Pacing Affects Cardiovascular Endpoints in Patients With Right Bundle-Branch Block (The PACE-RBBB Trial): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pacing Affects Cardiovascular Endpoints in Patients With Right Bundle-Branch Block (The PACE-RBBB Trial) (NCT01169493), a randomized na study. The primary outcome is The Primary Endpoint of the Trial Will be a Comparison of the Proportion of Patients in Each of the Three Treatment Groups Who Demonstrate Positive LV Remodeling, Defined as a Decrease in LV End Systolic Diameter of >5mm..

2. Clinical Question

The trial addressed whether pacing mode was associated with positive left-ventricular remodeling in people with heart failure and right bundle-branch block. Its registry summary describes the clinical context: evidence for resynchronization pacing had largely come from people with left bundle-branch block, while the role of pacing strategies in right bundle-branch block was uncertain. That background motivates testing these modes in this population; it is not itself evidence of benefit or harm in the trial.

The central outcome was a binary measure of remodeling: each completed six-month period was classified according to whether left-ventricular end-systolic diameter decreased by more than the specified threshold. The registry outcome population included participants who completed the six-month period for each of the three settings, regardless of randomized sequence, and allowed a participant to be counted in more than one period. This makes the unit of the primary summary a completed treatment period rather than necessarily a unique person across the whole trial.

The registry record reports outcome proportions for VVI-40, RV DDD-40, and Bi-V DDD-40. It also posts an unadjusted comparison of Bi-V DDD-40 with VVI-40. Those summaries address the observed proportions, but they do not by themselves describe every possible comparison across the three modes or account for the crossover structure.

3. Trial Design

PACE-RBBB was a randomized, triple-masked, crossover trial sponsored by Duke University. The registry lists an enrollment of 16, a phase of NA, and a terminated status. The recorded start is 2011-01, and primary completion is recorded as 2014-08. The reason for termination is not reported in the registry record.

The three device settings were VVI-40, RV DDD-40, and Bi-V DDD-40. Participants were assigned to sequences that placed each setting in a different order across Period 1, Period 2, and Period 3. The sequence descriptions include all six possible orderings of the three modes. In a crossover design, participants can therefore contribute observations under more than one setting, rather than being observed under only one assigned mode throughout.

The primary outcome timeframe was six months. Its stated population was all participants who completed the six-month period for each setting, irrespective of randomized sequence; the same participant could be counted as completing more than one period. The outcome summaries report 10.0 participants for VVI-40, 7.0 for RV DDD-40, and 10.0 for Bi-V DDD-40. Those counts describe the reported outcome groups, not necessarily the number of distinct people enrolled or randomized.

The registry record identifies triple masking but does not describe which roles were masked or how masking was maintained. Details such as the length of each period, any washout between settings, sequence-specific enrollment, adherence, and the reason the trial ended are not reported in the registry record. These omissions matter when interpreting a crossover study, because treatment period and sequence can affect the interpretation of within-participant comparisons.

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.

Period 1 (6 Months)

Reasons for not completing this period:

Period 2 (6 Months)

Period 3 (6 Months)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who completed the six month period for VVI-40, RV DDD-40, Bi-V DDD-40 regardless of which arm they are randomized to. Participants may be counted as completing more than one 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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as The Primary Endpoint of the Trial Will be a Comparison of the Proportion of Patients in Each of the Three Treatment Groups Who Demonstrate Positive LV Remodeling, Defined as a Decrease in LV End Systolic Diameter of >5mm., measured over 6 months.

The primary endpoint was the proportion of participants demonstrating positive left-ventricular remodeling, defined as a decrease in left-ventricular end-systolic diameter of >5mm. The timeframe was six months. For this binary outcome, each completed period contributes a classification: the diameter decreased beyond the stated threshold or it did not.

Left-ventricular end-systolic diameter is a measure of heart structure at the end of contraction. In general, a change in a structural measure can be used to describe remodeling over time, while a threshold-based outcome makes the result interpretable as the proportion crossing a specified change. This is a general explanation of the type of endpoint; the registry record does not give a separate rationale for selecting this threshold or describe how the measurement was obtained.

The primary summaries were 0.0% for VVI-40, 29.0% for RV DDD-40, and 20.0% for Bi-V DDD-40. The posted comparison is between Bi-V DDD-40 and VVI-40, with a risk difference of 0.2 and a confidence interval from -0.048 to 0.448. The registry record does not post a separate inferential comparison for RV DDD-40 against either of the other modes. The outcome population is based on completed periods, and participants could contribute more than one period, which should be kept in mind when reading these proportions as group-level summaries.

7. Results Posted in the Registry

• Bi-V DDD-40: 20.0% (2/10) versus 0.0% (0/10) on control; risk difference 20.0 percentage points (95% CI -4.8 to 44.8); unadjusted two-proportion z-test p = 0.136.

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.

Minnesota Quality of Life Questionnaire

• 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:
  • Bi-V DDD-40: mean 55.78 versus 39.30 on control; difference 16.48 (95% CI -5.18 to 38.14), standardized effect d = 0.67; z-test p = 0.136.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Bi-V DDD-40 and the control. The interval gives the range of effects that remain compatible with the data.

6-minute Walk Distance

• 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:
  • Bi-V DDD-40: mean 244.44 versus 292.40 on control; difference -47.96 (95% CI -135.29 to 39.37), standardized effect d = -0.48; z-test p = 0.282.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Bi-V DDD-40 and the control. The interval gives the range of effects that remain compatible with the data.

NYHA Function Class

• 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:
  • Bi-V DDD-40: mean 3.20 versus 3.30 on control; difference -0.10 (95% CI -0.81 to 0.61), standardized effect d = -0.12; z-test p = 0.782.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Bi-V DDD-40 and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes add different kinds of information to the primary structural measure: quality-of-life scores, walking distance, and functional class. Their posted comparisons are all unadjusted contrasts of Bi-V DDD-40 with VVI-40. In general, measures of daily function, symptoms, and structure can describe distinct aspects of a clinical study, and they need not move in parallel. The registry results do not establish that one category confirms another.

The secondary estimates do not resolve the uncertainty in the primary remodeling comparison. The secondary comparisons have confidence intervals that include zero, and their unadjusted p-values do not provide a multiplicity-controlled basis for strong conclusions. No numerical result is reported for the other listed secondary outcomes, so they cannot be used to complete or verify a broader pattern of findings.

When many outcomes are examined, the chance of seeing an apparently notable result by chance can increase. In general, adjustment procedures or a prespecified hierarchy can help address that issue. Whether PACE-RBBB planned such a procedure, and how secondary outcomes were prioritized, is not reported in the registry record. Without that information, isolated secondary findings deserve less weight than a single well-specified primary analysis. Even the primary result requires caution because the registry record does not describe its complete statistical plan or how the crossover structure was handled.

The secondary outcomes are therefore best viewed as descriptive, uncertain evidence accompanying the primary endpoint, rather than as independent confirmation of a treatment effect. This reading does not dismiss the measures; it reflects the limited precision, unadjusted comparisons, incomplete outcome reporting, and absence of a reported multiplicity strategy.

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

• Secondary Echocardiographic Endpoints
• Arrhythmic Events
• Minnesota Quality of Life Questionnaire
• 6-minute Walk Distance
• NYHA Function Class
• Left Ventricular Ejection Fraction (LVEF)
• Left Ventricular End-diastolic Size

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary: participants either meet the remodeling threshold or do not. A proportion expresses how often that outcome occurred in a group. The risk difference compares two proportions by subtracting one from the other; positive values indicate a higher observed proportion in the first group named in the comparison, while negative values indicate a lower proportion. The posted Bi-V DDD-40 versus VVI-40 risk difference is 0.2. This is an absolute contrast on the proportion scale, not a relative risk.

The registry record also reports a confidence interval for that risk difference. In general, a confidence interval describes the precision of an estimate under the assumptions of the method used: narrower intervals indicate greater precision, while wider intervals allow a broader range of values compatible with the data and method. An interval that includes zero does not rule out no difference. The primary interval runs from -0.048 to 0.448, so it includes zero and encompasses both negative and positive differences. The interval does not establish which direction the underlying difference takes.

The posted p-value for that comparison is unadjusted. In general, a p-value measures how unusual data at least as discrepant as those observed would be under a specified null hypothesis and statistical model. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. The registry record does not specify the model or null hypothesis details for the primary comparison, nor does it identify a prespecified significance threshold for the primary analysis. The p-value should therefore be read alongside the point estimate and interval, not as a stand-alone verdict.

Why does the crossover design matter?

In a crossover study, a participant can receive multiple settings in sequence. Measurements from the same participant are generally related: stable characteristics shared by that person can influence measurements in more than one period. A method that accounts for this within-participant dependence can differ from a method that treats every period as independent. Treatment period, order, and possible carryover from an earlier setting can also matter in general. The registry lists randomized sequences and permits a participant to contribute more than one completed period, but the specific statistical handling of participant-level correlation, period, sequence, and carryover is not reported in the registry record.

The reported outcome-group counts are 10.0 for VVI-40, 7.0 for RV DDD-40, and 10.0 for Bi-V DDD-40. These counts are not a substitute for the total enrollment of 16, and they should not be summed to infer a number of unique participants because the outcome definition allows repeated contributions across periods. The registry record does not give the number completing every period or the number of participants contributing to each sequence.

What do the secondary comparisons represent?

The Minnesota Quality of Life Questionnaire, 6-minute Walk Distance, and NYHA Function Class are reported as means with standard deviations. A mean describes the average observed score or distance in a group. A standard deviation describes the spread of observations around that mean; it is not the uncertainty in the mean itself. The posted mean differences compare Bi-V DDD-40 with VVI-40. Their confidence intervals describe uncertainty in those differences, subject to the assumptions of the calculations.

In general, continuous outcomes may be analyzed with methods that account for the crossover design and repeated measurements. The registry record does not report whether the posted comparisons use a paired or repeated-measures method, or whether they adjust for sequence or period. The statistical comparisons are marked as unadjusted. They should not be assumed to be the trial's prespecified analyses, since a detailed statistical plan is not reported in the registry record.

What do the planning illustrations mean?

The planning illustrations for the continuous secondary outcomes use an observed effect and consider specified fractions of that effect. They assume a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The resulting values are participants per arm for the stated power levels. In general, these are planning illustrations, not observed power and not evidence that the trial was designed with those sample sizes. They depend on the observed effect, which can be unstable in a small study, and they do not represent a reported sample-size justification for PACE-RBBB. A trial-specific sample-size rationale is not reported in the registry record.

Over-dispersion is a general concern for outcomes where the observed variability exceeds what a simple model assumes. If present, it can make uncertainty larger than a model that assumes less variability would suggest. The registry record does not describe an over-dispersion assessment or a model for the primary binary outcome, so no such adjustment can be attributed to the trial.

11. Confidence Intervals and Precision

The primary comparison is imprecise. The risk difference for Bi-V DDD-40 versus VVI-40 is 0.2, and its confidence interval ranges from -0.048 to 0.448. Because the interval includes zero and extends in both directions, the posted data do not pin down whether the underlying difference is negative, absent, or positive. Its width also means that quite different effect magnitudes remain compatible with the estimate and the calculation used.

The group sizes for this comparison are 10.0 and 10.0, while the primary outcome groups include 7.0 for RV DDD-40. Such small outcome groups limit precision, especially for a proportion that can only take a limited set of values as individual observations change. The crossover design means these counts may include repeated periods from the same participants, so they should not be treated as if they necessarily represented independent samples of unique people.

Confidence intervals are not guarantees that the true value lies within the particular interval, nor do they express the probability that a treatment effect is clinically important. In general, they indicate a range of estimates compatible with the observed data under the analysis assumptions. Here, the registry record does not describe the assumptions or method in enough detail to assess whether the interval accounts for repeated observations or the randomized sequence structure.

The three posted secondary comparisons also have uncertainty intervals, but the registry record does not report a detailed analysis plan or adjustment for multiple outcomes. The estimates should be interpreted as exploratory summaries rather than as precise, definitive estimates. The sample-size illustrations are separate planning exercises based on observed effects; they do not make the trial's observed estimates more precise and should not be read as observed power.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and multiple secondary outcomes. It reports numerical results for three secondary outcomes and lists additional secondary outcome names, including echocardiographic endpoints, arrhythmic events, and left-ventricular measures. A statistical plan specifying which outcomes were confirmatory, whether comparisons were hierarchically ordered, or whether multiplicity adjustments were planned is not reported in the registry record. The posted secondary p-values are unadjusted, so they do not account for examining multiple outcomes or contrasts.

The primary endpoint population is defined as participants completing the six-month period for each setting, regardless of randomized sequence, and a participant may be counted in more than one period. The registry record does not describe an intention-to-treat population, a per-protocol population, or how participants with incomplete periods were handled. The total enrollment is 16, but the number of participants with missing primary outcome data and the reasons for any missing data are not reported in the registry record.

In general, missing outcomes can affect both the estimated proportions and the interpretation of comparisons, particularly if missingness relates to health status, treatment sequence, or outcome. The record does not report a missing-data method, imputation approach, or sensitivity analysis. It also does not say whether all randomized participants were included in any analysis. Consequently, the posted outcome summaries should be understood as summaries for the defined completed-period population rather than assumed to represent every enrolled participant.

Because this was a crossover trial, analysis choices also need to address repeated measurements, period, and sequence. These details, along with any interim analyses or stopping rules, are not reported in the registry record. The registry status is terminated, but the reason for termination and whether it affected the availability of outcomes are not reported in the registry record.

13. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: heart failure exacerbation, heart transplant (16.7%), death (8.3%).

The serious adverse event summaries list 0 affected participants among 11 at risk for VVI-40, 0 among 13 at risk for RV DDD-40, and 3 among 12 at risk for Bi-V DDD-40. The registry also lists the serious terms “Heart Failure Exacerbation, Heart Transplant” at 16.7% and “Death” at 8.3%. These term-level figures should be read as the registry's listed serious-event information; the record does not provide further detail about timing, event counts by participant, or attribution.

The at-risk group sizes differ from the primary outcome group sizes. In a crossover study, safety exposure summaries may refer to treatment periods or exposure groups, and the registry record does not explain the exact counting method. They should not be combined with the efficacy summaries or treated as a direct estimate of comparative risk without that context. No non-serious adverse events are listed as affecting participants in the reported groups. The group-level death fields are not reported in the registry record, even though Death appears among the listed serious terms, so the term listing should not be used to infer a group-specific death count.

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

The registry results establish what was recorded in this trial: the proportions meeting the remodeling threshold differed across the reported groups, and the unadjusted Bi-V DDD-40 versus VVI-40 estimate was positive. The confidence interval is wide and includes zero. The results therefore do not establish a clear direction or precise magnitude for the underlying difference. The registry does not report a separate inferential comparison involving RV DDD-40.

These findings do not establish that any pacing setting works or does not work, and they do not establish equivalence between settings. A failure to exclude zero with an interval is not evidence that two settings are the same. Conversely, a positive point estimate does not establish a reliable benefit. The small outcome groups, crossover design, incomplete statistical detail, and terminated status all limit the strength of conclusions that can be drawn from the posted summaries.

The outcome population is based on completed six-month periods, with possible repeated contributions by the same person. The group summaries therefore should not be interpreted as if each row necessarily represented a separate randomized group of unique participants. Also, the comparison presented is unadjusted, and the record does not describe how dependence among repeated periods was handled. The precision and meaning of the estimates depend on those analytic details.

The data are specific to participants with heart failure and right bundle-branch block in this trial. The registry record alone cannot show whether the results generalize beyond the people and settings studied. It also does not provide enough information to infer why the study terminated, whether the stopping affected outcome collection, or how missing outcomes were handled. These limitations do not erase the observed data, but they constrain what those data can support.

15. Why This Trial Matters Statistically

PACE-RBBB is statistically interesting because its randomized crossover structure allows participants to experience more than one pacing mode, while also creating analytic dependencies that a simple independent-groups comparison may not capture. Repeated observations can potentially reduce the influence of stable differences between people, but they require methods that account for within-participant correlation, treatment order, and period. The registry record describes sequences but does not report the analysis details needed to evaluate those issues.

The primary endpoint is a thresholded structural measure reported as a proportion. That form is easy to express, but the estimate can be sensitive to a small number of participants crossing the threshold, particularly when outcome groups are small. The confidence interval makes the uncertainty visible: the point estimate alone would convey less about the range of plausible differences.

The trial also illustrates why an unadjusted p-value and a point estimate should not be treated as a complete account of evidence. Interpretation depends on the precision of the estimate, the prespecified analysis plan, the number of outcomes examined, and whether the analysis matches the crossover design. The record leaves several of those items unreported. Its planning illustrations for secondary outcomes are not a substitute for a trial-specific design justification or an account of the power the trial was intended to achieve.

For biostatisticians and clinical researchers, the key lesson is methodological: a posted numerical result can be informative while remaining limited by uncertainty, design complexity, and incomplete reporting. The most useful reading keeps the observed group summaries, the comparison interval, and the registry's reporting gaps in view together.

16. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The trial enrolled 16 participants and is listed as terminated. The reason for termination is not reported in the registry record, and the record does not explain whether termination affected recruitment, follow-up, or outcome availability. The reported completed-period outcome groups are small, and their counts need not correspond to mutually exclusive sets of people because participants may contribute more than one treatment period.

The registry gives randomized treatment sequences, but does not report period durations beyond the six-month outcome timeframe, washout procedures, adherence, or sequence-specific completion. It does not specify the statistical model for the primary outcome, the method used to calculate its confidence interval, or whether participant-level correlation was addressed. No primary comparison for RV DDD-40 against the other settings is posted.

Details of missing outcome data, analysis populations beyond the stated completed-period population, and sensitivity analyses are not reported in the registry record. The statistical plan, sample-size justification, interim analyses, and multiplicity strategy are also not reported. These omissions limit assessment of whether the presented comparisons reflect the intended analyses and how robust the conclusions would be to alternative assumptions.

Numerical results are available for only selected secondary outcomes, and their posted comparisons are unadjusted. The adverse event summaries use at-risk group sizes that differ from the primary outcome group sizes, without a detailed account of exposure or counting methods. Taken together, these trial-specific constraints mean that the observed results are useful as descriptive evidence but cannot support a precise comparative conclusion.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Pacing Affects Cardiovascular Endpoints in Patients With Right Bundle-Branch Block (The PACE-RBBB Trial) — NCT01169493.
• Registry record last updated 2016-09-23; status last verified 2016-08.
• Results first posted 2015-09-30.
• 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.

20. Record Summary

NCT01169493, PACE-RBBB, was a randomized, triple-masked crossover trial sponsored by Duke University. It enrolled 16 participants with heart failure and right bundle-branch block and compared VVI-40, RV DDD-40, and Bi-V DDD-40. The registry lists the study as terminated, with primary completion recorded as 2014-08.

The primary outcome was the proportion with a decrease in left-ventricular end-systolic diameter of >5mm after six months. The posted Bi-V DDD-40 versus VVI-40 risk difference was 0.2, with a confidence interval from -0.048 to 0.448 and an unadjusted p-value of 0.136. The interval includes zero and is broad, leaving considerable uncertainty about the comparison. The registry record does not report the reason for termination or a full statistical analysis plan.