Safety and Cardiovascular Efficacy of Hydralazine and Isosorbide Dinitrate in Dialysis-Dependent ESRD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Cardiovascular Efficacy of Hydralazine and Isosorbide Dinitrate in Dialysis-Dependent ESRD (NCT02228408), a randomized phase 4 study. The primary outcome is Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death.

2. Clinical Question

3. Trial Design

This was a Phase IV, randomized, parallel-group study at a single center. The official title calls it double-blind and active-controlled, while the masking field records quadruple masking and the listed comparator intervention is placebo. These descriptions are not identical: the registry identifies the medication and placebo as the two interventions, but does not explain the difference between the title’s wording and the masking entry. The record does not report which groups of people were included in the quadruple masking.

The study enrolled 17 participants and is marked completed. Its recorded start date is 2017-08-28, and its primary completion date is 2019-05-07. The brief summary describes a 26-week comparison; the primary outcome timeframe is recorded as 6 months. These are the registry’s stated duration descriptions, and the record does not provide further detail about how the assessment visits aligned with them.

Participants were assigned to hydralazine/isosorbide dinitrate or placebo. In the medication arm, doses were to be titrated between weeks 0-4 and could be decreased as necessary for adverse events. The target dose is stated as 40 mg of ISD and 75 mg of Hydralazine 3x/daily. The arm description’s list of allowable dosage forms is incomplete in the registry record, so it does not support a fuller account of the dosing schedule. The placebo description also refers to titration and possible dose decreases.

The stated aims include safety and cardiovascular effects, with secondary outcomes listed as changes in circulating fibrosis markers, angiogenesis markers and LVMI. The record lists 7 outcome measures and 4 analyses, but the details of the analyses are not reported in the registry record. It also does not report the allocation procedure, the sample-size justification or the statistical analysis plan.

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: intent to treat

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 Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death, measured over 6 months.

The primary outcome is described as the rate of hypotension, serious adverse events, gastrointestinal events and cardiovascular death. It is recorded as a count of participants, with a 6 months timeframe and an intent-to-treat population. This outcome brings together safety events and cardiovascular death rather than measuring a single biological marker or a direct measure of cardiac function.

Safety outcomes are used to describe the occurrence of unwanted events during a trial. Counting participants affected can help indicate how many people experienced an event, while a rate requires a defined time basis or denominator. The registry’s primary outcome title refers to a rate, but its measure is recorded as a participant count. The record does not report separate primary results for each listed category or a single combined primary comparison. It also does not specify how participants experiencing more than one category were handled in a combined outcome.

The trial summary mentions cardiovascular effects, but the stated primary endpoint is a safety composite, not a direct test of improvement in heart function or blood flow. Secondary outcomes include changes in fibrosis markers, angiogenesis markers and LVMI; their results are not reported in the registry record. Accordingly, the primary endpoint description identifies what the investigators intended to monitor, but the posted information does not establish the comparative result for that endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods are tools for converting observations into estimates and for describing the uncertainty around those estimates. In a randomized trial, the planned comparison is between groups assigned to different interventions. Randomization can help balance known and unknown characteristics on average, but it does not remove the need to report the outcomes, analysis choices and uncertainty. For this study, the registry identifies randomized allocation and parallel groups; the detailed randomization procedure and analysis plan are not reported in the registry record.

What do participant counts describe?

A participant count records how many people met a specified outcome definition. A count is not automatically a rate: a rate needs a meaningful denominator, and often a defined period of observation. Counts can be useful for a small study because they make the observed event burden visible, but they do not by themselves quantify how compatible the observations are with a range of possible underlying effects. The primary outcome is called a rate and recorded as a count of participants, so the registry description leaves uncertainty about the precise analysis scale and calculation.

The adverse-event entries distinguish participants at risk from participants affected. Those values describe the posted group-level counts, but the registry record does not provide definitions for the category labels beyond its terms, nor does it explain how repeated events in the same participant were counted. A participant-level count and an event-level count answer different questions: the former concerns people with an event, while the latter can include multiple events for a person. The record does not provide enough detail to reconstruct event-level analyses.

Why does uncertainty matter?

An estimate from a trial is subject to sampling variation: another group of participants could produce different observed counts even if the underlying conditions were unchanged. A confidence interval is a general statistical way to show a range of effect values compatible with the data under a specified method. Wider intervals indicate less precision. The registry record does not report confidence intervals for the safety counts or a comparative primary-outcome estimate. Without an estimate and its uncertainty, the reader cannot judge the precision of a treatment contrast from these counts alone.

A significance test, when planned and reported, evaluates how inconsistent the observed data are with a specified statistical model and null hypothesis. A p-value is not the probability that the treatment works, and it does not measure clinical importance. No primary comparison or p-value is reported in the registry record. It would therefore be inappropriate to infer statistical significance from the counts or from the trial’s completion status.

What can randomization and masking contribute?

Random assignment is intended to make intervention groups comparable in expectation, reducing systematic differences in treatment assignment. In a small pilot trial, chance imbalances can still occur. Masking is intended to limit the influence of knowledge about assignment on care, reporting or assessment. The record describes the study as double-blind in its official title and records quadruple masking in the masking entry, but does not define who was masked or how masking was maintained. These design labels do not substitute for reported outcome estimates.

Why can sparse event data be difficult to interpret?

When event counts are limited, estimates can be unstable and uncertainty can be substantial. Methods designed for large samples may not perform well in every sparse-data setting, depending on the outcome and analysis. The registry does not state what method was used for the adverse-event comparisons, so no method-specific claim can be made. More generally, over-dispersion occurs when observed variation is greater than a model assumes; it can make standard errors too small if ignored. This is a general concept, not a documented feature of this trial, and the record does not report an over-dispersion assessment.

What is a composite outcome?

A composite endpoint combines several distinct outcomes into a summary, often to capture a broader clinical domain. Its interpretation depends on the component definitions, whether each component is weighted equally, how multiple components in one participant are treated, and whether the components differ in importance or frequency. Here the primary endpoint lists hypotension, serious adverse events, gastrointestinal events and cardiovascular death. The registry record does not give a combined result or explain the handling of participants with multiple categories, so the component list alone does not establish how the composite was analyzed.

What does an intent-to-treat population mean?

In general, intent-to-treat analysis aims to analyze participants according to their randomized assignment, regardless of treatment received after assignment. This preserves the comparison created by randomization and reflects assignment to a treatment strategy. The primary outcome population is labeled intent to treat, but the registry record does not report participant flow, missing outcome handling, deviations from assigned treatment or whether every randomized participant contributed to each analysis. The label alone does not settle those details.

How should planning illustrations be read?

Sample-size calculations based on an observed effect are planning illustrations, not evidence that the trial had a particular power after the fact. Their interpretation depends on assumptions, including the selected effect size, significance level, allocation, and statistical approximation. The registry describes planning assumptions based on the observed effect, two-sided significance level 0.05, equal allocation, and a normal approximation. It also distinguishes participant-per-arm quantities from total event quantities for time-to-event settings. Those assumptions do not replace the trial’s own design justification, which is not reported in the registry record. The illustration is not observed power and should not be used as a result of the trial.

10. Multiplicity, Missing Data and Analysis Populations

The primary endpoint names multiple categories: hypotension, serious adverse events, gastrointestinal events and cardiovascular death. The registry record notes that the primary outcome has several categories or time points and was not reduced to one comparison. It does not report a prespecified hierarchy among those categories, a combined primary result, or a multiplicity adjustment. When several outcomes or comparisons are examined, the chance of at least one apparently notable result can increase; methods that control multiplicity can address that issue, but no such method is documented.

The record lists 7 outcome measures and 4 analyses, with secondary outcomes including circulating fibrosis markers, angiogenesis markers and LVMI. It does not report which analyses correspond to each measure, which were prespecified, or how the results were interpreted across the set. The statistical analysis plan is not reported in the registry record. Consequently, the posted information does not establish which analyses were confirmatory and which, if any, were exploratory.

The primary population is labeled intent to treat, but participant flow and missing-data handling are not reported in the registry record. There is no account of withdrawals, unavailable measurements, adherence, treatment discontinuation or the approach used for missing outcome values. The adverse-event counts include group-specific numbers at risk, but the record does not explain whether all randomized participants were followed for the full timeframe or how exposure time was handled. These omissions limit assessment of the completeness and comparability of the outcome data.

The enrollment total and the at-risk counts are posted, but the record does not explain the participant accounting across outcomes. It is therefore not possible to determine from the registry record whether the same analysis population was used for each result or how exclusions were handled.

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: nausea (14.3%), vomitting (14.3%), cv hospitalization (14.3%), fall (14.3%), gi bleeding (14.3%).

The posted serious-event figures are 5 affected participants among 7 at risk in the hydralazine/isosorbide dinitrate group and 3 affected among 10 at risk in the placebo group. The record also lists other adverse-event figures: 7 affected among 7 at risk in the medication group and 10 affected among 10 at risk in the placebo group. These are descriptive participant counts, not adjusted estimates of comparative risk. The record does not define the distinction between the serious and other-event categories in further detail.

Zero deaths are recorded in both groups. This is the count posted for the trial, not proof that a treatment eliminates the possibility of death. The serious-event terms listed include nausea, vomiting, cardiovascular hospitalization, fall and gastrointestinal bleeding at 14.3% each, and arteriovenous fistula thrombosis at 10.0%. The registry record does not state the denominator for these percentages or clarify whether terms refer to distinct participants or events. They should not be summed or treated as independent outcomes.

Safety comparisons require attention to how long participants were observed, how events were defined and whether people could contribute more than one event. Those details are not reported in the registry record. The small enrollment also means that the posted counts describe this trial’s participants, without establishing a precise estimate for a broader population.

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

The posted information establishes that this completed pilot trial compared hydralazine/isosorbide dinitrate with placebo in people receiving chronic hemodialysis, and that it recorded participant counts for serious and other adverse events. It also records zero deaths in both groups. These observations describe the trial record; they are not a definitive estimate of treatment effects or a complete account of the primary safety endpoint.

The primary outcome includes several categories, but the registry record does not report a single combined result or separate results for each category. It also does not provide a comparative effect estimate with an uncertainty interval. The serious-event counts therefore cannot answer the full primary question on their own. The percentages listed for serious-event terms have no reported denominator, and the record does not clarify how multiple events or terms within a participant were counted.

The record’s trial summary states the investigators’ hypothesis that the combination would be safe and would improve heart function and blood flow or blood-vessel supply. A hypothesis expresses what a study set out to examine; it is not evidence that the intended effect occurred. Results for cardiac structure and function, circulating fibrosis markers, angiogenesis markers and LVMI are not reported in the registry record. The information available does not establish cardiovascular efficacy.

Nor does the absence of a posted comparative analysis mean that the treatments are equivalent. Establishing equivalence or ruling out meaningful differences requires a suitable design and a sufficiently precise estimate, with a prespecified margin where appropriate. The registry record does not report such an analysis. Similarly, zero deaths in each group does not demonstrate an absence of risk; it is a descriptive count within this trial.

The appropriate interpretation is therefore limited: the record documents a randomized pilot design and a set of adverse-event counts, while leaving the primary comparison, uncertainty, missing-data handling and cardiovascular outcome results unresolved. Conclusions beyond those descriptive points are not supported by the registry record.

13. Why This Trial Matters Statistically

This trial is statistically important as an example of the gap between a stated clinical question and the information needed to interpret its answer. The record describes a randomized pilot study in a defined clinical setting, but its primary endpoint combines several types of safety events and cardiovascular death. Without a reported combined result, component-specific results or a clear analysis description, the endpoint cannot be interpreted as a single comparative estimate.

The posted counts also illustrate why raw participant counts and rates should not be treated as interchangeable. The registry calls the primary outcome a rate but records it as a count of participants. Understanding the result would require clear denominators, observation time, outcome definitions and rules for repeated or overlapping events. The available adverse-event terms include percentages, yet their denominators are not reported in the registry record.

Small pilot studies can be useful for describing feasibility, observing potential safety issues and informing later research. They usually provide limited precision for comparative estimates, particularly when outcomes are uncommon or multiple outcomes are considered. This is a general statistical consideration, not a reported analysis of this trial. The enrollment of 17 participants makes it especially important to distinguish descriptive observations from evidence that can support precise population-level conclusions.

The record’s omissions also matter for reproducibility. Details about the statistical analysis plan, participant flow, missing data, multiplicity and uncertainty estimates are not reported in the registry record. Such information allows readers to understand how outcomes were defined, whether analyses followed the plan and how much uncertainty surrounds the results. The trial’s stated cardiovascular aims therefore remain distinct from the results that can be interpreted from the posted record.

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 principal limitation of the available record is that it does not report a single primary-outcome comparison, despite listing a composite of hypotension, serious adverse events, gastrointestinal events and cardiovascular death. It also does not provide separate primary results for each category. The posted adverse-event counts cannot fill that gap, because the registry does not establish that they correspond to every component or to the primary analysis.

The trial enrolled 17 participants, and the posted group counts are small. This limits how precisely the counts can characterize comparative safety. No confidence intervals or statistical tests for the primary comparison are reported. The registry record also does not provide the sample-size justification, so the intended precision or rationale for the enrollment target cannot be assessed.

Outcome definitions and event accounting are incomplete. The record does not specify how overlapping categories, repeated events, observation time or changes in exposure were handled. The denominators for the listed serious-event percentages are not reported. Participant flow, withdrawals, missing measurements and missing-data methods are also not reported in the registry record.

The official title describes the study as double-blind and active-controlled, while the masking entry says quadruple and the listed comparator is placebo. The record does not explain these differences. It also does not report the allocation procedure or who was masked. These details limit evaluation of how the design was implemented.

Finally, the registry lists secondary outcomes related to cardiac structure, function and biomarkers, but their results are not reported. The posted information therefore cannot support interpretation of the trial’s cardiovascular efficacy aims, and it does not establish how multiple outcomes were handled statistically.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Cardiovascular Efficacy of Hydralazine and Isosorbide Dinitrate in Dialysis-Dependent ESRD — NCT02228408.
• Registry record last updated 2021-04-27; status last verified 2021-03.
• Results first posted 2021-04-27.
• 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 identifies NCT02228408 as a completed Phase IV randomized, parallel-group, single-center study in people with chronic hemodialysis-dependent ESRD. It records enrollment of 17 participants and compares hydralazine/isosorbide dinitrate with placebo. The brief summary describes a 26-week pilot; the primary outcome timeframe is 6 months.

The primary outcome concerns hypotension, serious adverse events, gastrointestinal events and cardiovascular death, with an intent-to-treat population. The record posts serious and other adverse-event counts and records zero deaths in each group. It does not report a single combined primary comparison, uncertainty estimates, or results for the listed cardiovascular and biomarker outcomes.

The record describes the investigators’ safety and cardiovascular hypotheses, but those hypotheses are not findings. Details of the statistical analysis plan, sample-size justification, participant flow, missing-data handling and multiplicity methods are not reported in the registry record.