RELieving Increasing oEdema Due to Heart Failure: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for RELieving Increasing oEdema Due to Heart Failure (NCT04142788), a randomized phase 4 study. The primary outcome is "Congestion Index" on Day 60.

2. Clinical Question

3. Trial Design

This was a Phase IV, registry-based, randomized, controlled trial in people with congestive heart failure. The registry record describes a parallel design and lists standard-dose MRA and patiromer with high-dose MRA as the treatment arms. Enrollment is recorded as 19. The status is terminated; the reason for termination is not reported in the registry record.

The study compared standard care with standard care plus patiromer-facilitated use of higher-dose MRA. In the standard-dose arm, titration to guideline-recommended MRA doses was to be attempted. In the patiromer arm, titration could reach 200mg/day spironolactone or the highest licensed dose of eplerenone, 50mg/day. These are descriptions of intended treatment, not evidence of the doses participants received. Actual adherence, treatment changes and achieved doses are not reported in the registry record.

The official title calls the trial open-label, while the registry’s masking field records single masking. Who, if anyone, was masked is not reported in the registry record. Allocation concealment and the randomization procedure are also not reported. The sponsor is NHS Greater Glasgow and Clyde. The recorded start date is 2020-08-26, and the primary completion date is 2022-12-20. The primary outcome timeframe was described as after 400 patients had been evaluated at Day 60. The record states that primary-outcome data were not collected due to early termination. It does not report a completed treatment comparison.

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: 139 participants entered the registry but the trial was stopped because of low recruitment into the run-in phase (due, in part at least, the COVID pandemic), and because of the 19 patients who did enter the run-in phase, despite receiving up to spironolactone 100mg/day or eplerenone 50mg/day, only 4 patients developed a serum potassium \>5.0 mmol/L, which was a requirement to enter the randomised phase of the trial.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Data were not collected due to early termination of the study.

5. Baseline Characteristics

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

6. Primary Endpoint

The registry lists the primary outcome as "Congestion Index" on Day 60, measured over After 400 patients have been evaluated at Day 60.

The primary endpoint was the “Congestion Index” on Day 60. It was intended to assess evidence of congestion and address whether patiromer-facilitated higher-dose MRA improved congestion compared with standard care. The registry record names the measure but does not define its components, scoring rules, direction of benefit, or clinically meaningful change. Those measurement details are not reported in the registry record.

In general, a congestion measure can provide a structured way to assess signs or symptoms associated with fluid congestion. A prespecified assessment time can make treatment groups comparable at a common point, provided the outcome is collected consistently and analyzed as planned. That general rationale does not establish what this trial’s index captured or how it was scored.

The stated timeframe was after 400 patients had been evaluated at Day 60. However, the record says the primary-outcome data were not collected because the study ended early. No values, group estimates, uncertainty intervals or statistical test for the Congestion Index are reported in the registry record. Consequently, the planned endpoint cannot be used to estimate the treatment contrast in this trial.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does randomization contribute?

In general, random assignment is intended to make treatment groups comparable, on average, with respect to factors that could affect outcomes. This supports a causal interpretation of a between-group comparison when allocation is implemented as planned, outcomes are measured appropriately and participants are analyzed according to a suitable prespecified approach. Randomization does not guarantee that groups will be balanced in a small trial, and it cannot compensate for outcomes that were never collected.

The registry record identifies the study as randomized and parallel, but does not report the sequence-generation method, allocation concealment, stratification, or the number assigned to each arm. It also does not report a participant flow accounting for screening, randomization, treatment or follow-up. Thus, the design labels establish the intended structure, but the practical details needed to assess implementation are not available in the registry record.

What would an endpoint comparison mean?

In general, an endpoint comparison would summarize the outcome in each randomized group and estimate the contrast between them. A confidence interval describes the range of effects compatible with the data under the statistical model and its assumptions; it conveys precision as well as the direction and magnitude of an estimate. A p-value, when used, measures how incompatible the observed data are with a specified null hypothesis under the analysis assumptions. Neither a confidence interval nor a p-value replaces the estimated effect or makes an underpowered or biased comparison reliable.

For this trial, the intended endpoint was the Congestion Index on Day 60, but its scale, distribution, summary measure and analysis method are not reported in the registry record. More importantly, the endpoint data were not collected. Without outcome values, no estimate, confidence interval or hypothesis test can be obtained from the posted results. The record reports 0 analyses.

What do the planning assumptions describe?

The registry’s sample-size assumptions are explicitly described as a planning illustration based on the observed effect, not the trial’s own design. They describe a two-sided significance level of 0.05, equal allocation, a normal approximation, and effects defined as stated fractions of the observed effect. In general, a planning calculation asks what sample size would be needed to detect a specified effect under chosen assumptions. It is not evidence that a trial had that sample size, that the assumed effect is true, or that the completed study had a particular probability of detecting an effect.

For this record, the primary outcome was not collected, and the registry does not report a primary effect estimate from which an observed effect could be interpreted. Any planning illustration should therefore be read only as a hypothetical design exercise under its stated assumptions. It is not observed power and does not recover the missing endpoint result. The trial’s actual sample-size justification and statistical plan are not reported in the registry record.

Why might over-dispersion matter in general?

For count outcomes, a statistical model may assume that variability follows a particular relationship to the average count. Over-dispersion means the observed variability is greater than that assumption allows. If ignored, uncertainty can be understated and tests can appear more decisive than the data warrant. A model that accounts for over-dispersion may be appropriate in some settings, depending on the outcome and design. This is a general statistical consideration, not a description of an analysis performed in this trial: the registry record reports no analyses and does not state a count-outcome model.

What can be inferred from the adverse-event summaries?

In general, adverse-event counts and rates are descriptive unless the study design, follow-up, event definitions and analysis support a treatment comparison. A denominator is essential to interpret a rate, and uncertainty can be substantial when few participants are at risk. The registry lists at-risk and affected counts for serious and other events by group, as well as selected serious-event terms with percentages. It does not report comparative safety estimates, confidence intervals, or the denominator and calculation method for those percentages. These entries should not be treated as a formal estimate of treatment effect.

The registry also records zero deaths in each listed group. This is a descriptive count in the submitted safety information, not evidence of no mortality risk or of equal mortality between treatments. Follow-up completeness and the handling of missing safety information are not reported in the registry record. The available entries cannot establish causation, comparative safety or the frequency of unreported events.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a broad set of secondary outcomes: MRA dose, Congestion Index, days dead or hospitalised during the first 60 days, EQ-5D and KCCQ-12 quality of life, NYHA Class, patient global assessment and reduced all-cause mortality. It also records 25 outcome measures. The record does not identify which secondary comparisons were prespecified as confirmatory, how multiple outcomes or time points were to be handled, or whether any multiplicity adjustment was planned. The statistical analysis plan is not reported in the registry record.

In general, testing many outcomes or making repeated comparisons can increase the chance of finding an apparently notable result by chance. Methods for addressing multiplicity can include defining a primary outcome in advance, controlling an overall error rate, or treating secondary findings as exploratory. These are general options; no particular approach can be attributed to this trial from the registry record.

Missing-data handling is also not reported. The primary endpoint statement says data were not collected due to early termination, rather than describing an analysis of partially observed endpoint values. The record does not explain whether secondary or safety information was incomplete, how missing observations would have been handled, or whether sensitivity analyses were planned. It does not report an intention-to-treat, per-protocol or other analysis population. The number randomized and the number contributing to each outcome are not reported in the registry record. Without these details, the extent and consequences of missing information cannot be assessed.

11. 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: acute kidney injury (50.0%), cystoscopy (50.0%), hyponatraemia (6.7%).

The registry reports serious and other adverse-event counts by group. In the run-in and not-randomised group, 15 were recorded at risk for serious events and 2 were recorded as affected; none were recorded at risk for other events, and none were affected. In the standard-dose MRA arm, 2 were recorded at risk for serious events and 1 was affected; 2 were recorded at risk for other events, with none affected. In the patiromer and high-dose MRA arm, 2 were recorded at risk for serious events and 1 was affected; 2 were recorded at risk for other events and 1 was affected. Deaths are recorded as 0 in each group.

The registry lists acute kidney injury at 50.0%, cystoscopy at 50.0%, and hyponatraemia at 6.7% among the top serious-event terms. The denominator and calculation basis for these percentages are not reported in the registry record, so they should not be converted into participant counts or interpreted as group-specific rates. The record does not provide a comparative safety analysis, event timing, severity details beyond the serious-event designation, or an assessment of causality. The small recorded at-risk counts in the randomized arms also mean that the entries offer limited descriptive information, not a precise comparison of harms.

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

The record documents a clinical question of practical interest: whether patiromer could facilitate higher-dose MRA use alongside standard care and improve congestion in people with worsening congestion due to heart failure and hyperkalaemia. It identifies a randomized, controlled, parallel trial and names the planned Day 60 Congestion Index as the primary endpoint. This establishes what the study set out to investigate, not what the treatment comparison found.

The primary endpoint data were not collected because the trial ended early. As a result, the posted results do not show whether congestion changed, whether the groups differed, or how precise any difference might have been. The record does not establish benefit, lack of benefit, equivalence, or harm for the primary question. It also does not report results for the listed secondary outcomes.

The safety entries describe reported counts and selected event terms, but they do not quantify comparative risk or establish that treatment caused an event. Zero recorded deaths in the listed groups is not evidence that mortality risk was absent. No conclusions about treatment safety or effectiveness should be drawn beyond the limited descriptive information in the record.

In general, an inconclusive record due to missing outcome collection is different from a completed trial whose estimates are imprecise or whose findings are compatible with no effect. Here, the central limitation is that the intended primary endpoint is unavailable, rather than that a reported estimate has a wide confidence interval. The reason the study was terminated and whether any unposted results exist are not reported in the registry record. The record therefore leaves the planned clinical comparison unanswered.

13. Why This Trial Matters Statistically

This trial matters statistically because its registry record makes the distinction between a planned endpoint and an observed result especially clear. A primary outcome can be named, a comparison can be randomized and a target timeframe can be described, yet no treatment effect can be estimated if the endpoint data are not collected. The record explicitly states that the Day 60 Congestion Index data were not collected due to early termination.

The record also illustrates why enrollment and outcome availability are not interchangeable. Enrollment is recorded as 19, while the stated primary-outcome timeframe refers to evaluation of 400 patients at Day 60. These entries do not reveal how many participants were randomized, reached the endpoint assessment, or contributed to any analysis. The record reports 0 analyses, and those missing details cannot be reconstructed from the design description.

Finally, the safety information shows the limits of sparse descriptive counts. At-risk counts in the randomized arms are small, and the record gives no comparative estimates or uncertainty intervals. Selected event percentages also lack a reported denominator. Statistical interpretation must distinguish these descriptive entries from a properly quantified treatment contrast. The trial is therefore useful as an example of why registry outcomes, analysis details and participant flow matter when assessing what a trial can support.

14. 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 dominant limitation is that the primary endpoint was not collected. This prevents estimation of the intended Day 60 Congestion Index comparison and leaves the principal clinical question unanswered. The registry status is terminated, but why the trial ended early is not reported in the registry record. The relationship between the recorded enrollment of 19 and the planned evaluation after 400 patients at Day 60 is not explained.

Participant flow and analysis populations are not reported. The number randomized to each arm, the number treated, follow-up completeness, withdrawals and outcome-specific denominators are not available. The record does not report baseline characteristics, achieved MRA doses, adherence, treatment changes or concomitant care. These omissions limit assessment of implementation and comparability, even apart from the missing primary endpoint.

Important methodological details are also absent: the randomization and allocation-concealment methods, the identity of any masked parties, the outcome’s scoring rules, the statistical analysis plan, missing-data procedures, multiplicity handling and sample-size justification are not reported in the registry record. The official title describes the trial as open-label, whereas the masking field records single masking; the record does not explain this difference.

Safety reporting is limited to group counts and selected serious-event terms. The denominator behind the reported percentages, event timing, follow-up completeness and comparative estimates are not reported. The counts do not support a reliable estimate of treatment-related risk. Together, these limitations mean that the registry record describes the intended study more fully than it reports evaluable results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: RELieving Increasing oEdema Due to Heart Failure — NCT04142788.
• Registry record last updated 2025-03-04; status last verified 2024-12.
• Results first posted 2025-03-04.
• 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.

18. Record Summary

The registry record describes RELieving Increasing oEdema Due to Heart Failure, a Phase IV, registry-based, randomized, controlled, parallel trial sponsored by NHS Greater Glasgow and Clyde. It compares standard care, including attempted titration to guideline-recommended MRA doses, with patiromer-facilitated use of higher-dose MRA. Enrollment is recorded as 19, and the status is terminated.

The primary endpoint was the Congestion Index on Day 60, intended to assess evidence of congestion. The planned timeframe referred to evaluation after 400 patients had been assessed at Day 60, but the registry states that primary-outcome data were not collected due to early termination. The record reports 0 analyses. It lists secondary outcomes and adverse-event summaries, but does not report a comparative efficacy result or a comparative safety analysis. The reason for termination and key analysis details are not reported in the registry record.