OptiVol® Care Pathway: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for OptiVol® Care Pathway (NCT00847288), a randomized phase 4 study. The primary outcome is Compare the Time to Initiation of Clinical Action Prompted by an OptiVol Threshold Crossing Between Monthly and Quarterly Review of Cardiac Compass Trends With OptiVol.

2. Clinical Question

The trial’s stated hypothesis was that monthly review would shorten the time to clinical action compared with quarterly review. The primary outcome focuses on the timing of an action after a threshold crossing, rather than on whether a threshold crossing occurs. The registry record also lists secondary questions about changes in subject self-care, patient groups more likely to have actions triggered by monthly review, and time to action with or without an OptiVol threshold crossing. Those questions provide context for the study, but the primary comparison is the time to action prompted by a crossing.

The clinical question is therefore about review frequency and the speed of clinical response within the specified analysis population. The registry record does not report the types of clinical action counted, nor does it give further operational details about how a qualifying action was identified.

3. Trial Design

OptiVol® Care Pathway is a completed, phase 4, prospective, randomized, multi-center, post-market clinical trial in the United States, sponsored by Medtronic Cardiac Rhythm and Heart Failure. The registry record gives an enrollment of 1682. The study started in 2009-03 and had primary completion in 2011-03.

The trial used a parallel design with no masking. The two arms were Monthly Review Arm and Quarterly Review Arm. The arm descriptions say that patients enrolled at centers assigned to monthly review had their device data reviewed monthly, while patients at centers assigned to quarterly review had data reviewed every 3 months. The record identifies the study as randomized, but does not report the randomization mechanism, allocation unit, or details of any procedures used to preserve allocation concealment.

The primary outcome was a time-to-event measure: time to initiation of clinical action prompted by an OptiVol threshold crossing. Its stated timeframe was 1 year. The primary analysis population was more specific than the overall enrollment: participants needed an eligible study device, signed informed consent and HIPAA, and at least one threshold crossing after the study start date. The arm-specific outcome summaries report 639 patients for monthly review and 605 for quarterly review.

The registry record lists three secondary outcomes, in addition to the primary outcome. It records two analyses and four outcome measures overall. Further details about the study’s original statistical plan, including its own sample-size justification, are not reported in the registry record.

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: There were 1682 enrollments from 106 study centers. 1668 of those enrollments met the inclusion criteria for the study and thus were randomized. Fourteen did not meet the inclusion criteria and were excluded before randomization.

Overall Study

Analysis population for the primary outcome, as defined in the registry: All patients enrolled in the study, who have eligible study device, signed inform consent, signed HIPAA, and have at least one OptiVol threshold crossing post the start date, were included in this analysis.

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 Compare the Time to Initiation of Clinical Action Prompted by an OptiVol Threshold Crossing Between Monthly and Quarterly Review of Cardiac Compass Trends With OptiVol, measured over 1 year.

The primary endpoint measures the time from an OptiVol threshold crossing to initiation of clinical action, comparing monthly with quarterly review of Cardiac Compass® Trends with OptiVol. The registry describes the endpoint as a median time, measured in months, with a 1-year timeframe. The stated analysis population includes patients who had at least one qualifying threshold crossing after the study start date, as well as the specified device and consent requirements.

A time-to-event endpoint retains information about when an event occurs, rather than reducing the outcome to a simple count of participants with or without an event at a single visit. The median gives the point in time by which half of the analyzed event times are at or below that value, under the usual interpretation of a time-to-event median. This is a general statistical explanation; the registry record does not give additional details about how event times or incomplete follow-up were handled.

Review frequency is directly connected to the endpoint: the study asks whether the interval between reviews is associated with a different time to action after a threshold crossing. The endpoint does not, by itself, describe the clinical appropriateness or consequences of an action. Nor does it measure the frequency of threshold crossings in all enrolled patients, because the primary analysis population was restricted to participants with at least one qualifying crossing.

7. Results Posted in the Registry

• Monthly Review Arm vs Quarterly Review Arm: hazard ratio 1.50 (95% CI 1.10–2.00), reported p = 0.004 (as reported in the registry).

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports an arm-specific median time and a Cox regression hazard ratio. These methods answer related but different questions: the medians describe the time-to-event distribution within each arm, while the hazard ratio summarizes a relative event rate across follow-up under a regression model.

What does a median time summarize?

For a time-to-event outcome, the median is the time at which the estimated event-time distribution reaches its midpoint. In ordinary terms, it marks the time by which half of the relevant event-time distribution has occurred. The reported median was 8.9 months for monthly review and 12.4 months for quarterly review. Each estimate has its own 95% confidence interval. A median does not show the full distribution of event times, and it does not tell how many events occurred at each point in follow-up.

General explanation: time-to-event analyses can account for participants whose event time is not observed during follow-up by using censoring information. The registry record does not report how censoring, loss to follow-up, or incomplete observations were handled for this analysis. It is therefore not possible to describe the specific implementation from the record alone.

What does the Cox hazard ratio represent?

The reported Cox regression hazard ratio is 1.5 for monthly review compared with quarterly review. In general, a hazard ratio compares event rates at a given point in time between groups, conditional on the model’s structure. It is not a ratio of the two medians, and it does not mean that the median time is reduced by a specified percentage. The estimate depends on the event definition, follow-up, and model assumptions. The record identifies the method as Regression, Cox, but does not report covariates, checks of model assumptions, or further model specifications.

A common Cox model assumption is proportional hazards: the relative event rate between groups is treated as constant over time. This is a general description of the model, not a claim that the assumption was tested or met in this trial. Whether that assumption was assessed is not reported in the registry record. If the relative event rate changes over time, one overall hazard ratio may not capture that pattern well.

How should the p-value be read?

The reported p-value is 0.004. General explanation: a p-value measures how unusual a test result at least as incompatible with a null hypothesis would be if the null model and the test assumptions were correct. It is not a measure of effect size, clinical importance, or the probability that a finding is due to chance. The hazard ratio and its confidence interval describe the estimated effect and uncertainty; the p-value describes the test result under a null hypothesis. The registry record does not report a multiplicity adjustment for the primary comparison.

What does randomization contribute?

Random allocation is intended, in general, to make comparison groups similar on average with respect to factors that could affect outcomes. This can support causal interpretation when allocation and follow-up are appropriately conducted. The record says the study was randomized and parallel, and that centers were assigned to monthly or quarterly review in the arm descriptions. It does not specify the randomization procedure, whether allocation was by center or another unit, or how the analysis accounted for the allocation process. No masking was reported.

The primary analysis population was restricted to patients who met the stated eligibility conditions and had at least one threshold crossing after the start date. Restricting an analysis to a post-allocation event can affect how randomized groups compare, depending on how that event relates to assignment and outcomes. This is a general methodological consideration, not evidence of bias in this trial. The registry record does not report analyses of the full randomized population or explain how this restriction was addressed.

10. Confidence Intervals and Precision

The arm-specific estimates include 95% confidence intervals. The monthly review median was 8.9 months, with an interval from 7.2 to 9.9 months; the quarterly review median was 12.4 months, with an interval from 12.0 to 13.1 months. The Cox hazard ratio was 1.5, with an interval from 1.1 to 2.0. The reported p-value for that comparison was 0.004.

General explanation: a confidence interval describes a range of values compatible with the data and the statistical procedure, under the method’s assumptions. It conveys uncertainty around an estimate; it is not a range containing a fixed proportion of individual participant outcomes. A narrower interval indicates greater precision for that estimate than a wider interval would, but precision does not establish that the endpoint is clinically important or that the model assumptions are valid.

The hazard-ratio interval extends from 1.1 to 2.0, so the posted estimate is not highly precise as a single value: a range of effect sizes remains compatible with the analysis. The arm-specific median intervals express uncertainty around each median separately. Their limits should not be used as a substitute for a confidence interval for a between-arm difference. The registry reports the Cox model comparison separately.

The record does not report further uncertainty measures, such as confidence intervals for secondary outcomes, or details of sensitivity analyses. Precision should therefore be assessed from the estimates and intervals actually reported, while recognizing that the registry record does not document all analysis details needed to evaluate model fit or robustness.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size material is a planning illustration based on the observed effect, not the trial’s own original design assumptions. For this time-to-event comparison, the values are total events, not participants per arm. The listed planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The event calculations use the Schoenfeld method, with the target effect set to the stated fraction of the observed effect.

The 80% power column gives the total number of events the illustration estimates would be needed for an 80% chance of detecting the specified effect under those assumptions. The 90% power column gives the corresponding event total for a 90% chance. These are planning probabilities under an assumed effect and statistical model, not a description of what happened in the trial.

For 100% of the observed effect, the illustration lists 191 total events for 80% power and 256 for 90% power. For 75% of the observed effect, it lists 340 and 455 total events. For 50% of the observed effect, it lists 764 and 1,023 total events. The pattern reflects a general planning principle: smaller effects are harder to distinguish from no effect, so more events are needed to detect them at a given power level.

This is not observed power. It is an illustration of event requirements under stated assumptions. The registry record does not report the trial’s own original sample-size justification or planning assumptions.

12. How the Sample Size Is Derived

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

Formula

d is the total number of events needed (Schoenfeld's formula) with 1:1 allocation and proportional hazards.

Worked calculation for this trial

1. Hazard ratio HR = 1.500, so ln(HR) = 0.4055.
2. d = 4 × (1.96 + 0.842)² / [ln(1.500)]² = 191.0, rounded up to 191 events in total for 80% power.

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

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
hr <- 1.5                              # observed hazard ratio
events_needed <- function(power, frac = 1) ceiling(round(4 * (z_a + qnorm(power))^2 / log(hr^frac)^2, 6))   # Schoenfeld, 1:1 allocation
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: events = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(events_needed(0.80, f), big.mark = ","), format(events_needed(0.90, f), big.mark = ",")))

# Simulation: given d total events under proportional hazards, events in the treatment arm are Binomial(d, hr / (1 + hr)).
# The score (log-rank type) statistic is (D1 - d / 2) / sqrt(d / 4).
set.seed(847288)
d    <- events_needed(0.80)
reps <- 20000
D1 <- rbinom(reps, d, hr / (1 + hr))
z  <- (D1 - d / 2) / sqrt(d / 4)
cat(sprintf("Simulated power with %s events: %.3f (%d replicates)\n", format(d, big.mark = ","), mean(abs(z) > z_a), reps))

Output from running the code

100% of observed effect: events = 191 (80% power), 256 (90% power)
 75% of observed effect: events = 340 (80% power), 455 (90% power)
 50% of observed effect: events = 764 (80% power), 1,023 (90% power)
Simulated power with 191 events: 0.769 (20000 replicates)

The simulation uses the fact that, with d events in total and proportional hazards, the number of events in the treatment arm is binomial. It is an approximation that conditions on the total number of events, and it should land close to the target power.

13. Analyses Reported by the Sponsor

The registry reports the sponsor’s Cox regression result as a hazard ratio of 1.5 for Monthly Review Arm versus Quarterly Review Arm, with a 95% confidence interval from 1.1 to 2.0 and p = 0.004. The arm summaries separately report median times of 8.9 months and 12.4 months. These quantities are not interchangeable: the Cox estimate compares event rates over follow-up, while the medians summarize each arm’s time distribution.

The registry record does not flag a discrepancy between the reported comparison and a recalculation. It also does not provide a second, competing Cox estimate. The sponsor-reported analysis is therefore the inferential comparison available in the record; the arm-specific summary statistics alone are not sufficient to reproduce a Cox regression result or its p-value.

Any simple recalculation from posted summary statistics would be unadjusted and would not recreate the sponsor’s patient-level time-to-event model. The model specification, covariates, handling of incomplete follow-up, and diagnostic checks are not reported in the registry record. The reported Cox result should consequently be interpreted as the sponsor’s posted analysis, with those details unavailable for independent evaluation.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists three secondary outcomes in addition to the primary outcome. They concern changes in subject self-care over time, patient groups more likely to have clinical actions triggered by monthly rather than quarterly reviews, and time to clinical action with or without an OptiVol threshold crossing. It also records four outcome measures and two analyses. The presence of several outcomes means that more than one statistical question was considered, but the record does not state how those questions were prioritized or whether any multiplicity procedure was used.

Multiplicity is a general statistical concern: when several hypotheses are tested, the chance of at least one result appearing unusual under a collection of null hypotheses can increase. Methods such as pre-specifying a primary outcome, adjusting significance thresholds, or treating secondary results as exploratory can address different aspects of that concern. The trial’s multiplicity plan, including any adjustment or hierarchy, is not reported in the registry record. The primary p-value of 0.004 should therefore be read as reported, without assuming that it was adjusted for other outcomes or analyses.

The record describes the primary analysis population and its qualifying conditions, but does not report a missing-data plan. It does not explain how participants with incomplete follow-up, missing device data, or no observed clinical action were handled, nor does it describe imputation or sensitivity analyses. General explanation: in time-to-event studies, incomplete follow-up may be represented through censoring, but the method and assumptions need to be documented to assess how it affects interpretation. The specific approach in this trial is not reported in the registry record.

The analysis population is defined by eligibility requirements and at least one OptiVol threshold crossing after the study start date. The record does not describe a separate intention-to-treat analysis of all randomized participants, or explain whether other analysis populations were used. The number of patients reported in each primary outcome arm is available, but further accounting for exclusions or missing observations is not reported.

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

The posted results show shorter median time to clinical action in the monthly review arm than in the quarterly review arm within the stated primary analysis population: 8.9 months versus 12.4 months. The reported Cox hazard ratio for monthly versus quarterly review was 1.5, with a 95% confidence interval from 1.1 to 2.0 and p = 0.004. Together, these are the registry’s estimates for the comparison of review schedules on time to action after a qualifying threshold crossing.

These estimates do not show how often threshold crossings occurred among all enrolled participants, because the primary analysis was restricted to participants with at least one crossing after the study start date. They also do not identify the kinds of clinical actions taken or describe their consequences. The record does not report whether the timing difference was associated with changes in health outcomes, quality of life, or other clinical measures beyond the listed secondary questions.

General explanation: statistical evidence about a group comparison is not a recommendation for an individual, and an estimated difference in timing is not by itself a measure of benefit or harm. The posted result cannot establish the appropriateness of a particular review schedule for a specific patient. No medical advice follows from the registry statistics alone.

The findings should be interpreted in the context of the design and analysis information available. The study is reported as randomized, but details of allocation and model implementation are limited. The record does not report the handling of missing follow-up, the proportional-hazards assessment, or a multiplicity strategy. Those omissions constrain independent assessment of robustness and generalizability; they do not change the numerical results reported in the registry.

16. Why This Trial Matters Statistically

This trial’s statistical question is about timing, not merely whether clinical action occurred. A time-to-event analysis can use the ordering and timing of events during follow-up, making it suited to the stated question of whether monthly rather than quarterly review is associated with earlier action after a threshold crossing. The Cox hazard ratio and arm-specific medians offer complementary summaries of that timing.

The design also illustrates an important distinction between an overall enrolled population and an analysis population defined by a post-start event. The primary outcome includes patients who had at least one OptiVol threshold crossing after the study start date, so the estimated comparison is specifically about that group. It does not describe the timing outcome for participants without a qualifying crossing.

From a biostatistical perspective, the report makes the central estimates and their uncertainty visible: arm-specific medians with confidence intervals and a Cox hazard ratio with its interval and p-value. It also lists outcomes beyond the primary endpoint, making multiplicity and analysis-population definitions relevant to interpretation. At the same time, the registry record leaves key analytical details undocumented, including the missing-data approach and model diagnostics. This combination makes the trial useful for understanding the interpretation of reported time-to-event results while emphasizing the importance of transparent analysis reporting.

17. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary analysis applies to patients who met the specified device and consent requirements and had at least one OptiVol threshold crossing after the study start date. It is not an analysis of every enrolled participant. The registry record does not report how many participants were excluded for each reason, or provide a full accounting of participants with missing or incomplete follow-up.

Although the trial is identified as randomized, the record does not explain the randomization mechanism or allocation unit. The arm descriptions refer to centers assigned to monthly or quarterly review, but further details about assignment and analysis of the allocation process are not reported. Masking was none. The record also does not report the Cox model’s covariates, assessment of proportional hazards, or other model diagnostics.

The registry record does not state how censoring or missing data were handled, whether sensitivity analyses were conducted, or whether multiplicity adjustments were used across the primary and secondary outcomes. It does not report the original sample-size justification. These gaps limit independent evaluation of the planned analysis and the robustness of the reported inference.

Safety fields list zero participants at risk and zero affected in both arms, while deaths are recorded as null. These entries do not provide enough detail to interpret safety outcomes or to conclude that no adverse events occurred. The registry record also does not provide additional operational definitions for clinical actions or explain how the action endpoint was adjudicated.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: OptiVol® Care Pathway — NCT00847288.
• Registry record last updated 2013-05-03; status last verified 2013-04.
• Results first posted 2013-05-03.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

21. Record Summary

OptiVol® Care Pathway was a completed, phase 4, prospective, randomized, multi-center, post-market, parallel trial with no masking. It compared monthly with quarterly review of Cardiac Compass® Trends with OptiVol. The registry reports enrollment of 1682, a start date of 2009-03, and primary completion in 2011-03.

The primary endpoint was median time to initiation of clinical action prompted by an OptiVol threshold crossing, with a 1-year timeframe. The reported medians were 8.9 months for monthly review and 12.4 months for quarterly review. The sponsor’s Cox regression comparison was a hazard ratio of 1.5, with a 95% confidence interval from 1.1 to 2.0 and p = 0.004.

The primary analysis was restricted to eligible patients with at least one qualifying crossing after the study start date. Further details about missing-data handling, multiplicity, model diagnostics, and the trial’s original sample-size assumptions are not reported in the registry record.