Norepinephrine vs Phenylephrine During General Anesthesia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Norepinephrine vs Phenylephrine During General Anesthesia (NCT04789330), a randomized phase 4 study. The primary outcome is Number of Participants With Assigned Vasopressor Given.

2. Clinical Question

The trial also lists postoperative outcomes, including death within 30 days, acute kidney injury, severe acute kidney injury, hospital length of stay, myocardial injury after non-cardiac surgery, adverse cardio-renal events, and rehospitalization within 30 days. These outcomes address clinical events after surgery, whereas the primary endpoint is about whether the assigned vasopressor was administered. The registry record does not report numerical results for the primary endpoint or these secondary outcomes.

The study is described as a pilot pragmatic cluster cross-over randomized trial. In general, a pragmatic trial evaluates an intervention in a setting intended to resemble routine care, while cluster allocation assigns groups rather than individuals and a cross-over design uses different interventions in different periods or groups. The registry record does not report the cluster unit, sequence details, or period-specific results, so the exact allocation and treatment comparisons cannot be reconstructed from this record.

3. Trial Design

VEGA-1 is registered as a randomized, single-masked, cross-over trial and is described in its official title as a pilot pragmatic cluster cross-over randomized trial. The interventions were continuous infusions of norepinephrine or phenylephrine, each designated as the first-line vasopressor. The recorded enrollment is 3626. The trial is listed as phase 4 and completed. Its recorded start date is 2021-07-01, and its primary completion date is 2022-04-01.

The population described in the study summary consists of patients undergoing major surgery under general anesthesia who need vasopressor infusion to maintain systemic arterial pressure. The conditions listed are anesthesia, surgery, and hypotension. The sponsor is the University of California, San Francisco. The record does not state the specific criteria used to determine which patients were eligible, how many were excluded, or how many received each intervention in the primary analysis.

Randomization is intended to reduce systematic differences between treatment groups. In a cluster-randomized study, allocation occurs at a group level, so observations within the same cluster may be more alike than observations from different clusters. A cross-over design involves different interventions across study periods or groups, but the registry record does not specify how clusters were formed, which sequence they followed, how long periods lasted, or whether any washout was used. Those details are important for understanding the trial’s implementation and the analysis needed to account for its design.

The record identifies single masking but does not report who was masked or how masking was maintained. It also does not report the planned sample-size justification, detailed statistical analysis plan, interim analyses, or a breakdown of enrollment by cluster or intervention. Although the registry record describes the trial as a pilot, it does not state the specific feasibility criteria that defined its pilot objectives. The recorded enrollment should therefore be read as a trial-level registry figure, not as evidence about the number included in any particular outcome analysis.

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: To maintain a de-identified dataset, the date of participant enrollment/surgery was not collected. Therefore. the Participant Flow cannot be presented according to the sequence assigned to the sites, as the number of participants enrolled in each site per month was not collected, nor can it be derived. Data are reported according to the total number of participants randomized to NE and PE and sites are not shown as the units assigned to avoid double-counting sites in the Participant Flow.

Overall 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 Number of Participants With Assigned Vasopressor Given, measured over Anesthesia time, up to 24 hours.

The primary endpoint is the number of participants given their assigned vasopressor, with the description specifying that first-line vasopressor administration would be measured as a percentage of eligible participants who received the assigned drug during anesthesia, up to 24 hours. It is therefore an implementation or treatment-delivery measure: it concerns whether the assigned infusion was administered, rather than directly measuring postoperative recovery or a complication.

Such a measure can help assess whether a trial’s assigned treatment was put into practice in the intended setting. In general, documenting treatment delivery is useful when interpreting a pragmatic trial because the effect of assigning an intervention depends in part on whether it was actually received. The endpoint could also indicate whether the study procedures were feasible, although specific feasibility targets are not reported in the registry record.

The registry record does not report the observed number or percentage for this endpoint, the count of eligible participants forming its denominator, or the rules used to classify administration. It therefore does not establish how often either assigned vasopressor was given, how the arms compared on this measure, or whether any difference was statistically distinguishable from chance. The listed timeframe is anesthesia time, up to 24 hours; the record does not describe how exposure outside that window was handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The trial is described as randomized, single-masked, and cross-over, with a pragmatic cluster design stated in its official title. These features shape what a suitable analysis would need to address. The registry record does not give the full statistical plan or enough structural detail to reproduce the sponsor’s analysis.

Why does clustering matter?

In general, cluster randomization assigns groups rather than individual participants. Participants within a group may share clinical practices, staff, or other features, making their outcomes more alike than outcomes from participants in different groups. This within-cluster similarity is called correlation. If it is ignored, a standard individual-level analysis can treat correlated observations as more independent information than they really are and can give misleading measures of uncertainty.

The registry record explicitly cautions that a simple individual-level re-analysis would be misleading because of the cluster-randomized design. Accordingly, an unadjusted reconstruction from the posted summary counts would not be an appropriate substitute for the sponsor’s analysis. The cluster unit, number of clusters, intracluster correlation, and analytic method are not reported in the registry record. Without those details and the sponsor’s outcome estimates, it is not possible to assess how clustering was handled or to reproduce the inferential results.

What does cross-over add?

In general, a cross-over design compares interventions across different periods or sequences, rather than assigning each participant or group to one intervention for the entire study. Such designs can be efficient, but their interpretation depends on the allocation sequence, the timing of periods, and whether effects from an earlier period could carry into a later one. Analyses may need to account for period and sequence as well as the clustered allocation. The registry record does not report the sequences, period lengths, transition procedures, or whether carry-over was assessed. These are unknown design details, not grounds for assuming a particular protocol.

How should a treatment estimate be read?

In general, an effect estimate describes the contrast between treatments for a defined outcome and population. A confidence interval expresses statistical uncertainty around that estimate under the model’s assumptions. Its width is informative about precision, while its position relative to a no-difference value is relevant to statistical compatibility with no effect. A p-value, when reported, addresses compatibility with a null hypothesis under a specified analysis; it does not measure the probability that a treatment is effective. No treatment-effect estimate, confidence interval, or p-value for the primary or secondary outcomes is reported in the registry record.

For binary outcomes, the analysis must specify what counts as an event, the population included, the observation window, and the comparison measure. A count by itself does not provide an adjusted treatment contrast, and counts from clustered groups do not account on their own for within-cluster dependence. The registry record’s safety entries include counts and at-risk values, but do not provide the definitions and analysis details needed to turn them into a reliable inferential comparison.

What do planning calculations mean?

In general, sample-size planning asks how many participants or events might be needed to detect a specified effect under stated assumptions about the significance level, allocation, and statistical model. A planning illustration is conditional on those assumptions; it is not an observed finding and does not establish the study’s actual power after data collection. The planning description associated with the registry record refers to a two-sided significance level of 0.05, equal allocation, a normal approximation, and effect sizes expressed as fractions of the observed effect. It also distinguishes participant-per-arm planning for most outcomes from total-event planning for time-to-event outcomes.

Those planning assumptions do not supply an observed effect estimate or a sample-size justification for the trial’s original design. The registry record does not report the sponsor’s observed effect values or numerical planning outputs. Any such planning values should therefore be understood only as illustrations conditional on their assumptions, not as evidence that the trial was adequately powered or as observed power.

Why can’t a simple recalculation replace the sponsor analysis?

A recalculation from summary data can sometimes reproduce a simple unadjusted comparison, but that approach is not appropriate when the design requires accounting for clustering and cross-over. The record specifically flags this limitation. It also reports no analyzed outcome estimates from which to conduct a recalculation. The sponsor’s own analysis would take precedence over a simple individual-level calculation; however, that analysis is not reported in the registry record. The statistical model, handling of missing observations, analysis population, and any adjustments are likewise not reported. As a result, the registry information supports explanation of the design and its statistical implications, but not a reconstructed estimate of comparative treatment effects.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Norepinephrine", "Phenylephrine")
n      <- c(1809, 1817)
events <- c(1570, 1627)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Norepinephrine  1809  1570  86.8  85.1  88.3  85.1  88.3  85.1  88.3
ARM  Phenylephrine  1817  1627  89.5  88.0  90.9  88.1  90.9  88.1  90.9

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary endpoint and multiple secondary outcomes, but it does not report a statistical analysis plan specifying how hypotheses were ordered or how multiple comparisons were handled. When several outcomes are tested, general statistical practice recognizes that the chance of at least one apparently unusual result can increase if all tests are treated as confirmatory. Methods such as prespecified outcome hierarchies or multiplicity adjustments can address that concern, but whether any were planned or used is not reported in the registry record.

The record does not state how missing outcome data were handled, whether participants were excluded from particular analyses, or how incomplete follow-up was treated. It also does not describe the analysis populations, such as whether the main analysis included all randomized clusters or participants, or whether analyses followed treatment assignment regardless of actual exposure. These details matter because exclusions and missing data can affect both the estimate and its uncertainty.

The registry entry lists the trial as randomized and cluster cross-over, but does not report the sponsor’s statistical model or the population used for each outcome analysis. The record cautions against a simple individual-level re-analysis and identifies the sponsor’s own analysis as the relevant approach. Because numerical sponsor analyses and these methodological details are not reported in the registry record, the completeness and confirmatory status of any outcome comparison cannot be assessed from the record alone.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: mortality (1.2%).

The registry record lists serious adverse event counts of 20 among 1809 at risk for norepinephrine and 22 among 1817 at risk for phenylephrine. It lists other adverse event counts of 168 among 1809 at risk for norepinephrine and 159 among 1817 at risk for phenylephrine. The death counts in the safety group entries are 20 for norepinephrine and 22 for phenylephrine. The top serious adverse event term is mortality, listed at 1.2%.

These figures are descriptive entries, not a reported adjusted comparison. The record does not report event definitions, whether counts represent participants or events beyond the group labels, the timing of safety observation, exposure duration, or an analysis accounting for the clustered cross-over design. The at-risk figures should not automatically be assumed to be the denominator for every listed outcome or to match the population analyzed for the secondary outcome of death within 30 days.

Death counts in the safety record should also be distinguished from the separately listed secondary outcome, number of participants who died within 30 days after surgery. Numerical results for that secondary outcome are not reported in the registry record. The safety entries alone cannot establish a causal difference or comparative risk.

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

The record establishes that VEGA-1 was a randomized pilot pragmatic cluster cross-over trial comparing norepinephrine and phenylephrine as first-line continuous vasopressor infusions during general anesthesia. It specifies a primary endpoint concerning whether the assigned vasopressor was administered and lists postoperative outcomes including death, kidney injury, myocardial injury, length of stay, adverse cardio-renal events, and rehospitalization. These details define the research question and the outcomes the trial intended to examine.

The record does not report the numerical primary endpoint result or results for the listed secondary outcomes. It gives no treatment-effect estimates, confidence intervals, or outcome-specific hypothesis tests. Therefore, it cannot show the direction or magnitude of any difference between the vasopressors, nor how precisely such a difference was estimated. The lack of numerical outcome results in the registry record should not be interpreted as evidence of no difference.

The selected adverse-event counts provide descriptive safety information as recorded, but they do not replace a trial analysis. In particular, the registry does not give the definitions, analysis population, follow-up details, or design-adjusted comparison needed to interpret them as estimates of comparative safety. The listed mortality term and death counts also should not be conflated with a reported result for the specified 30-day mortality outcome.

In general, randomized allocation can support a causal comparison when the study is implemented and analyzed according to its design. Here, the cluster cross-over structure requires appropriate handling of dependence and treatment periods; the registry record itself warns that simple individual-level re-analysis would be misleading. Since the sponsor’s numerical analysis is not reported in the registry record, readers cannot use this entry alone to determine whether either intervention was associated with better postoperative outcomes or more precise estimates. The trial description and outcome definitions are informative, but they are not a substitute for comparative results.

14. Why This Trial Matters Statistically

This trial is statistically notable because its stated design combines cluster randomization with a cross-over structure. Those features affect what counts as independent information and what comparisons are appropriate. A routine analysis that treats every participant as independent could misstate uncertainty when participants share clusters, and a cross-over comparison may need to account for treatment sequence and period. The registry record explicitly warns that a simple individual-level re-analysis would be misleading.

The distinction between treatment delivery and patient outcomes is also important. The primary endpoint concerns receipt of the assigned first-line vasopressor during anesthesia, up to 24 hours. The listed secondary outcomes concern postoperative events and resource use. Together, these address different questions: whether the assigned approach was implemented and what clinical outcomes were recorded. Without numerical outcome results, the relationship between treatment delivery and postoperative outcomes cannot be evaluated.

The registry entry demonstrates why design descriptions and outcome definitions alone are not enough to interpret a clinical trial. A useful statistical account also needs the analysis population, model, handling of cluster and period effects, missing-data approach, and effect estimates with uncertainty. Those details and numerical sponsor results are not reported in the registry record. The record’s selected safety counts can be read descriptively, but cannot by themselves provide a design-aware comparison.

Finally, the trial is described as a pilot, but the registry record does not report the specific feasibility targets or original sample-size justification. Planning illustrations based on an observed effect are not observed power and do not establish what the trial was designed to detect. The statistical significance of the study therefore lies in the questions its design raises about dependence, implementation, and analysis—not in a comparative efficacy conclusion that cannot be derived from the reported results.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record does not report the numerical result for the primary endpoint or the listed secondary outcomes. This prevents assessment of effect size, direction, and precision. The record also does not report confidence intervals, p-values, or the sponsor’s outcome estimates, so statistical evidence for the treatment comparisons cannot be evaluated.

Important details of the cluster cross-over design are absent. The cluster unit, allocation sequences, period lengths, transition procedures, and any assessment of carry-over are not reported in the registry record. The record warns that simple individual-level re-analysis would be misleading, but does not provide the sponsor’s statistical model or sufficient information to reproduce it.

The participant eligibility criteria, analysis populations, missing-data handling, outcome definitions beyond the brief endpoint descriptions, and follow-up completeness are not reported. The record also does not specify who was masked, the original sample-size justification, interim analyses, or the planned approach to multiple outcomes. Because these details affect interpretation, their absence limits assessment of bias, precision, and the status of any outcome comparisons.

The safety entries include counts and at-risk values, but the registry record does not explain their definitions or how they relate to the separate 30-day mortality endpoint. They cannot be treated as a complete account of comparative safety or as an adjusted analysis. These limitations concern what can be established from the registry record and do not, by themselves, indicate that the trial was conducted improperly.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Norepinephrine vs Phenylephrine During General Anesthesia — NCT04789330.
• Registry record last updated 2026-09-01; status last verified 2026-08.
• Results first posted 2025-12-18.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

VEGA-1 is a completed phase 4 randomized trial described as a pilot pragmatic cluster cross-over study. It compared continuous norepinephrine and phenylephrine infusions as first-line vasopressors for patients undergoing major surgery with general anesthesia who needed vasopressor support. Recorded enrollment was 3626. The registry lists the primary endpoint as administration of the assigned vasopressor during anesthesia, up to 24 hours, and lists postoperative outcomes including death within 30 days, acute kidney injury, myocardial injury, length of stay, adverse cardio-renal events, and rehospitalization.

The registry record includes selected adverse-event counts but does not report numerical results for the primary or secondary outcomes, treatment-effect estimates, confidence intervals, or the sponsor’s statistical analyses. It cautions that simple individual-level re-analysis would be misleading because of the cluster-randomized design. The available record therefore describes the trial question and design but does not establish comparative treatment outcomes.