Antiarrhythmic Effects of Spironolactone in Patients With ICDs: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Antiarrhythmic Effects of Spironolactone in Patients With ICDs (NCT04495712), a randomized phase 4 study. The primary outcome is Time to First Appropriate Implantable Cardioverter Defibrillator (ICD) Therapy.

2. Clinical Question

3. Trial Design

This was a randomized, parallel-group, phase 4 study of spironolactone versus placebo in patients with ICDs. The registry record lists an enrollment of 90 and describes quadruple masking. The brief study description says half of the patients would receive spironolactone and half placebo; the posted primary-outcome groups contain 44 participants assigned spironolactone and 46 assigned placebo. Randomization supports a between-group comparison, while masking is intended to reduce the influence of treatment knowledge on participant or study-team behavior and outcome assessment. The registry does not detail how the masking was implemented or which roles were included.

The study started on 2004-07-28, had primary completion on 2008-05-28, and is listed as completed. The primary outcome was followed through study completion, described as an average of 35 months. This is a time-to-event design: the endpoint concerns when a participant first experienced a qualifying ICD therapy, rather than simply whether an event occurred at one fixed visit. The registry lists all enrolled patients as the primary outcome population, but does not report further detail about the analysis set or handling of participants with incomplete follow-up.

All-cause hospitalization, ventricular refractoriness, SF36V, patient concerns assessment, and KCCQ are listed as secondary outcomes. The posted results include endpoint-specific sample sizes, which are not identical across outcomes. The registry record does not report the study’s sample-size justification, the planned statistical analysis document, or whether any interim analyses were conducted. Those omissions limit how far the posted results can be used to reconstruct the design decisions or the full analysis strategy.

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

Analysis population for the primary outcome, as defined in the registry: all enrolled patients

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 Time to First Appropriate Implantable Cardioverter Defibrillator (ICD) Therapy, measured over through study completion, an average of 35 months.

The primary endpoint is time from randomization to the first documented ICD therapy for ventricular tachycardia or ventricular fibrillation. An ICD may deliver therapy in response to a detected rhythm; restricting the endpoint to the first appropriate therapy focuses the measure on the timing of a qualifying arrhythmia-related device intervention. The registry describes the result in months and reports medians with full ranges for the two randomized groups.

Time-to-event outcomes are useful when both whether an event occurs and when it occurs matter. They can also make use of differing follow-up durations, provided the analysis appropriately accounts for participants whose event time is not observed during follow-up. General time-to-event methods distinguish such incomplete observation from a confirmed event. The registry record does not explain the handling of censoring or give participant-level follow-up details, so those procedures cannot be assessed from the posted results.

The reported follow-up extends through study completion, an average of 35 months. The registry reports a log-rank comparison but does not report a hazard ratio or confidence interval for the primary comparison. Consequently, the median times describe the observed group results, while the log-rank p-value describes evidence from a comparison of event-time distributions. Neither alone supplies a precise estimate of the relative event rate over follow-up.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Time-to-event analysis concerns the time until an event, rather than only the proportion with an event at a fixed time. Here the event is the first documented appropriate ICD therapy for ventricular tachycardia or ventricular fibrillation after randomization. The registry reports group medians and full ranges, then gives a log-rank p-value for the primary comparison. The medians describe the middle of the observed event-time distribution in each group. The full ranges show the minimum and maximum reported times, but do not describe how observations are distributed between those endpoints.

What does the log-rank test assess?

In general, the log-rank test compares event-time patterns between groups across follow-up. It is not a direct estimate of the size of a treatment effect. A p-value measures how compatible the observed test result is with a null comparison under the test’s assumptions; it does not give the probability that the null hypothesis is true. The registry reports p = 0.71 for the primary log-rank comparison. Without a hazard ratio, confidence interval, or event counts, the registry’s primary result does not quantify the relative event rate or its precision.

Time-to-event methods commonly account for participants whose event has not been observed by the end of their available follow-up. This is often called censoring. In general, the validity of such analyses depends on how censoring is handled and on assumptions about the relationship between censoring and event occurrence. The registry record does not describe the censoring procedure, report numbers censored by group, or provide detailed follow-up distributions. Those details cannot be inferred from the reported median, range, and log-rank p-value.

How should the recalculated comparisons be read?

For secondary endpoints, the recalculated estimates are simple, unadjusted comparisons based on posted summary statistics. A confidence interval describes a range of effect estimates compatible with the data and the method used, subject to its assumptions. A wide interval indicates limited precision; an interval that includes no difference does not establish that the true difference is zero. These recalculations do not incorporate unreported covariate adjustment, repeated-measures procedures, or other analysis choices that may have been used by the sponsor. The registry record does not report such details for every endpoint.

For all-cause hospitalization, the recalculated risk difference is 0.115, with a 95% confidence interval from -0.088 to 0.317, and an unadjusted p-value of 0.271. This is a comparison of the posted participant counts, not the sponsor’s log-rank analysis, which reports p = 0.07. The methods differ, so the estimates and p-values need not match. For ventricular refractoriness, the recalculated mean difference is 15.9 milliseconds, with a 95% confidence interval from -10.64 to 42.44 and an unadjusted p-value of 0.24; the registry’s sponsor analysis is a two-sided t-test with p = 0.42. For SF36V, the recalculated mean difference is -8.44, with a 95% confidence interval from -17.32 to 0.436 and an unadjusted p-value of 0.062; no sponsor analysis is listed for that outcome.

General statistical interpretation should distinguish statistical significance from clinical importance. A p-value does not reveal whether an effect, if present, would matter to patients, and these results do not supply a threshold for meaningful change. Confidence intervals address uncertainty about estimates but do not account for every possible source of bias or measurement error.

What do the planning illustrations mean?

The planning illustrations for secondary endpoints use the observed effect as a starting point and show hypothetical sample sizes for specified fractions of that effect. Their stated assumptions are a two-sided significance level of 0.05, equal allocation, and a normal approximation. These figures are planning illustrations, not observed power and not evidence about the trial’s original design. The registry record does not report its own sample-size justification. The primary time-to-event endpoint does not have an estimable recalculated comparison in the posted analysis, so a primary-endpoint planning estimate should not be inferred from the secondary-outcome illustrations.

General power calculations depend on assumptions about the effect to detect, variability or event frequency, analysis method, allocation, and significance level. Changing those assumptions changes the planning result. A planning calculation based on an observed effect can be especially unstable when that effect is estimated from a small or noisy study. It cannot establish retrospectively whether the trial was adequately designed to detect a meaningful effect.

Why does multiplicity matter?

When multiple outcomes are analyzed, the chance of at least one apparently unusual result can rise if each is interpreted independently without adjustment. Prespecified outcome hierarchies or multiplicity adjustments can address that issue, but the registry record does not report whether either was used. The p-values for secondary endpoints should therefore be viewed as unadjusted evidence unless the registry explicitly identifies a sponsor analysis and method. This consideration does not change the primary log-rank result; it affects how confidently secondary findings can be treated as confirmatory.

10. Analyses Reported by the Sponsor

For the primary endpoint, the registry reports a sponsor log-rank p-value of 0.71. It does not report a sponsor hazard ratio or confidence interval, and a recalculated two-group effect estimate is not available for this median-time endpoint. The reported medians and ranges remain descriptive; they do not supply the missing relative-effect estimate. The registry record does not flag a discrepancy for the primary result.

For all-cause hospitalization, the registry’s sponsor analysis is reported as a log-rank comparison with p = 0.07. The simple recalculation from participant counts gives an unadjusted risk-difference p-value of 0.271. These analyses are not identical: the recalculation treats the outcome as a binary participant count, whereas the sponsor result is labeled log-rank. Differences in analysis method mean the two p-values should not be treated as competing estimates of the same calculation.

For ventricular refractoriness, the sponsor’s two-sided t-test reports p = 0.42, compared with the recalculated unadjusted p-value of 0.24. The registry does not list a sponsor analysis for SF36V. These recalculations are not substitutes for the sponsor analyses, which may reflect analysis choices not described in the registry record. The registry does not provide enough detail to reconcile all method differences or determine whether additional adjustment was used.

11. Multiplicity, Missing Data and Analysis Populations

The registry distinguishes a primary endpoint from several secondary outcomes, but it does not report a complete statistical analysis plan, a testing hierarchy, or a multiplicity adjustment. When multiple outcomes are tested, unadjusted p-values do not account for the greater chance of finding at least one apparently unusual result across the collection of tests. Accordingly, secondary findings should be treated cautiously, particularly where no sponsor analysis is listed. The registry record does not establish whether these outcomes were prespecified in the same way or whether all planned analyses are posted.

The primary outcome population is described as all enrolled patients. Beyond that statement, the registry record does not define the analysis population for each endpoint or explain how deviations from randomized assignment were handled. It does not report how missing endpoint measurements, withdrawal, incomplete follow-up, or other unavailable observations were addressed. These omissions matter because the posted sample sizes vary by endpoint, including a smaller sample for ventricular refractoriness than for the primary outcome.

For the time-to-event outcome, the record does not explain censoring procedures or report event counts by group. These details are needed to assess how much information contributed to the log-rank analysis and how participants without an observed event were treated analytically. The registry also does not report the number of participants with incomplete follow-up or the amount of follow-up by group.

Interim analyses and stopping rules are not reported in the registry record. Their absence from the record does not establish that none occurred. The original sample-size justification and the statistical plan are also not reported. The posted secondary-outcome planning illustrations are hypothetical calculations based on observed effects and stated assumptions; they do not reconstruct the trial’s original design or resolve missing analysis details.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hospitalization (86.4%), death (29.5%).

The safety summaries list serious adverse events affecting 39 of 44 participants assigned spironolactone and 37 of 46 assigned placebo. The registry also lists deaths in 13 participants in the spironolactone group and 12 in the placebo group. For other adverse events, the counts show 44 of 44 and 46 of 46 participants affected, respectively. These figures describe reported participant counts; they do not by themselves establish that an event was caused by the assigned treatment.

Hospitalization and death are listed among the top serious adverse event terms, with 86.4% and 29.5%, respectively. The registry record does not clarify the denominator or provide a group-specific breakdown for those term percentages in the information. They should not be interpreted as percentages of all randomized participants in either arm without that context. The record also does not provide event-level timing, severity detail beyond the serious classification, or a causal assessment. Safety counts are descriptive and should be read alongside these reporting limitations.

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

The primary result describes the time to first appropriate ICD therapy observed among participants assigned to spironolactone or placebo. The registry reports median times of 8.8 months and 12.3 months, respectively, and a log-rank p-value of 0.71. That analysis does not provide strong statistical evidence of a difference in the event-time distributions, but the available information cannot establish that the treatments are equivalent or that any true effect is absent.

The result does not quantify the relative event rate because a hazard ratio and its confidence interval are not reported. It also does not show whether a possible difference would be clinically important. The primary p-value is not a measure of treatment benefit, a probability that the finding is due to chance, or a substitute for an effect estimate with uncertainty. The ranges and medians offer descriptive information, but they cannot show the full timing pattern for every participant.

Secondary outcomes provide additional measurements, not a definitive resolution of the primary comparison. Their sample sizes and methods vary, some sponsor analyses are not listed, and the registry record does not report whether multiplicity was addressed. The unadjusted recalculations are simple comparisons from posted summaries and do not account for analysis procedures that are not documented. Safety summaries likewise count reported events and affected participants; they do not establish causation.

These findings apply to the trial population and outcomes recorded in this study. The registry record does not provide enough detail to assess all analysis assumptions, missing data procedures, or the representativeness of the enrolled participants. The evidence should therefore be understood as an incomplete account of the estimated effects and their precision, not as a treatment recommendation or a definitive statement about effects in other populations.

14. Why This Trial Matters Statistically

This trial is statistically instructive because the primary outcome is a time-to-event measure, while the available registry summary gives medians, ranges, and a log-rank p-value without a hazard ratio or confidence interval. Those quantities answer different questions: medians describe the observed middle event time, while the log-rank test compares event-time patterns. A p-value alone cannot convey the magnitude or precision of a possible difference. The record therefore illustrates why an effect estimate and its uncertainty are important companions to a test result.

The secondary outcomes also demonstrate that sponsor analyses and simple recalculations may not match when their methods differ. A participant-count comparison and a log-rank analysis need not produce the same p-value because they do not necessarily use the same information or target the same feature of the data. Transparent reporting of the analysis method, population, and uncertainty allows readers to distinguish such comparisons rather than treat them as contradictory calculations.

Finally, the record highlights limits on what can be learned from registry results alone. Missing details about the sample-size justification, multiplicity, missing data, censoring, and analysis populations constrain interpretation. Planning illustrations based on observed effects are not evidence of observed power or a reconstruction of the original design. These distinctions matter in clinical research because statistical summaries are most useful when their assumptions and scope are clear.

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 primary comparison has no reported hazard ratio, confidence interval, or group-specific event count. Its median and full range are not enough to reconstruct the magnitude and precision of a relative time-to-event effect. The registry record also does not describe censoring or provide detailed follow-up by group, limiting assessment of the log-rank analysis. Although the outcome population is stated as all enrolled patients, the record does not explain how incomplete follow-up or other missing observations were handled.

Endpoint sample sizes vary. In particular, ventricular refractoriness is reported for 12 participants in the spironolactone group and 13 in the placebo group, whereas the primary outcome groups include 44 and 46. The registry record does not explain why these numbers differ. The smaller endpoint sample means its reported comparison is based on less information, and its estimate should be interpreted with attention to the broad uncertainty interval.

Several reporting details are absent: the study’s sample-size justification, a full analysis plan, multiplicity procedures, analysis populations for every endpoint, and information about interim analyses. The registry does not list sponsor analyses for every named secondary outcome. Serious adverse event term percentages also lack a clearly stated denominator and group-specific breakdown in the record. Finally, the posted secondary recalculations are unadjusted comparisons of summary data; they cannot account for undocumented analysis decisions. These limitations do not invalidate the reported summaries, but they restrict the conclusions that can be drawn from them.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Antiarrhythmic Effects of Spironolactone in Patients With ICDs — NCT04495712.
• Registry record last updated 2020-10-09; status last verified 2020-10.
• Results first posted 2020-09-04.
• 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

NCT04495712 is a completed, randomized, quadruple-masked, parallel-group phase 4 study of spironolactone versus placebo in patients with ICDs. The registry lists 90 participants overall. Its primary endpoint is time to first appropriate ICD therapy for ventricular tachycardia or ventricular fibrillation, followed through study completion, an average of 35 months. The reported medians are 8.8 months for spironolactone and 12.3 months for placebo; the sponsor’s log-rank analysis reports p = 0.71.

The registry also lists secondary outcomes including hospitalization, ventricular refractoriness, health status, patient concerns, and KCCQ, along with adverse-event counts. Several design and analysis details—including the original sample-size justification, missing-data handling, multiplicity procedures, and primary effect estimate with confidence interval—are not reported in the registry record. The posted results therefore support descriptive interpretation, with limited precision about the size of the primary comparison.