ADVANCE Direct Aortic Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for ADVANCE Direct Aortic Study (NCT01676727), a registered phase not stated study. The primary outcome is All-cause Mortality.

2. Clinical Question

That question is narrower than whether the device is generally safe or effective. It concerns mortality during a specified follow-up period in a population selected for a particular access approach. The registry also lists a secondary outcome, a Kaplan-Meier estimate of major adverse cardiovascular and cerebrovascular events (MACCE), but its result is not reported in the registry record.

Without a randomized control comparison, the study description does not establish a basis for attributing observed outcomes to the device rather than to patient characteristics, clinical decisions, or other factors. The registry describes data collection about the intervention; it does not provide a comparative effect estimate for the primary question.

3. Trial Design

The registry identifies this study as the ADVANCE Direct Aortic Study, with the official title CoreValve® ADVANCE Direct Aortic Study. Its stated purpose was to collect data regarding the clinical utility, safety and performance of the Medtronic CoreValve® System for transcatheter aortic valve implantation in patients with severe symptomatic aortic valve stenosis for whom direct aortic access was selected. The listed sponsor is Medtronic Cardiac Rhythm and Heart Failure.

The study is marked completed. The registry lists enrollment of 100, a start date of 2012-09, and primary completion in 2014-04. These are registry-level study details; enrollment does not by itself establish how many participants were included in each outcome analysis or how many contributed complete follow-up.

The intervention is listed as a device: the CoreValve aortic valve. The arm description specifies implantation via a direct aortic approach. The record identifies no randomized comparison, and allocation is not stated. It therefore does not describe a controlled treatment contrast that would support a like-for-like comparison between intervention and control groups.

The primary outcome is all-cause mortality, expressed as a percentage of subjects and estimated with the Kaplan-Meier method at 30 days post-implant. Its stated population consists of subjects who underwent an attempted implant and were implanted with the CoreValve device via the direct aortic approach. The listed secondary outcome is a Kaplan-Meier estimate of MACCE. The registry lists two outcome measures and no analyses. The primary estimate, confidence interval, and secondary outcome result are not reported in the registry record.

The registry record does not report a detailed protocol, a sample-size justification, interim analyses, or a full statistical analysis plan. Those design features should not be inferred from the study status or the enrollment figure.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: all subjects who underwent an attempted implant of whom all were implanted with the CoreValve device via the direct aortic approach

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.

Population: All enrolled population.

6. Primary Endpoint

The registry lists the primary outcome as All-cause Mortality, measured over 30 days post-implant.

All-cause mortality counts deaths from any cause during the specified follow-up, rather than deaths attributed to a particular diagnosis or mechanism. The primary endpoint is expressed as a percentage of subjects and defined as a Kaplan-Meier estimate of 30-day all-cause mortality after implant. The time frame is 30 days post-implant.

As a general statistical concept, the Kaplan-Meier method estimates the probability of remaining free of an event over time while accounting for participants whose event status becomes unknown during follow-up through censoring. For mortality, the corresponding estimate of event occurrence is derived from the survival estimate. This approach is useful when follow-up time varies or when some participants have incomplete observation, provided the method's assumptions are reasonably met. The registry record does not report the censoring details or other information needed to assess those assumptions for this study.

All-cause mortality is a clear outcome in the sense that it does not depend on judging whether a death was caused by the device or the underlying disease. It is also a broad measure: it does not describe nonfatal complications, the timing or cause of a death, or the overall balance of benefits and harms. The registry lists MACCE as a secondary outcome, but does not report its result.

The mortality estimate and its 95% confidence interval are not reported in the registry record. Consequently, the endpoint definition and follow-up window can be described, but the observed mortality level and the precision of its estimate cannot be assessed from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a time-to-event measure summarized as a Kaplan-Meier estimate of 30-day all-cause mortality. The endpoint is stated as a percentage of subjects, and the registry specifies a 95% confidence interval. Neither the estimate nor the interval is reported in the registry record. The distinction between an endpoint definition and an endpoint result is important: a stated method does not reveal the value calculated from participants’ follow-up.

What does a Kaplan-Meier estimate do?

As a general explanation, Kaplan-Meier estimation uses the observed event times and accounts for participants who stop being observed before the end of follow-up. Such participants are commonly treated as censored at their last known time without the event. The method combines information over time to estimate survival, from which the probability of the event by a specified time can be expressed. It is designed for time-to-event data rather than simply dividing an event count by an enrollment total.

That distinction matters because follow-up may not be complete or equal for everyone. A simple percentage based on a fixed denominator does not necessarily handle varying observation time in the same way. The registry says the mortality result is a Kaplan-Meier estimate, but does not report individual event times, censoring, the number at risk over follow-up, or the details of the calculation. Those omissions prevent independent evaluation of the estimate’s implementation and assumptions.

How should the confidence interval be understood?

In general, a confidence interval describes statistical uncertainty around an estimated quantity under the method’s assumptions. It is not a guarantee that the true value lies in the particular interval, nor does it account for every source of uncertainty, such as selection bias or outcome reporting. The registry specifies a 95% confidence interval for the primary outcome, but does not report its limits. No conclusion about precision can therefore be drawn from the stated confidence level alone.

Precision and bias are different concerns. An estimate can be numerically precise yet still be affected by selection or measurement limitations. Conversely, a broad interval can indicate substantial sampling uncertainty even in a well-conducted analysis. A confidence interval cannot make a nonrandomized study equivalent to a randomized comparison.

What can be inferred from the study description?

The study description identifies the intervention as CoreValve implantation through a direct aortic approach and gives a specific primary population: subjects who underwent an attempted implant and were implanted with the device by that approach. This is an outcome-defined population, not automatically everyone enrolled. The registry lists enrollment of 100, but does not report the number included in the primary endpoint analysis or how participants who did not meet the stated population definition were handled.

The study is marked as not a randomized comparison, while allocation is not stated. The record does not describe a like-for-like control group. A single-group outcome can describe what was observed in the studied setting, but it cannot by itself separate the intervention’s contribution from other influences. Comparisons with other studies would also require careful attention to differences in eligibility, baseline risk, follow-up, endpoint definitions, and analysis.

What do the planning assumptions mean?

The registry describes sample-size planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect; time-to-event illustrations use a total number of events under the Schoenfeld approach, while other illustrations use participants per arm. No planning illustration values or observed effect are reported in the registry record.

These assumptions are not a report of the study’s own design rationale. The record explicitly characterizes the illustrations as planning based on the observed effect, rather than the trial’s own design. Such illustrations are hypothetical sample-size calculations, not observed power and not evidence that the original study was adequately or inadequately sized. The record’s description of equal allocation between two arms also does not establish that the study itself used that allocation; allocation is not stated, and a randomized comparison is not described.

What is not available for statistical review?

The registry lists two outcome measures and no analyses. It does not report the primary mortality estimate, the confidence interval limits, the MACCE result, analysis code or detailed methods, censoring rules, missing-data handling, or an interim-analysis plan. It also does not report a sample-size justification or the detailed statistical analysis plan. As a result, the registry record supports a limited account of the planned endpoint and broad study structure, but not a full review of statistical execution or results.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Implanted Population")
n      <- c(92)
events <- c(4)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Implanted Population  92  4  4.3  1.2  10.8  1.7  10.7  1.8  10.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures: 30-day all-cause mortality as the primary outcome and a Kaplan-Meier estimate of MACCE as a secondary outcome. It lists no analyses, and neither outcome result is reported in the registry record. The record does not describe a multiplicity strategy, such as a prespecified hierarchy or adjustment for assessing more than one outcome. It is therefore not possible to determine how the study planned to control the chance of false-positive findings across outcome analyses. This is a reporting gap, not evidence that an adjustment was or was not used outside the registry record.

Missing-data methods are also not reported in the registry record. For a Kaplan-Meier analysis, censoring is part of the general approach to incomplete follow-up, but the record does not specify how censoring was defined, how loss to follow-up was handled, or whether any sensitivity analyses were conducted. It does not give the number of participants with incomplete follow-up for either outcome.

The primary population is described as subjects who underwent an attempted implant and were implanted with the CoreValve device via the direct aortic approach. The registry’s enrollment figure of 100 is not an outcome-specific denominator, and the number contributing to the mortality estimate is not reported. The record does not explain whether an intention-to-treat population was defined or how participants outside the stated implanted population were handled. These details limit assessment of selection into the analysis and the completeness of outcome ascertainment.

12. 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

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: bleeding (26.1%), vascular access site and access-related complications (16.3%), permanent pacemaker implantation (14.1%), renal failure (13.0%), new or worsened conduction disturbances and arrhythmias without pacemaker implant (12.0%).

The registry’s implanted-population safety summary lists serious-event terms and percentages. The most prominent listed terms are Bleeding, 26.1%; Vascular access site and access-related complications, 16.3%; Permanent Pacemaker Implantation, 14.1%; Renal Failure, 13.0%; New or worsened conduction disturbances and arrhythmias without pacemaker implant, 12.0%; and Failure of current therapy for AS requiring hospitalization or worsening congestive heart failure, 10.9%.

These entries are registry listings, not a comparison against an untreated or alternative-treatment group. The record does not report the definitions used for each term, their event counts, or the denominators underlying these percentages. It also does not explain whether participants could contribute to more than one category. The percentages therefore should not be added together or interpreted as mutually exclusive portions of the population.

The implanted-population summary also lists 92 at risk and 72 affected in one grouping, and 92 at risk and 68 affected in another, along with 16 deaths. The meaning of each grouping and how these figures relate to the listed event terms are not explained in the registry record. They should not be treated as a complete account of all safety outcomes or as directly comparable measures without further definitions.

Safety interpretation also depends on follow-up duration and ascertainment. Apart from the primary endpoint’s 30-day post-implant time frame, the relevant observation period for these serious-event listings is not reported in the registry record.

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

The registry record identifies a clinically specific setting: CoreValve implantation through direct aortic access in people with severe symptomatic aortic valve stenosis for whom that access approach was selected. It records a completed study and states that the study was intended to collect data on clinical utility, safety, and performance. That context explains the question the study was designed to address, but it does not supply the primary outcome result.

The primary endpoint was all-cause mortality estimated at 30 days post-implant using the Kaplan-Meier method. The estimated percentage and its 95% confidence interval are not reported in the registry record. Thus, the posted information does not establish the observed mortality level or how precisely it was estimated. The MACCE secondary outcome is also listed without a reported result.

The study is not described as randomized, and allocation is not stated. This limits causal interpretation: outcomes after implantation cannot, from this record alone, show what would have happened to comparable people under another treatment or approach. No like-for-like control comparison is described. The listed serious-event terms and percentages offer some safety information, but their definitions, denominators, and overlap are not reported, so they cannot be interpreted as a complete comparative safety profile.

These limitations do not make the study description meaningless. A registry record can document the intended population, intervention, outcome definitions, and selected reported safety information. But those details are not substitutes for the missing endpoint estimates, uncertainty intervals, or transparent analysis methods. A reader should distinguish the existence of a completed study from the availability of its results in the registry record.

The information does not support a conclusion that the intervention improved outcomes, worsened them, or was equivalent to another approach. The absence of a reported result is not a null finding. It means that the relevant numerical result is not reported in the registry record.

14. Why This Trial Matters Statistically

This study raises a recurring statistical challenge: how to describe outcomes for a selected group receiving a procedure when the registry does not describe a randomized comparison. An outcome estimate in that setting can be informative as a description of the observed group, but it cannot by itself establish what caused the outcome. Separating descriptive evidence from comparative or causal evidence is essential to sound interpretation.

The endpoint also illustrates why follow-up and analysis populations matter. The primary outcome is a Kaplan-Meier estimate of 30-day mortality after implant, and its stated population is limited to people who underwent an attempted implant and were implanted with the device. The registry lists enrollment separately, but does not report the number included in the estimate or follow-up completeness. Readers therefore need more than the overall enrollment figure to evaluate the endpoint.

Statistical precision is another central issue. A confidence interval is specified, but its limits are not reported. Without the estimate and interval, readers cannot assess the scale of the observed outcome or distinguish a precisely estimated result from one with substantial uncertainty. Reporting a method without its result leaves the key inferential question unanswered.

The safety listings further show why denominators and event definitions are necessary. Percentages without stated denominators or an explanation of overlapping categories can be difficult to compare or combine. Registry-based evidence is most useful when outcome definitions, analysis populations, follow-up, missingness, and uncertainty are all transparent. The gaps in this record make those statistical principles especially relevant.

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 limitations are specific to the information recorded for this study. The primary outcome is defined, but its Kaplan-Meier estimate of 30-day all-cause mortality and its 95% confidence interval are not reported in the registry record. The MACCE result is also absent. This prevents assessment of the outcome levels, their precision, or the relationship between the primary and secondary results.

The study is not described as randomized, allocation is not stated, and a like-for-like control comparison is not described. Consequently, the record does not support a comparative causal interpretation. The stated primary population is limited to people who underwent an attempted implant and were implanted with the CoreValve device via direct aortic access; the registry does not report the outcome-specific analysis population or how other participants were handled.

Although enrollment is listed as 100, the number followed for the endpoint, the completeness of follow-up, censoring details, and missing-data methods are not reported in the registry record. The record also does not provide a detailed statistical analysis plan, a sample-size justification, or interim-analysis information. The sample-size assumptions described for planning illustrations should not be mistaken for the study’s original design rationale or for observed power.

Safety interpretation is constrained by unreported definitions, denominators, and possible overlap among serious-event categories. The follow-up period for those listings is not stated. These limitations apply to what can be learned from the registry record and do not establish what may have been documented elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: ADVANCE Direct Aortic Study — NCT01676727.
• Registry record last updated 2018-09-19; status last verified 2018-08.
• Results first posted 2018-07-30.
• 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.

19. Record Summary

The ADVANCE Direct Aortic Study is listed as completed, with enrollment of 100, a start date of 2012-09, and primary completion in 2014-04. It studied the CoreValve aortic valve implanted via a direct aortic approach in people with severe symptomatic aortic valve stenosis for whom that access was selected.

The primary outcome was a Kaplan-Meier estimate of 30-day all-cause mortality after implant, expressed as a percentage with a 95% confidence interval. The registry record does not report the estimate or interval. MACCE is listed as a secondary outcome, but its result is also not reported. The study is not described as randomized, allocation is not stated, and no like-for-like control comparison is described.

The record lists serious adverse-event terms and percentages, but does not report their denominators or definitions. It lists two outcome measures and no analyses. A full assessment of results, precision, missingness, and statistical methods is therefore not possible from the registry record.