This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Levosimendan in Patients With Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery On Cardiopulmonary Bypass (NCT02025621), a randomized phase 3 study. The primary outcome is Number of Dual Efficacy Endpoint Events.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02025621 |
| Phase | Phase 3 |
| Condition | Coronary Artery Bypass Grafting, Mitral Valve Surgery, Low Cardiac Output Syndrome |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 882 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Tenax Therapeutics, Inc. |
| Results posted | Yes |
2. Clinical Question
Population
Adults are not specified in the registry record. The study population is described as subjects with reduced ejection fraction undergoing cardiac surgery requiring cardiopulmonary bypass. The listed conditions include coronary artery bypass grafting, mitral valve surgery, and low cardiac output syndrome. The registry’s primary endpoint population is described as mITT, meaning participants receiving any study drug; additional details about eligibility and the analysis population are not reported in the registry record.
Intervention
Participants assigned to levosimendan received 0.2 µg/kg/min for the first hour, followed by 0.1 µg/kg/min for an additional 23 hours. The study evaluated levosimendan in the setting of cardiac surgery on cardiopulmonary bypass. The record does not give further detail about when the infusion began in relation to surgery.
Comparator
The comparator was placebo, administered at the same listed infusion rates and durations: 0.2 µg/kg/min for the first hour, followed by 0.1 µg/kg/min for an additional 23 hours. The trial was randomized, parallel-group, placebo-controlled, and quadruple-masked.
Primary question
The study’s stated objective was to evaluate levosimendan compared with placebo on a composite event outcome in patients with reduced ejection fraction undergoing cardiac surgery with cardiopulmonary bypass. The brief summary describes all-cause death, perioperative myocardial infarction, new dialysis, or mechanical assistance. The posted primary outcome is titled “Number of Dual Efficacy Endpoint Events” and its description specifies all-cause death at 30 days or use of a mechanical assist device through Day 5. The registry does not report a statistical comparison for the posted primary event counts, so those counts alone do not establish whether the groups differed beyond chance variation.
3. Trial Design
This was a Phase 3, randomized, quadruple-masked, parallel-group trial comparing levosimendan with placebo. The registry lists total enrollment as 882. The primary outcome population is described as mITT, specifically participants receiving any study drug. Posted primary outcome counts are reported for 428 participants in the levosimendan group and 421 in the placebo group; the reason those arm counts do not account for the full enrollment is not reported in the registry record.
The study addressed patients with reduced ejection fraction undergoing cardiac surgery requiring cardiopulmonary bypass. Listed conditions include coronary artery bypass grafting, mitral valve surgery, and low cardiac output syndrome. The levosimendan and placebo infusion schedules were each 0.2 µg/kg/min for the first hour and 0.1 µg/kg/min for an additional 23 hours. The registry does not give further detail about treatment timing, adherence, or co-interventions.
The study started in 2014-07, reached primary completion in 2016-11, and is listed as completed. The registry record lists three secondary outcomes: duration of ICU/CCU stay, incidence of low cardiac output syndrome, and postoperative use of a secondary inotrope. Results are posted for the latter two, while results for duration of ICU/CCU stay are not reported in the registry record. The record lists seven outcome measures but does not report a statistical analysis plan or sponsor-reported analyses.
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
| Stage | Levosimendan | Placebo |
|---|---|---|
| STARTED | 442 | 440 |
| COMPLETED | 428 | 421 |
| NOT COMPLETED | 14 | 19 |
Reasons for not completing this period:
| Reason | Levosimendan | Placebo |
|---|---|---|
| Withdrawal by Subject | 1 | 0 |
| Death | 0 | 1 |
| No longer eligible | 10 | 15 |
| Surgery initiated before infusion | 3 | 3 |
Analysis population for the primary outcome, as defined in the registry: mITT; population receiving any study drug
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: Patients that received any study drug
| Characteristic | Unit | Levosimendan | Placebo | Total |
|---|---|---|---|---|
| Participants analysed | 428 | 421 | 849 | |
| Age, Continuous | years | 65 (59 to 73) | 65 (58 to 72) | 65 (58 to 72) |
| Sex: Female, Male: Female | Participants | 81 | 89 | 170 |
| Sex: Female, Male: Male | Participants | 347 | 332 | 679 |
| Race/Ethnicity, Customized: White/Caucasian | Participants | 385 | 375 | 760 |
| Race/Ethnicity, Customized: Black | Participants | 21 | 23 | 44 |
| Race/Ethnicity, Customized: Asian | Participants | 9 | 10 | 19 |
| Race/Ethnicity, Customized: American Indian or Alaska Native | Participants | 2 | 4 | 6 |
| Race/Ethnicity, Customized: Native Hawaiian or other Pacific Islander | Participants | 1 | 0 | 1 |
| Race/Ethnicity, Customized: Other | Participants | 5 | 7 | 12 |
| Race/Ethnicity, Customized: Not given | Participants | 5 | 2 | 7 |
| Region of Enrollment: Canada | participants | 71 | 88 | 159 |
| Region of Enrollment: United States | participants | 357 | 333 | 690 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Dual Efficacy Endpoint Events, measured over 30 days.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | events |
| Endpoint classification | not reduced to a single comparison |
The primary outcome is titled “Number of Dual Efficacy Endpoint Events.” Its description combines all-cause death at 30 days with use of a mechanical assist device, including IABP, LVAD, or ECMO, through Day 5 after the start of surgery. The device-use description refers to poor cardiac function despite inotropic support and adequate fluid replacement. The registry’s brief summary describes a broader composite that also includes perioperative myocardial infarction and new dialysis. Because the title, brief summary, and detailed primary-outcome description are not identical in scope, readers should distinguish the posted outcome definition from the broader objective wording.
A composite endpoint can capture more than one clinically important event in a single outcome. In general, this can increase the number of observed events available for comparison, but the components may differ in frequency, severity, and interpretation. A count of events does not by itself indicate how many participants experienced an event unless the outcome definition and counting method make that clear. The registry does not explain whether its count represents participants with at least one event or total events, nor does it report component-specific primary outcome results.
The posted primary result is 56 events in the levosimendan arm and 48 in the placebo arm. No confidence interval, p-value, or sponsor-reported comparative analysis is reported in the registry record. Therefore, the posted counts describe the groups but do not establish the size or precision of a between-group effect.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The primary outcome counts are 56 in the levosimendan arm and 48 in the placebo arm, with posted arm sizes of 428 and 421 respectively. These are descriptive counts. The registry does not report an effect estimate, confidence interval, p-value, or other comparative analysis for this outcome. Without those results, the precision of a between-group contrast cannot be assessed from the registry record. The counts should not be treated as evidence of a statistically established difference.
The primary outcome description concerns death at 30 days or mechanical assist device use through Day 5. The brief summary, however, names a wider composite that also includes perioperative myocardial infarction and new dialysis. The registry does not clarify this difference in wording or give separate results for the composite components. This limits how specifically the primary outcome can be interpreted: the posted count cannot be attributed to any one component, and the exact relationship between the stated objective and the posted endpoint is not explained.
Two secondary outcomes have comparative estimates in the registry: low cardiac output syndrome through 5 days and postoperative use of a secondary inotrope within 24 hours. The calculated unadjusted risk-difference intervals for these outcomes exclude zero, and their unadjusted p-values are 0.009 and 0.021. These calculations describe the posted arm counts using unadjusted methods; the registry does not report sponsor analyses for these outcomes. They do not replace the missing primary comparison, and the registry does not report whether secondary outcomes were prespecified as confirmatory or adjusted for multiple testing.
The low cardiac output syndrome comparison is based on 78 participants in the levosimendan arm and 108 in the placebo arm. The secondary inotrope comparison is based on 235 and 264 participants respectively. The estimates are not independent summaries of the primary outcome: they are different outcomes, measured over different timeframes. A secondary outcome can provide context about postoperative care or events, but it does not determine the result of the primary endpoint.
Statistical significance on an unadjusted secondary comparison does not by itself establish a definitive treatment effect. The strength of evidence depends on the analysis plan, the number of outcomes considered, the handling of missing data, and whether results were prespecified. Those details are not reported in the registry record. The registry also does not report a confidence interval or analysis for the duration of ICU/CCU stay, another listed secondary outcome. Overall, the primary endpoint remains descriptively reported, while the two posted secondary comparisons should be read as unadjusted and exploratory in the absence of further analysis details.
9. Statistical Methods Explained
The posted primary outcome is a count-type result rather than a continuous measurement with a reported mean and standard deviation. The registry gives the event count and the number of participants in each arm, but does not provide a comparative estimate or uncertainty interval. A count alone is not a complete statistical comparison: interpretation also depends on how events were defined and counted, the analysis population, and the model or test used. Those details are not reported in the registry record.
What does a confidence interval add?
In general, a confidence interval describes the range of effect estimates compatible with the observed data under a particular statistical method. A narrow interval indicates greater precision than a wide interval, while an interval spanning no difference can be compatible with both little effect and effects in either direction. The secondary comparisons have calculated unadjusted risk differences and intervals, but the registry does not post confidence intervals for the primary outcome. The secondary intervals therefore should not be mistaken for primary-endpoint uncertainty.
How should risk differences be read?
For a binary outcome, a risk difference compares the proportion of participants with the event in one arm with the proportion in the other arm. A negative estimate in these comparisons represents a lower observed event proportion in the levosimendan arm than in the placebo arm under the stated direction of subtraction. The posted risk differences are recalculated, unadjusted summaries from the arm counts. They are not evidence that the trial’s sponsor used the same method, because sponsor-reported analyses are not posted for these outcomes. The registry does not report adjusted analyses or covariate methods.
Risk ratios and odds ratios are alternative ways to express a binary-outcome comparison. A risk ratio compares event proportions as a relative quantity; an odds ratio compares event odds. These measures can communicate a different scale of contrast from an absolute risk difference. In general, relative measures can look different from absolute measures, particularly when event frequencies vary. The registry’s posted recalculations include relative measures for the secondary comparisons, but they remain unadjusted and should be interpreted with their intervals and the trial’s analysis limitations in mind.
What do the p-values mean?
A p-value describes how unusual data at least as extreme as those observed would be under a specified null model and assumptions. It does not give the probability that the null hypothesis is true, nor does it measure clinical importance. The secondary p-values are unadjusted. The registry does not report the test or model used by the sponsor, a prespecified testing hierarchy, or any multiplicity adjustment. The p-values therefore should not be interpreted as confirmatory evidence without those details. No primary-endpoint p-value is reported.
Why does multiplicity matter?
When many outcomes or comparisons are examined, the chance of at least one apparently notable result can increase. Statistical procedures can control that risk, but the registry does not report a multiplicity plan or identify which outcomes were intended to be confirmatory. It lists seven outcome measures, with results described for some outcomes but not all. Without a documented plan, the secondary comparisons are best treated as descriptive and hypothesis-generating rather than as a definitive set of independent tests.
How should the planning illustrations be used?
The sample-size illustrations are based on the observed secondary effects, with equal allocation, a two-sided significance level of 0.05, and a normal approximation. They show participants per arm for 80% or 90% power when planning to detect 100%, 75%, or 50% of the observed effect. For low cardiac output syndrome, the displayed figures are 486 and 651 participants per arm for 100% of the observed effect; 891 and 1,192 for 75%; and 2,062 and 2,760 for 50%. For postoperative secondary inotrope use, the corresponding figures are 624 and 835; 1,102 and 1,474; and 2,459 and 3,292 participants per arm. These are planning illustrations, not observed power and not the trial’s own sample-size justification. The trial’s design assumptions and sample-size rationale are not reported in the registry record.
In general, detecting a smaller effect requires more participants than detecting a larger effect, all else held constant. The illustrations do not establish what effect the trial was designed to detect or whether its actual analysis met a prespecified target. They also do not account for any design features beyond the listed assumptions. No time-to-event planning illustration is relevant to the posted count outcome; the registry does not report a primary time-to-event analysis.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists seven outcome measures, but does not report a statistical analysis plan describing how the primary and secondary outcomes were prioritized or tested. It does not state whether a hierarchy, multiplicity correction, or other control of false-positive findings was planned. The two posted secondary comparisons have unadjusted p-values and are not accompanied by sponsor-reported analyses. Without the prespecified testing strategy, those values should not be treated as a family of confirmatory findings.
Missing-data methods are not reported in the registry record. This includes whether missing outcomes were expected, how participants with unavailable measurements were handled, and whether any imputation or sensitivity analyses were used. The record does not report reasons for the differences between total enrollment and the posted arm sizes, so those differences should not be interpreted as a particular type of exclusion or loss to follow-up.
The primary population is described as mITT, meaning participants receiving any study drug. The registry does not give further detail about the population definition, exclusions after randomization, or whether the secondary outcomes used the same analysis population. The posted arm sizes for the outcomes are 428 for levosimendan and 421 for placebo, but a full participant flow and outcome-specific denominators are not reported.
These omissions matter because analysis choices can affect estimates and uncertainty. In general, excluding participants, handling missing outcomes differently between arms, or testing many outcomes without adjustment can change how results should be interpreted. The registry record does not provide enough information to assess those possibilities. No claim about the intended analysis population, missing-data strategy, or multiplicity handling can be made beyond the details explicitly stated in the record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Levosimendan | 34 | 428 | 7.9% |
| Placebo | 37 | 421 | 8.8% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Levosimendan | 20 of 428 |
| Placebo | 30 of 421 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 2% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Levosimendan | 238 of 428 |
| Placebo | 232 of 421 |
Most frequent serious adverse event terms
| Event term | Organ system | Levosimendan | Placebo |
|---|---|---|---|
| Cardiogenic Shock | Cardiac disorders | 5 of 428 | 5 of 421 |
| Pericardial effusion | Cardiac disorders | 1 of 428 | 6 of 421 |
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | 1 of 428 | 6 of 421 |
| Acute kidney injury | Renal and urinary disorders | 3 of 428 | 3 of 421 |
| Cardiac tamponade | Cardiac disorders | 2 of 428 | 2 of 421 |
| Post procedural haemorrhage | Injury, poisoning and procedural complications | 2 of 428 | 2 of 421 |
| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders | 2 of 428 | 1 of 421 |
| Hypercapnia | Respiratory, thoracic and mediastinal disorders | 1 of 428 | 1 of 421 |
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | 1 of 428 | 1 of 421 |
| Respiratory accidosis | Respiratory, thoracic and mediastinal disorders | 1 of 428 | 1 of 421 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Levosimendan | Placebo |
|---|---|---|---|
| Hypotension | Cardiac disorders | 155 of 428 | 138 of 421 |
| Atrial fibrillation/flutter | Cardiac disorders | 159 of 428 | 134 of 421 |
| Acute kidney injury | Renal and urinary disorders | 49 of 428 | 51 of 421 |
| Ventricular tachycardia/fibrillation | Cardiac disorders | 46 of 428 | 41 of 421 |
| Thrombocytopenia | Blood and lymphatic system disorders | 38 of 428 | 38 of 421 |
| Anaemia | Cardiac disorders | 35 of 428 | 24 of 421 |
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | 22 of 428 | 30 of 421 |
| Leukocytosis | Blood and lymphatic system disorders | 16 of 428 | 23 of 421 |
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | 18 of 428 | 19 of 421 |
| Cardiogenic shock | Cardiac disorders | 17 of 428 | 15 of 421 |
Serious events with the highest arm-level rate: pericardial effusion (1.4%), pleural effusion (1.4%), cardiogenic shock (1.2%), acute kidney injury (0.7%), cardiac tamponade (0.5%).
The registry reports serious adverse events in 34 of 428 participants in the levosimendan group and 37 of 421 participants in the placebo group. It reports other adverse events in 238 of 428 and 232 of 421 participants, respectively, and deaths in 20 and 30 participants. These are descriptive counts; the registry does not provide comparative safety estimates, confidence intervals, or p-values for them. They should not be read as proof of a difference between groups.
The listed serious adverse-event terms and percentages are pericardial effusion, 1.4%; pleural effusion, 1.4%; cardiogenic shock, 1.2%; acute kidney injury, 0.7%; cardiac tamponade, 0.5%; and post procedural haemorrhage, 0.5%. The record does not specify in this summary whether these terms are mutually exclusive, how event attribution was assessed, or whether the percentages use a particular denominator beyond the posted adverse-event reporting.
In general, adverse-event counts depend on definitions, ascertainment, duration of follow-up, and whether participants can contribute more than one event. The registry record does not provide enough detail to compare the safety profiles statistically or to infer causation. The listed figures describe reported events and deaths in the study groups, not a complete account of individual risk.
12. What the Result Does, and Does Not, Mean
The registry records a randomized, placebo-controlled trial of levosimendan in patients with reduced ejection fraction undergoing cardiac surgery on cardiopulmonary bypass. It posts primary outcome event counts for the two arms, but does not report a primary comparative estimate or its uncertainty. As a result, the primary counts alone cannot determine the magnitude, precision, or statistical strength of a between-arm difference.
The two posted secondary comparisons have unadjusted calculated estimates and intervals. They offer information about low cardiac output syndrome and postoperative secondary inotrope use, but the registry does not report sponsor analyses, multiplicity handling, or a hierarchy that would establish these as confirmatory results. A secondary result cannot be substituted for the primary analysis or be used to resolve the primary outcome’s missing inferential statistics.
In general, a trial result is not simply a yes-or-no statement about whether a treatment works. Estimates describe the observed data, intervals describe uncertainty under a method, and study design and analysis choices affect how much confidence can be placed in a conclusion. Here, key statistical details—including the primary comparative analysis, missing-data approach, and analysis plan—are not reported in the registry record. The outcome definition also differs in scope between the brief summary and detailed primary outcome description.
The posted information supports a careful description of the recorded counts and unadjusted secondary calculations. It does not support a definitive claim about the primary endpoint, the overall balance of benefits and harms, or causal explanations for individual events. The absence of reported analysis details is a limit on interpretation, not evidence that an analysis was or was not performed outside the registry.
13. Why This Trial Matters Statistically
This trial is statistically notable because it presents a primary endpoint with arm-level counts but no reported comparative analysis. Readers can see how many events were recorded in each group and the number of participants in each arm, but cannot assess the primary effect estimate or its precision from the registry record. This illustrates why descriptive counts and an inferential comparison answer different questions.
The endpoint wording also matters. The brief summary describes a composite involving death, perioperative myocardial infarction, new dialysis, and mechanical assistance, whereas the detailed primary outcome description specifies death at 30 days or mechanical assist device use through Day 5. A clear, consistent definition is important for interpreting what a composite result represents and how well it matches the study objective. The registry does not explain the difference in scope or provide component-level results.
The record also includes secondary recalculations and planning illustrations. These show how interpretation depends on the measure chosen, the uncertainty around an estimate, and the assumptions used for planning. The illustrations are not the study’s original sample-size justification and do not amount to observed power. Because the analysis plan and multiplicity approach are not reported, unadjusted secondary results require particular caution.
More broadly, registry entries can contain useful trial design and outcome information while still leaving essential analytical questions unresolved. Distinguishing posted counts, recalculated unadjusted comparisons, and sponsor-reported analyses helps prevent descriptive results from being mistaken for definitive evidence. The record’s limitations are central to the statistical interpretation, not merely administrative details.
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.
Several limitations are specific to the information recorded for this trial. The primary outcome is reported as a count, without a comparative effect estimate, confidence interval, p-value, or component-specific results. The outcome title, brief summary, and detailed definition do not describe exactly the same composite. The registry does not explain how that difference should be reconciled or whether the posted count represents participants with events or total events.
The registry lists an mITT population receiving any study drug, but does not provide a detailed participant flow, an explanation for the posted arm sizes relative to total enrollment, or outcome-specific missing-data information. It does not report the primary analysis method, the statistical plan, the sample-size justification, or the sponsor’s analyses. The two available secondary comparisons are unadjusted recalculations, and multiplicity handling is not reported.
One listed secondary outcome, duration of ICU/CCU stay, has no result reported in the registry record. The record also does not provide enough detail about outcome definitions, event adjudication, timing of treatment relative to surgery, adherence, or co-interventions to evaluate those features. These gaps limit the interpretation of both efficacy outcomes and adverse-event counts.
Finally, the safety information is descriptive and does not include comparative uncertainty estimates. The event counts and listed serious-event terms cannot establish whether observed differences are statistically reliable or attributable to treatment. These limitations concern what can be concluded from the registry record; they do not establish that the underlying trial lacked additional analyses or documentation.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Levosimendan in Patients With Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery On Cardiopulmonary Bypass — NCT02025621.
- Registry record last updated 2018-06-21; status last verified 2018-05.
- Results first posted 2018-05-22.
- 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.
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18. Record Summary
NCT02025621 is a completed Phase 3 randomized, quadruple-masked, parallel-group study sponsored by Tenax Therapeutics, Inc. It compared levosimendan with placebo in patients with reduced ejection fraction undergoing cardiac surgery requiring cardiopulmonary bypass. Enrollment was 882; the study started in 2014-07 and reached primary completion in 2016-11.
The primary outcome is reported as a count of dual efficacy endpoint events, with 56 in the levosimendan arm and 48 in the placebo arm. The registry does not report a statistical comparison for this outcome. Results and unadjusted recalculations are available for low cardiac output syndrome and postoperative use of a secondary inotrope; duration of ICU/CCU stay is listed without a result.
The registry does not report the statistical analysis plan, missing-data methods, multiplicity approach, or sponsor-reported analyses. The primary endpoint wording also varies between the brief summary and detailed outcome description. These omissions constrain interpretation of both the primary and secondary findings.