Comparison of Metoprolol and Tramadol With Remifentanil in Endoscopic Sinus Surgery: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Comparison of Metoprolol and Tramadol With Remifentanil in Endoscopic Sinus Surgery (NCT02484859), a randomized phase 4 study. The primary outcome is Intraoperative Bleeding Score.

2. Clinical Question

3. Trial Design

This was a phase 4, randomized, parallel-group trial with quadruple masking, listed as completed. The registry identifies Recep Tayyip Erdogan University as the sponsor. The study start is recorded as 2015-07, and primary completion as 2015-12. The stated enrollment was 88. The primary outcome summaries list 44 participants in the remifentanil arm and 44 in the tramadol plus metoprolol arm.

The intervention comparison reflects two approaches to anesthesia during functional endoscopic sinus surgery: remifentanil for controlled hypotension, and tramadol combined with metoprolol for normotensive anesthesia. The registry describes intravenous administration for both approaches, but the intervention descriptions are truncated, so details beyond the visible regimen text are not reported in the registry record. It does not report the randomization sequence method, concealment procedures, or operational details of masking.

Randomization and parallel-group assignment are relevant because they define how the trial set up the comparison, but they do not by themselves guarantee that all potential sources of bias were controlled. Quadruple masking is the registry’s classification; the record does not specify which roles were masked or how masking was maintained. The primary outcome was assessed by a surgeon, making the masking details pertinent to interpretation, but further information is not reported in the registry record.

The registry lists five outcome measures and six analyses. The primary endpoint is an ordinal surgical-field bleeding score. Secondary outcomes include time to achieve a bleeding score below 3, bleeding rate, postoperative pain, and postoperative nausea and vomiting. Numerical summaries are available for three secondary outcomes in the record described in the posted results; numerical results for postoperative pain are not reported in the registry record. The record does not report a protocol-based sample-size justification, recruitment flow, or the analysis populations used.

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: A total of 105 patients were evaluated. Three patients declined to participate in the study. Eleven patients did not meet inclusion criteria. On 29 December 2015, we reached the target number of patients (88). Since patients were matched for severity of sinonasal disease, we evaluated three more patients anticipating possible dropouts.

Overall Study

5. Baseline Characteristics

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

6. Primary Endpoint

The registry lists the primary outcome as Intraoperative Bleeding Score, measured over throughout surgery, up to 3 hours.

The primary endpoint is the intraoperative bleeding score reported by the surgeon using the Boezaart Surgical Field Grading scale. The registry describes a scale from 0 to 5, where 0 is the best outcome and represents no bleeding, and 5 is the worst outcome and represents severe bleeding requiring constant suction. The intermediate categories describe increasing bleeding and suction requirements, including how quickly bleeding threatens the surgical field after suction is removed.

The score is used to characterize the visibility and bleeding conditions encountered during surgery. It is an ordinal outcome: the categories have a meaningful order, but the spacing between adjacent scores is not necessarily equal. A score of 1 therefore should not be interpreted as a measured amount of bleeding or as a fixed interval away from another score. The registry says the surgeon could report a score whenever considered appropriate throughout surgery, up to 3 hours.

The posted primary summaries give a median score of 1 in each arm. The interquartile ranges are not reported in the registry record, even though the endpoint is identified as a median with interquartile-range dispersion. A median alone describes the central rank of the observed scores but does not show their spread or the full distribution. The registry reports a Wilcoxon (Mann-Whitney) comparison, which evaluates differences in the distributions or ranks rather than directly estimating a difference in medians. The endpoint is clinically relevant to the surgical field, but these summary data do not establish that the treatment approaches are equivalent.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is an ordinal score, not a continuous measurement with known equal spacing between values. A median is a useful way to describe the middle of an ordered distribution, while an interquartile range would indicate the spread of the central portion. The registry identifies the primary summaries as medians with interquartile ranges, but gives only the medians: 1 for remifentanil and 1 for tramadol plus metoprolol. The interquartile ranges are not reported in the registry record. Without them, readers cannot assess how concentrated or dispersed the scores were within either arm.

The sponsor’s reported primary test is Wilcoxon (Mann-Whitney). In general, this rank-based method compares the ordering of observations across groups. It does not require treating the difference between score categories as a constant interval, which is useful for ordinal data. A p value describes how compatible the observed data are with a specified null model, under the test’s assumptions; it is not the probability that the null hypothesis is true. The reported p >0.69 does not identify the size of a possible difference and does not prove that the groups are equivalent. An equivalence or non-inferiority conclusion requires a prespecified margin and an analysis designed to evaluate that margin; neither is reported in the registry record.

For continuous secondary outcomes, the registry reports means and standard deviations, and the posted recalculations compare the arm means with unadjusted mean differences. A mean difference expresses the contrast on the outcome’s original scale. A confidence interval gives a range of effect estimates compatible with the data and the calculation’s assumptions; it is not a guarantee that the true effect lies inside the interval. The recalculated intervals are unadjusted and based on posted summary statistics, rather than participant-level data. They should therefore be distinguished from the sponsor’s own analyses.

The recalculated p values for these continuous outcomes are also unadjusted. They test each comparison separately and do not account for the fact that several outcomes are examined. Their interpretation depends on the assumptions used in the calculation, including the summary statistics and the treatment of the two groups. In general, an unadjusted analysis can make chance findings more likely across a collection of tests than a prespecified multiplicity-adjusted strategy. The registry does not report a multiplicity strategy, so the recalculated values should not be treated as confirmatory evidence on their own.

For the binary nausea-and-vomiting outcome, a risk difference is the contrast between the proportions of participants with the event in the two arms. Its confidence interval conveys uncertainty in that absolute difference. The recalculation also lists relative measures, but none of these should be treated as a substitute for the sponsor-reported analysis. The sponsor reports a chi-squared test; the recalculation uses the posted counts to obtain an unadjusted comparison. Differences between these p values can arise because analyses use different methods, assumptions, or details unavailable in aggregate summaries. The registry record does not report enough information to reconcile every analytic detail.

The sample-size illustrations are planning exercises based on the observed effects, not an account of the trial’s original design. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the arms, and a normal approximation. Each illustration considers detecting a stated fraction of the observed effect. Such calculations answer a hypothetical design question: how many participants per arm would be required under those assumptions to detect an effect of the chosen size with the stated power. They do not estimate the power achieved by this completed trial, and the registry does not report that these assumptions were used when the trial was planned.

Using an observed effect to plan a future study can be unstable, particularly when the estimate comes from a small study or is uncertain. A smaller assumed effect requires a larger planning sample under otherwise fixed assumptions. These illustrations are therefore sensitivity analyses, not definitive recruitment targets. They also assume a simplified statistical setting; the record does not report adjustments for missing data, outcome correlation, multiplicity, or any design features beyond the stated assumptions.

General statistical note: over-dispersion occurs when variability is greater than a model assumes. If present and ignored, standard errors can be too small and uncertainty can be understated. The posted summaries do not report a dispersion assessment or model-based analysis for the primary ordinal endpoint. No claim about over-dispersion in these data is warranted. More broadly, a p value, an effect estimate, and a confidence interval answer different questions: a p value evaluates compatibility with a null model, an estimate describes the direction and scale of a contrast, and an interval conveys its precision under the analysis assumptions. The primary registry result includes the p value but does not report an effect estimate or interval.

10. Analyses Reported by the Sponsor

The sponsor-reported primary analysis uses a Wilcoxon (Mann-Whitney) test and gives p >0.69. That is the registry’s own inferential result for the primary endpoint. The posted primary summaries show a median of 1 in each arm, but the registry does not report an interquartile range, an effect estimate, or a confidence interval. There is therefore no primary recalculated estimate in the posted results that can supply the missing precision information or replace the sponsor’s analysis.

For the secondary outcomes, the sponsor reports a two-sided t-test for time to achieve a bleeding score below 3 and bleeding rate, and a chi-squared test for postoperative nausea and vomiting. The reported p values are <0.001, 0.052, and 0.47, respectively. The simple unadjusted recalculations from the posted summary statistics give p <0.001, 0.034, and 0.338 for those same outcomes. These recalculations are not participant-level analyses, and the record does not provide enough detail to determine exactly why the p values differ for bleeding rate and nausea and vomiting.

The two sets of results should be read as distinct analyses, not blended into a single estimate. The sponsor’s tests are the analyses reported by the registry; the recalculations are supplementary, unadjusted calculations from summaries. The discrepancy flag is false, but that does not make the methods identical or remove the need to distinguish the sponsor’s reported tests from the recalculated values. Neither set addresses multiplicity unless an adjustment is specified, and the registry does not report such a strategy.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures and six analyses, but it does not report a multiplicity strategy. It is therefore not clear whether the primary endpoint was protected as a single confirmatory test, whether secondary outcomes were arranged in a prespecified hierarchy, or whether any adjustment was used for multiple comparisons. Without that information, secondary p values should be viewed as unadjusted unless the registry explicitly identifies otherwise. A collection of unadjusted tests can produce apparently notable findings by chance, even when no individual outcome has a reliably established effect.

The 0.05 significance level appears in the assumptions for the planning illustrations. That is a stated planning assumption, not evidence that the trial’s primary or secondary analyses used that threshold or that it was chosen in the protocol. The registry does not report the trial’s statistical analysis plan, the intended handling of multiple outcomes, or whether there were interim analyses.

Missing-data procedures and analysis populations are also not reported in the registry record. The outcome summaries list 44 participants per arm, but that alone does not establish which analysis population was used, whether all randomized participants contributed to every endpoint, or how any missing observations were handled. The record does not describe imputation, exclusions, or sensitivity analyses. Numerical postoperative-pain results are not reported in the registry record, and the reason for their absence is not reported.

For the primary endpoint, the registry identifies medians and interquartile ranges as the summary approach, but only the medians are posted. It does not report an interval estimate or a test statistic for the primary comparison. These omissions make it difficult to assess precision and the sensitivity of the result to analytic choices. They also mean that a non-significant p value should not be recast as evidence that the approaches are equivalent. The necessary details for a fuller assessment of multiplicity, missingness, and analysis-population choices are not reported in the registry record.

12. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: intraoperative bradycardia (40.9%), intraoperative hypotension (6.8%), intraoperative bleeding (0.0%).

The registry reports serious adverse events affecting 21 participants in the remifentanil arm and 0 in the tramadol plus metoprolol arm. Each arm’s serious-event group lists 44 participants at risk. The record lists intraoperative bradycardia at 40.9%, intraoperative hypotension at 6.8%, and intraoperative bleeding at 0.0% among the serious-event terms. These listed terms should be read as registry safety reporting, not as a complete account of all possible harms or as a causal comparison.

The adverse-event summary also records 0 other affected participants in each arm. Death counts are not reported in the registry record. The listed serious-event count is not itself a measure of event severity distribution or duration, and the record does not provide participant-level descriptions, timing, relatedness assessments, or the number of events per affected participant. A participant count and a term percentage answer different questions; the registry does not provide enough detail to reconstruct every event-level relationship.

These figures describe what the registry records for this trial. They do not establish that one regimen caused or prevented a particular event. Interpretation is limited by the absence of fuller safety definitions and reporting details in the record, and these summaries should not be used as individualized medical guidance.

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

The primary result means that the registry’s reported test did not detect a statistically significant difference in the surgeon-rated bleeding-score distributions between the two treatment arms. The posted medians are both 1, and the sponsor-reported Wilcoxon (Mann-Whitney) result is p >0.69. This describes the analysis that was reported; it does not establish that the treatments have the same effect.

In particular, failure to find a statistically detectable difference is not proof of equivalence. Equivalence requires a defined range of differences considered unimportant and an analysis that tests whether the uncertainty falls within that range. Non-inferiority likewise requires a prespecified margin and an appropriate design and analysis. Neither margin is reported in the registry record. The primary outcome’s interquartile ranges, effect estimate, and confidence interval are also not reported, so the precision and plausible range of the primary contrast cannot be evaluated from the posted summary.

The secondary outcomes provide additional observations but do not supply the missing primary precision information. Their measures differ, and the record does not report a multiplicity plan. The recalculated p values are simple unadjusted analyses from posted summaries, not replacements for the sponsor’s tests or evidence of an effect that is independent of the broader analysis context. The registry’s missing numerical postoperative-pain result further narrows what can be concluded about the secondary outcomes as a whole.

The reported safety counts are part of the trial record, but they are not sufficient to infer causation or to compare risks comprehensively. The available information does not include event-level detail, deaths, or a full account of how adverse events were assessed. Overall, the posted results answer a limited statistical question about the recorded score comparison and report selected additional outcomes. They do not establish a general treatment recommendation, a complete safety profile, or that either approach is superior, equivalent, or non-inferior across all relevant outcomes.

14. Why This Trial Matters Statistically

This trial is statistically instructive because its primary outcome is ordinal and its posted summaries are incomplete. The scale has ordered categories from 0 to 5, and the primary analysis uses a rank-based test rather than assuming that each step on the scale represents an equal change. That method choice fits the kind of outcome described, while the missing interquartile ranges and effect interval leave substantial uncertainty about the distribution and precision of the comparison.

It also illustrates a common interpretive distinction: a non-significant superiority test is not an equivalence test. Equal posted medians and a large p value do not demonstrate that two approaches have effects close enough to be considered clinically alike. That conclusion would require a prespecified margin and an analysis designed to evaluate it, neither of which is reported in the registry record.

The secondary outcomes show why analysis context matters. Several outcomes use distinct scales and tests, and the sponsor-reported p values do not always match simple recalculations from aggregate summaries. Those recalculations can be useful for understanding the posted means, standard deviations, and counts, but they omit participant-level information and do not account for any unreported analysis-plan features. The absence of a reported multiplicity strategy also limits the confirmatory interpretation of secondary findings.

Finally, the planning illustrations are not observed power calculations. They demonstrate how hypothetical sample-size requirements change under stated assumptions and effect fractions, but do not reveal the trial’s original design rationale. The record does not report its sample-size justification or statistical analysis plan. Together, these points make the study useful for teaching careful reading of outcome type, test choice, uncertainty, and the boundary between descriptive results and stronger claims.

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.

The registry record leaves important primary-outcome information unavailable. Although the outcome is summarized as a median with an interquartile range, only the median is posted for each arm. There is no primary effect estimate or confidence interval, so the magnitude and precision of the between-arm comparison cannot be judged from the record. The reported p value alone cannot answer whether a clinically important difference remains plausible.

The intervention descriptions are truncated, including the text about the remifentanil target and details of the tramadol plus metoprolol regimen. The registry also does not explain which roles were covered by quadruple masking or how masking was maintained. Those omissions make it harder to assess intervention implementation and outcome assessment. The record does not report the randomization sequence method or allocation concealment procedures.

For secondary outcomes, the registry does not report the numerical postoperative-pain result. The simple recalculations rely on aggregate summaries, and the sponsor-reported p values differ from those recalculations for some outcomes. Without participant-level data, the protocol, or a statistical analysis plan, those differences cannot be fully reconciled. The record also does not report a multiplicity strategy, missing-data methods, analysis populations, or interim analyses.

Safety reporting is limited to the listed affected-participant counts and event terms. Death counts are not reported, and further details about event timing, relatedness, duration, and event-level counts are not given in the registry record. These trial-specific reporting limits do not show that unreported events occurred; they mean only that the record does not supply those details. The completed status and enrollment figures alone do not resolve these uncertainties or establish how the results generalize beyond the enrolled trial population.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Comparison of Metoprolol and Tramadol With Remifentanil in Endoscopic Sinus Surgery — NCT02484859.
• Registry record last updated 2023-12-20; status last verified 2023-12.
• Results first posted 2019-09-10.
• 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.

19. Record Summary

The registry describes a completed, randomized, quadruple-masked, parallel-group phase 4 trial comparing remifentanil with tramadol plus metoprolol during endoscopic sinus surgery. Enrollment is listed as 88, with 44 participants in each arm for the posted primary summaries. The primary endpoint was the surgeon-reported Boezaart bleeding score during surgery, on a scale from 0 to 5.

The primary median was 1 in each arm, and the reported Wilcoxon (Mann-Whitney) test gave p >0.69. The registry does not report primary interquartile ranges, an effect estimate, or a confidence interval, so the result does not establish equivalence or non-inferiority. Secondary outcomes include time to a bleeding score below 3, bleeding rate, postoperative pain, and postoperative nausea and vomiting; numerical postoperative-pain results are not reported in the registry record. Multiplicity, missing-data methods, and analysis populations are also not reported.