inferred about clinical outcomes or other populations. The primary endpoint timeframe is 7 days, and the registry record does not report longer-term outcome assessment. These limitations do not negate the posted estimates, but they constrain the conclusions that can be drawn from them.
16. Related Tutorials
17. Related Statistical Calculators
18. Sources
- ClinicalTrials.gov: Drug-drug Interaction Study of Aggrenox and Omeprazole in Normal Volunteers — NCT01303445.
- Registry record last updated 2013-12-24; status last verified 2012-07.
- Results first posted 2012-07-24.
- 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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19. Record Summary
NCT01303445 is a completed Phase 1 randomized, open-label crossover study sponsored by Boehringer Ingelheim. It enrolled 60 healthy volunteers, with a recorded start of 2011-03 and primary completion of 2011-04. The study examined Aggrenox alone and in combination with omeprazole, with treatment descriptions that include differing treatment order.
The primary endpoint was plasma dipyridamole Cmax over 7 days. The registry reports geometric mean summaries and sponsor-reported percent mean ratios with 90% confidence intervals for the combination conditions compared with Aggrenox alone. Secondary outcomes include platelet aggregation inhibition and peak-to-trough fluctuation. The registry record does not report the full statistical plan, non-inferiority or equivalence margin, sample-size justification, complete missing-data account, or multiplicity strategy.