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 Vitamins in Nitrous Oxide Study (NCT00655980), a randomized na study. The primary outcome is Myocardial Ischemia.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00655980 |
| Phase | NA |
| Condition | Major Surgery, Coronary Artery Disease |
| Allocation | Randomized |
| Design model | Factorial |
| Masking | Quadruple |
| Enrollment | 687 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Washington University School of Medicine |
| Results posted | Yes |
2. Clinical Question
The study asks whether nitrous oxide anesthesia is associated with postoperative cardiac complications among patients with a particular MTHFR genetic profile, and whether vitamin B12 and folic acid given during surgery can prevent that risk. The registry describes major surgery and coronary artery disease as conditions of interest, but eligibility details and the genetic profile required for participation are not reported in the registry record.
Population
Participants undergoing major surgery, in a study concerned with coronary artery disease and MTHFR gene mutations. The registry does not report the enrolled participants’ genetic-profile distribution or further eligibility details.
Intervention
Vitamin B12 and folic acid are listed as a drug intervention. The brief description says the vitamins were given during surgery; dosing and administration details are not reported in the registry record.
Comparator
Nitrous oxide and placebo are listed as a drug intervention, alongside a standard-of-care group. The registry labels the study factorial, but the precise allocation structure and comparisons are not reported in the registry record.
Primary question
Whether postoperative myocardial ischemia, measured during the first 3 postoperative days, differs across the study’s interventions. The registry does not provide a single primary-outcome contrast or an analysis answering that question.
This framing separates the scientific aim from what can be concluded from the registry results. The study description sets out an interest in nitrous oxide, genetic susceptibility, and vitamin prevention, but the posted primary endpoint is myocardial ischemia measured by serial troponin and ECG. Those are related parts of the study’s rationale and outcome assessment, but the registry record does not establish the degree to which its primary endpoint represents every cardiac complication named in the brief description. It also does not report a treatment-effect estimate, confidence interval, or test for the primary endpoint. The clinical question is therefore identifiable; its answer is not available from the posted primary-outcome results.
3. Trial Design
The registry describes a randomized, quadruple-masked, factorial study with 687 participants enrolled. The recorded phase is NA, and the status is COMPLETED. Washington University School of Medicine is listed as the sponsor. The study start is recorded as 2008-02, and primary completion as 2016-12.
Interventions are listed as vitamin B12 and folic acid, nitrous oxide and placebo, and standard of care. The arm descriptions use the labels Treatment, Comparator, and Standard of Care for those interventions. The factorial designation indicates that the registry classifies the design as factorial; however, the allocation structure, the factors and their levels, and the planned comparisons are not reported in the registry record. It would therefore be unwarranted to infer a particular factorial layout or to assume exactly which participants received each combination of interventions.
Randomization means that assignment is intended to use a chance-based process. In general, random assignment can help balance prognostic characteristics across assigned groups, although it does not guarantee balance in any particular trial. Quadruple masking indicates that the registry uses that masking label, but it does not identify which roles were masked or describe how masking was maintained. Those details are not reported in the registry record.
The record lists non-fatal MI as a secondary outcome. It reports two outcome measures and zero analyses. The primary outcome is myocardial ischemia during the first 3 postoperative days, assessed by serial troponin and ECG. The study is marked completed, but completion status alone does not supply an analysis or an answer to the clinical question. The registry does not report protocol-specific details such as allocation concealment, the randomization 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
| Stage | Treatment | Comparator | Standard of Care |
|---|---|---|---|
| STARTED | 276 | 281 | 130 |
| COMPLETED | 250 | 250 | 125 |
| NOT COMPLETED | 26 | 31 | 5 |
Reasons for not completing this period:
| Reason | Treatment | Comparator | Standard of Care |
|---|---|---|---|
| surgery canceled; or subject or anesthes | 26 | 31 | 5 |
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.
| Characteristic | Unit | Treatment | Comparator | Standard of Care | Total |
|---|---|---|---|---|---|
| Participants analysed | 250 | 250 | 125 | 625 | |
| Age, Continuous | years | 64.7 (SD 10.6) | 65.2 (SD 10.7) | 67.6 (SD 10.9) | 65.5 (SD 10.7) |
| Sex: Female, Male: Female | Participants | 92 | 97 | 45 | 234 |
| Sex: Female, Male: Male | Participants | 158 | 153 | 80 | 391 |
| Region of Enrollment: United States | Participants | 250 | 250 | 125 | 625 |
| Smoking history | Participants | 195 | 175 | 94 | 464 |
| Diabetes | Participants | 96 | 88 | 39 | 223 |
| Hypertension | Participants | 200 | 204 | 100 | 504 |
| Chronic renal failute | Participants | 16 | 35 | 16 | 67 |
| on hemodialysis | Participants | 1 | 3 | 1 | 5 |
| Coronary artery disease | Participants | 140 | 148 | 84 | 372 |
| Congestive heart failure | Participants | 27 | 31 | 15 | 73 |
| Peripheral vascular disease | Participants | 81 | 85 | 44 | 210 |
| ASA staging: ASA 1-A normal healthy patient | Participants | 1 | 0 | 0 | 1 |
| ASA staging: ASA 2 A patient with mild systemic disease | Participants | 45 | 42 | 11 | 98 |
| ASA staging: ASA 3 - A patient with severe systemic disease | Participants | 199 | 196 | 106 | 501 |
| ASA staging: ASA 4 -A patient with severe systemic disease tha | Participants | 5 | 10 | 8 | 23 |
| Lee's revised cardiac risk index (Mean | units on a scale | 1.9 (SD 0.8) | 2.0 (SD 0.9) | 2.1 (SD 0.8) | 2.0 (SD 0.8) |
| Plasma total homocysteine mol/L | mcmol/L | 13.5 (SD 5.7) | 13.4 (SD 5.8) | 11.6 (SD 4.2) | 13.1 (SD 5.5) |
6. Primary Endpoint
The registry lists the primary outcome as Myocardial Ischemia, measured over first 3 postoperative days.
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is titled Myocardial Ischemia. Its unit is participants, and the registry describes it as a count of participants. The measurement window is the first 3 postoperative days, with serial troponin and ECG used for assessment. In this context, the endpoint is a participant-level event count, not a continuous measurement of troponin concentration or an ECG score.
In general, a postoperative endpoint can help assess whether evidence of cardiac ischemia occurs during a defined period after an operation. Serial measurements can capture changes over the stated assessment window, while using a participant count expresses the outcome as whether an event was identified for a participant. The registry does not describe the diagnostic threshold, event-adjudication process, handling of discordant tests, or whether different categories or time points were combined into a single event definition.
The registry indicates that this primary outcome has several categories or time points and is not reduced to one comparison. Thus, the endpoint’s general clinical purpose can be described, but a single overall count or treatment contrast cannot be inferred from the record. The posted primary-outcome data do not include a result estimate or analysis that would show how the groups compared.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry identifies a randomized study of vitamin B12 and folic acid, nitrous oxide and placebo, and standard of care, with myocardial ischemia as its primary outcome. The outcome is described as a count of participants assessed by serial troponin and ECG during the first 3 postoperative days. These details clarify what the trial set out to assess, but they do not provide an estimate of the primary outcome across groups.
The registry explicitly indicates that the primary outcome has several categories or time points and is not reduced to one comparison. It reports two outcome measures and zero analyses. No primary-outcome event counts by group, effect estimate, confidence interval, or statistical test are included in the record. Consequently, the registry results do not establish the direction, size, or precision of a primary-outcome difference. A treatment conclusion cannot be drawn from the endpoint description or from the study’s completed status.
The record includes adverse-event counts. In the Treatment group, serious events are listed as 0 among 250 at risk, and other events as 39 among 250 at risk. In the Comparator group, serious events are 3 among 250 at risk, and other events are 61 among 250 at risk. In the Standard of Care group, serious events are 1 among 125 at risk, and other events are 27 among 125 at risk. These are descriptive safety counts as recorded; they are not a substitute for the missing primary-outcome analysis and should not be treated as an adjusted comparison. Death counts are separately listed as 0, 3, and 1 in those groups, respectively. Death is also listed among serious-event terms at 1.2%.
Even when event counts are available, interpretation depends on the outcome definition, follow-up, analysis population, and uncertainty around the comparison. The registry does not report those details sufficiently for a comparative statistical assessment. It also does not provide results by genetic profile, so the stated interest in MTHFR mutations cannot be evaluated from the posted results. The listed adverse-event denominators and counts can be read as recorded, but no causal explanation for differences among groups is reported.
The sample-size material is described as a planning illustration based on an observed effect, rather than the trial’s own design justification. Such illustrations depend on their stated assumptions and are not evidence that the trial had a particular probability of detecting an effect. The registry does not report a protocol-based sample-size justification or an observed-power analysis. Overall, the available record describes the question, design labels, endpoint, and some safety counts, while leaving the principal efficacy comparison and its precision unreported.
9. Statistical Methods Explained
Several statistical ideas help distinguish what the registry describes from what its results can support. General explanations below are not claims about unreported procedures in this trial. The registry record does not report a complete analysis plan, a primary-outcome estimate, or a confidence interval for the primary comparison.
What does randomization contribute?
In general, randomization assigns participants to intervention groups by chance. Its purpose is to reduce systematic differences in baseline characteristics between groups, so that a comparison can more credibly be interpreted as an effect of assignment. It does not ensure that every characteristic is balanced, and it cannot correct problems such as substantial missing outcome data or departures from the intended analysis. The record identifies the allocation as randomized but does not report the randomization sequence method, allocation concealment, or implementation details.
What does factorial design mean?
In general, a factorial design studies more than one intervention factor within one trial structure, allowing specified effects of factors—and sometimes their interaction—to be assessed. The registry labels this study FACTORIAL and lists vitamin B12 and folic acid, nitrous oxide and placebo, and standard of care. However, it does not report the factor structure, assignment combinations, or prespecified contrasts. The label alone is not enough to reconstruct which comparisons were planned or how the results should be pooled. In particular, an interaction analysis should not be assumed merely because a trial is labelled factorial.
How should a participant count be understood?
The primary outcome is a count of participants with myocardial ischemia, rather than a continuous measurement. In general, a binary endpoint records whether each participant did or did not meet an event definition during the stated period. A comparison might report group event counts and denominators, then express the contrast as a risk difference, risk ratio, or odds ratio. Each measure answers a somewhat different question. The registry does not report a single primary comparison, event counts for that endpoint, or an effect measure. No such estimate can be reconstructed from the endpoint description alone.
What does a confidence interval add?
In general, a confidence interval expresses the statistical uncertainty around an estimate under the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, while the interval’s position relative to a null value can help readers assess compatibility with different effect sizes. An interval does not establish that the analysis is unbiased, and it does not replace judgment about the endpoint or study design. No primary-outcome confidence interval is reported in the registry record, so the precision of a primary comparison cannot be assessed.
Why do analysis choices matter?
General statistical interpretation depends on the comparison being estimated, the participants included, the outcome definition, and the treatment of incomplete data. An intention-to-treat analysis generally compares participants according to randomized assignment, while a per-protocol analysis generally restricts attention to participants meeting specified adherence criteria. These approaches can answer different questions and can be affected differently by missingness and protocol deviations. The registry does not report the analysis population, handling of missing outcomes, protocol deviations, or a primary statistical model. Neither analysis approach should be attributed to this study without that information.
How should the planning illustration be read?
The registry describes a planning illustration using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Its target effect is a stated fraction of the observed effect. For time-to-event outcomes, the description says the illustration gives the total number of events using the Schoenfeld method; for other outcomes, it gives participants per arm. These are planning quantities, not observed trial results and not observed power. The illustration is explicitly not the trial’s own design calculation. The record does not report the trial’s sample-size justification, so the planning illustration should not be treated as a description of how enrollment was set.
In general, planning calculations depend on assumptions about the effect to detect, outcome variability or event frequency, allocation, significance level, and statistical model. Changing an assumed effect changes the required amount of information. A calculation based on an observed effect can be especially dependent on that estimate and should be interpreted as an illustration, not as independent confirmation of the effect. No new planning values should be inferred from the assumptions alone.
Why can over-dispersion matter?
General note: over-dispersion arises when count data vary more than a chosen statistical model expects. If a model assumes less variability than the data actually contain, its uncertainty estimates may be too small and statistical tests may be too optimistic. This is a general consideration for some count outcomes, not a reported feature of this trial. The registry describes the primary measure as participants with an event, so no over-dispersion model is specified in the record.
These concepts explain why knowing the design label and outcome title is not enough to reproduce or interpret a trial analysis. The posted record would need to identify the actual contrast, event data, analysis population, missing-data handling, and uncertainty estimate to support a detailed statistical reading of the primary endpoint. Those items are not reported in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The registry indicates that the primary outcome has several categories or time points and is not reduced to one comparison. It also lists non-fatal MI as a secondary outcome and reports two outcome measures, but it does not identify a hierarchy of tests or a method for controlling multiplicity. The statistical plan, including whether any adjustment was planned for multiple outcomes, categories, time points, or comparisons, is not reported in the registry record.
In general, when many statistical comparisons are made, the chance of at least one apparently unusual result can increase. A prespecified testing strategy can distinguish the principal question from secondary or exploratory analyses. This does not mean every multiple-outcome analysis requires the same adjustment; interpretation depends on the questions and analysis plan. Because no analyses are reported and no primary contrast is specified, the record does not permit assessment of how multiplicity was handled.
Missing-data methods and analysis populations are also not reported in the registry record. The record does not say how unavailable troponin or ECG measurements, incomplete follow-up, or other missing endpoint information were handled. It does not report whether analyses followed randomized assignment, used a per-protocol population, or applied another population definition. These omissions matter because the interpretation of a group comparison can depend on who is included and how missing outcomes are treated.
General guidance: missingness can be related to participant characteristics or clinical course, and different assumptions about that process can affect estimates. A statistical method does not remove the need to state the assumptions it makes. Without the endpoint-level participant flow and analysis details, readers cannot determine whether missing data or exclusions could have influenced the primary comparison. The completion status and enrollment total do not supply those missing analysis details.
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 |
|---|---|---|---|
| Treatment | 0 | 250 | 0.0% |
| Comparator | 3 | 250 | 1.2% |
| Standard of Care | 1 | 125 | 0.8% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Treatment | 0 of 250 |
| Comparator | 3 of 250 |
| Standard of Care | 1 of 125 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Treatment | 39 of 250 |
| Comparator | 61 of 250 |
| Standard of Care | 27 of 125 |
Most frequent serious adverse event terms
| Event term | Organ system | Treatment | Comparator | Standard of Care |
|---|---|---|---|---|
| Death | Cardiac disorders | 0 of 250 | 3 of 250 | 1 of 125 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Treatment | Comparator | Standard of Care |
|---|---|---|---|---|
| Readmission | General disorders | 9 of 250 | 23 of 250 | 13 of 125 |
| Wound Infection | Infections and infestations | 15 of 250 | 18 of 250 | 5 of 125 |
| Cardiovascular | Cardiac disorders | 5 of 250 | 11 of 250 | 1 of 125 |
| Deep venous thrombosis | Vascular disorders | 2 of 250 | 5 of 250 | 3 of 125 |
| Bleeding | Blood and lymphatic system disorders | 4 of 250 | 2 of 250 | 2 of 125 |
| Any Pulmonary | Respiratory, thoracic and mediastinal disorders | 3 of 250 | 2 of 250 | 2 of 125 |
| Renal | Renal and urinary disorders | 0 of 250 | 0 of 250 | 1 of 125 |
| Ileus | Gastrointestinal disorders | 1 of 250 | 0 of 250 | 0 of 125 |
Serious events with the highest arm-level rate: death (1.2%).
The registry reports serious and other adverse-event counts by the listed groups. For Treatment, serious events are 0 among 250 at risk, and other events are 39 among 250 at risk. For Comparator, serious events are 3 among 250 at risk, and other events are 61 among 250 at risk. For Standard of Care, serious events are 1 among 125 at risk, and other events are 27 among 125 at risk. The record separately lists deaths as 0, 3, and 1, respectively, and identifies Death among the serious-event terms at 1.2%.
These counts describe what the registry reports; they are not, on their own, an adjusted comparison of safety between interventions. The meaning of the “other” category, the event-collection period, event definitions, and whether participants could contribute more than one event are not reported in the registry record. Counts of participants at risk should not be read as evidence that every participant had identical follow-up or complete ascertainment. The death counts and the listed serious-event term are also distinct record entries; the registry does not explain their relationship further. No causal attribution or statistical test for these safety counts is reported.
12. What the Result Does, and Does Not, Mean
The record establishes that the trial was randomized, quadruple-masked, and labelled factorial, and that it enrolled 687 participants. It identifies myocardial ischemia as the primary endpoint, assessed by serial troponin and ECG during the first 3 postoperative days. It also records vitamin B12 and folic acid, nitrous oxide and placebo, and standard of care as interventions or group labels. Those details describe the trial’s scope and intended assessment, but they are not themselves evidence of a treatment effect.
The posted results do not provide a single primary-outcome comparison. The registry says the endpoint has several categories or time points and is not reduced to one comparison, and it reports zero analyses. Accordingly, the record does not show whether myocardial ischemia differed among the listed groups, in which direction any difference might lie, or how precise a comparison would be. The MTHFR-related question in the brief description also cannot be evaluated: participant genetic-profile results and analyses by genetic profile are not reported in the registry record.
The adverse-event counts offer descriptive information about serious and other events, including the recorded death counts, but do not establish that an intervention caused or prevented an event. The record does not supply the event definitions, comparative model, uncertainty estimates, or analysis populations needed for a fuller safety comparison.
General statistical principle: absence of a reported estimate is not evidence that groups were identical, and a completed trial label does not substitute for results. Conversely, a count in one group cannot by itself establish a difference or explain its cause. The most defensible reading is limited to the study design labels, endpoint description, and adverse-event counts that the registry records. No conclusion about benefit, harm, or the stated clinical hypothesis can be drawn from the primary-outcome information posted in the registry.
13. Why This Trial Matters Statistically
This study brings together several issues that make clinical trial interpretation more demanding than reading a treatment label and an event count. Its question involves nitrous oxide, vitamin B12 and folic acid, postoperative cardiac outcomes, and a stated interest in MTHFR genetic profiles. The registry identifies a factorial design, but does not report enough detail to reconstruct its factors or the contrasts used. That distinction matters: a design label can suggest the general structure of an experiment without specifying the exact statistical questions answered.
The primary endpoint also illustrates the importance of outcome definition. Myocardial ischemia is described as a participant count assessed through serial troponin and ECG during the first 3 postoperative days. Yet the registry notes several categories or time points and does not reduce them to one comparison. A clearly named endpoint is not necessarily a fully interpretable result when its component definitions, event counts, and analysis are absent.
The record further shows why enrollment and completion are not substitutes for statistical results. Enrollment is 687 and status is COMPLETED, but the registry reports zero analyses and no primary-outcome estimate or interval. Without an estimate and its uncertainty, readers cannot assess the magnitude or precision of a group difference. The descriptive adverse-event counts are useful record details, but they do not fill that gap or establish causation.
Finally, the planning illustration is explicitly distinguished from the trial’s own design calculation. Keeping planning assumptions separate from observed evidence prevents a sample-size exercise from being mistaken for a result or for proof that a study could detect a particular effect. This case therefore highlights the need for transparent contrasts, definitions, analysis populations, and uncertainty estimates when interpreting randomized clinical research.
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 available registry record leaves important trial-specific information unreported. Although it labels the study randomized, quadruple-masked, and factorial, it does not describe the allocation structure, randomization procedure, concealment, or which roles were masked. The listed intervention and arm names do not fully specify which combinations participants received or which contrasts were intended.
The primary endpoint is described as a participant count measured by serial troponin and ECG during the first 3 postoperative days, but the record does not state diagnostic thresholds, adjudication procedures, or how its several categories or time points relate to a single event definition. It explicitly does not reduce the primary outcome to one comparison. No primary-outcome group counts, effect estimate, confidence interval, or analysis is reported.
The brief description emphasizes a specific MTHFR genetic profile, but genetic eligibility criteria, the distribution of genetic profiles, and results by profile are not reported in the registry record. The relationship between that stated scientific interest and the posted endpoint results therefore cannot be assessed.
The record also does not report the statistical analysis plan, sample-size justification, analysis population, multiplicity strategy, missing-data handling, participant flow, or protocol deviations. For the adverse-event entries, event definitions, collection periods, and the meaning of the other-event category are not described. These gaps limit both comparative interpretation and assessment of the completeness of outcome ascertainment. The enrollment and completion fields do not resolve those uncertainties, and the planning illustration should not be mistaken for the trial’s own design rationale.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Vitamins in Nitrous Oxide Study — NCT00655980.
- Registry record last updated 2020-10-01; status last verified 2020-09.
- Results first posted 2020-10-01.
- 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
The Vitamins in Nitrous Oxide Study (NCT00655980) is listed as a completed, randomized, quadruple-masked, factorial study sponsored by Washington University School of Medicine. The registry records 687 participants, a study start of 2008-02, and primary completion at 2016-12. Its listed interventions are vitamin B12 and folic acid, nitrous oxide and placebo, and standard of care.
The primary endpoint is myocardial ischemia, recorded as a participant count and assessed by serial troponin and ECG during the first 3 postoperative days. Non-fatal MI is listed as a secondary outcome. The registry states that the primary outcome has several categories or time points and is not reduced to one comparison; it reports two outcome measures and zero analyses. Primary-outcome estimates and the analysis plan are not reported in the registry record. Descriptive serious and other adverse-event counts are listed by group, as are death counts, but they do not provide a comparative primary-outcome result.