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 A Study in Participants With Acute Major Bleeding to Evaluate the Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Direct and Indirect Oral Anticoagulants (Extension Study) (NCT02329327), a na phase 3 study. The primary outcome is Percent Change From Baseline In Anti-fXa Activity By FXa Inhibitor.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02329327 |
| Phase | Phase 3 |
| Condition | Bleeding |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 479 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Alexion Pharmaceuticals, Inc. |
| Results posted | Yes |
2. Clinical Question
Population
Participants had acute major bleeding while receiving a factor Xa inhibitor: apixaban, rivaroxaban, edoxaban, or enoxaparin. The primary efficacy population was narrower than everyone enrolled: participants had to receive any amount of andexanet, meet clinical bleeding criteria, and have an anti-factor Xa level meeting the specified threshold for their drug. The thresholds were ≥75 nanograms/milliliter for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin.
Intervention
Participants received andexanet as an intravenous bolus administered over approximately 15 to 30 minutes, followed immediately by a continuous infusion administered over approximately 120 minutes.
Comparator
The study is recorded as single-group, with no masking and no randomized allocation. The registry lists low-dose and high-dose andexanet safety groups, but does not identify a control group. These dose groups are not a like-for-like control comparison.
Primary question
The primary endpoint asks how much anti-factor Xa activity changed from baseline by factor Xa inhibitor, expressed as a percent reduction. Baseline was the last measurement before the andexanet bolus; the reduction was based on the on-treatment nadir between the end of the bolus and the end of the infusion. The registry record does not report the numerical primary endpoint results, so the size and precision of the observed reduction cannot be assessed from this record.
3. Trial Design
The registry describes a phase 3, prospective, open-label, single-group study of andexanet alfa in participants receiving a factor Xa inhibitor who had acute major bleeding. The official title identifies the study as ANNEXA-4. The stated purpose was to evaluate hemostatic efficacy and safety. Enrollment was 479. The record lists the study as completed, with a start date of 2015-04-10 and a primary completion date of 2020-09-24.
All participants received andexanet; there was no randomized comparator and masking was none. The recorded intervention was an intravenous bolus followed immediately by a continuous infusion. The registry describes the bolus as administered over approximately 15 to 30 minutes and the infusion over approximately 120 minutes. It lists low-dose and high-dose groups for safety reporting, but does not report how participants were assigned to those groups. Because the design is single-group, the dose groups should not be read as equivalent to randomized treatment and control arms.
The primary outcome was percent change from baseline in anti-factor Xa activity, reported by factor Xa inhibitor. The record defines baseline as the last value obtained before the bolus and defines the on-treatment nadir as the minimum value between the end of the bolus and the end of the infusion. The outcome description also gives a timeframe of baseline and 12 hours post infusion. The record does not report the numerical primary outcome results or the statistical analysis used to summarize them.
Eligibility for the efficacy population required receipt of andexanet, clinical bleeding criteria, and an anti-factor Xa level meeting the drug-specific thresholds stated in the clinical question. Thus, the efficacy population was defined by treatment, clinical status, and laboratory measurement, rather than simply by enrollment. The registry record does not report how many participants met these criteria or how many contributed to the primary endpoint 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.
Overall Study
| Stage | Andexanet | Andexanet - Additional Participants |
|---|---|---|
| STARTED | 477 | 2 |
| Received At Least 1 Dose of Study Drug | 477 | 2 |
| Efficacy Population | 347 | 2 |
| Death | 3 | 0 |
| COMPLETED | 392 | 2 |
| NOT COMPLETED | 85 | 0 |
Reasons for not completing this period:
| Reason | Andexanet | Andexanet - Additional Participants |
|---|---|---|
| Death | 78 | 0 |
| Withdrawal by Subject | 3 | 0 |
| Lost to Follow-up | 4 | 0 |
Analysis population for the primary outcome, as defined in the registry: Efficacy Population: all participants who received any amount of andexanet, met clinical bleeding criteria, and had an anti-fXa level of ≥75 nanograms/milliliter (ng/mL) for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 international units (IU)/mL for enoxaparin.
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: Safety Population: all participants who received any amount of andexanet.
| Characteristic | Unit | Andexanet | Andexanet - Additional Participants | Total |
|---|---|---|---|---|
| Participants analysed | 477 | 2 | 479 | |
| Age, Continuous | years | 77.9 (SD 10.66) | 71.0 (SD 11.31) | 77.9 (SD 10.66) |
| Sex: Female, Male: Female | Participants | 218 | 1 | 219 |
| Sex: Female, Male: Male | Participants | 259 | 1 | 260 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 16 | 0 | 16 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 449 | 2 | 451 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 12 | 0 | 12 |
| Race/Ethnicity, Customized: Race : White | participants | 414 | 0 | 414 |
| Race/Ethnicity, Customized: Race : Black or African American | participants | 29 | 0 | 29 |
| Race/Ethnicity, Customized: Race : Other | participants | 25 | 2 | 27 |
| Race/Ethnicity, Customized: Race : Missing | participants | 9 | 0 | 9 |
| Region of Enrollment: North America | participants | 212 | 0 | 212 |
| Region of Enrollment: Europe | participants | 248 | 0 | 248 |
| Region of Enrollment: Japan | participants | 17 | 2 | 19 |
| FXa Inhibitor: Apixaban | Participants | 245 | 0 | 245 |
| FXa Inhibitor: Rivaroxaban | Participants | 174 | 2 | 176 |
| FXa Inhibitor: Edoxaban | Participants | 36 | 0 | 36 |
| FXa Inhibitor: Enoxaparin | Participants | 22 | 0 | 22 |
| Bleed Type: Gastrointestinal | Participants | 109 | 0 | 109 |
| Bleed Type: Intracranial Hemorrhage | Participants | 329 | 2 | 331 |
| Bleed Type: Other | Participants | 39 | 0 | 39 |
6. Primary Endpoint
The registry lists the primary outcome as Percent Change From Baseline In Anti-fXa Activity By FXa Inhibitor, measured over Baseline, 12 Hours (post infusion).
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | 95% Confidence Interval |
| Unit | Percent Change |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint measures the percent reduction in anti-factor Xa activity from baseline, reported separately by factor Xa inhibitor. Anti-factor Xa activity is a laboratory measure used in this study to assess the anticoagulant effect of factor Xa inhibitors. The endpoint is therefore a pharmacodynamic measure: it describes a change in a laboratory value after andexanet administration, rather than directly counting clinical bleeding outcomes.
Baseline was defined as the last anti-factor Xa measurement before the andexanet bolus. The reduction was calculated using the maximum change from baseline, corresponding to the minimum on-treatment value between the end of the bolus and the end of the infusion, relative to the baseline value. The registry gives the primary timeframe as baseline and 12 hours post infusion. It specifies that the planned summary was a median with a 95% confidence interval.
In general, a laboratory endpoint can help characterize whether a biological measure changes over the treatment period. The median describes the middle of the observed values and is less influenced by unusually high or low values than the mean. A confidence interval conveys uncertainty around the estimated median under the method used; it does not show the spread of individual participant measurements. The numerical median and confidence interval for the primary endpoint are not reported in the registry record, so neither the magnitude of change nor its precision can be described from this record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry describes a single-group study in which participants with acute major bleeding received andexanet. It identifies percent change from baseline in anti-factor Xa activity by factor Xa inhibitor as the primary endpoint and describes how baseline and the on-treatment nadir were defined. However, the registry record does not report the numerical primary endpoint results. There is therefore no posted median or confidence interval from which to characterize the size or precision of the laboratory change.
The endpoint is a laboratory measure, not a direct count of bleeding control. The study summary states that hemostatic efficacy was evaluated, and a secondary outcome is described as percent change from baseline in anti-factor Xa activity by hemostatic efficacy. But the record does not provide numerical results for that secondary outcome or a clinical hemostatic efficacy result. The registry record also reports no analyses. It is not possible to assess from this information whether the laboratory endpoint changed in the observed participants, how consistently it changed, or how that change related to clinical bleeding outcomes.
The design affects what can be inferred. Because this was a single-group study without randomized allocation or a control group, its observed changes would not by themselves establish what would have happened to similar participants without andexanet. General statistical interpretation: a control group can help distinguish changes associated with an intervention from changes related to the underlying illness, other care, or the passage of time. This registry record does not supply a concurrent control comparison.
The record lists serious adverse event counts separately for low-dose and high-dose andexanet groups, along with deaths and other adverse events. These are descriptive counts. The record does not identify randomized assignment to dose groups, so differences between the groups cannot be treated as causal estimates of dose effects. The counts also do not, on their own, establish how the event experience compares with an untreated or alternative-treatment group.
The appropriate reading is therefore limited to what the record documents: a completed, open-label, single-group study; a defined laboratory endpoint; and descriptive safety counts. The record does not support a numerical interpretation of the primary endpoint or a controlled estimate of treatment effect. No conclusion about clinical benefit or lack of benefit follows from the absence of those results in the registry record.
9. Statistical Methods Explained
The registry defines the primary endpoint as percent change from baseline in anti-factor Xa activity, analyzed by factor Xa inhibitor. It specifies a median and a 95% confidence interval as the summary measures. The record describes a reduction from baseline to the on-treatment nadir, with baseline taken as the last value before the andexanet bolus and the nadir defined as the minimum between the end of the bolus and the end of the infusion.
What does the median describe?
General statistical explanation: the median is the central value when observations are ordered. Half of the observed values lie at or below it and half at or above it, subject to ties. It is often useful for data that are not symmetrically distributed or that contain unusually extreme observations. In this study, the registry says the percent change was summarized by a median. The numerical median is not reported in the registry record, so the direction and size of the observed result cannot be stated.
What does a confidence interval add?
General statistical explanation: a confidence interval communicates uncertainty around an estimated quantity under the assumptions of the statistical method. It is not a range containing a specified proportion of individual participant values, and it is not a guarantee that the true value lies within the interval. Its width depends on features such as the amount of information in the data and variability. The registry specifies a 95% confidence interval for the primary median, but the interval itself is not reported in the registry record. Its precision therefore cannot be evaluated.
How should the endpoint timing be read?
The endpoint description distinguishes baseline from the on-treatment nadir. Baseline is the last value before the bolus, while the nadir is the minimum value between the end of the bolus and the end of the infusion. The stated timeframe also refers to baseline and 12 hours post infusion. The record does not explain how the timeframe wording relates to the calculation based on the on-treatment nadir. It does not report the detailed analytic procedure, including how measurements were handled if a participant lacked a usable baseline or post-treatment value.
General statistical explanation: selecting a minimum from repeated measurements focuses on the lowest observed value during a defined interval. This is a different summary from comparing only two fixed-time measurements, because the value used can depend on how often and when measurements were taken. The registry provides the interval definition but does not report the measurement schedule, the number of measurements per participant, or analyses of sensitivity to the chosen nadir.
Why does the study structure matter?
The study is recorded as single-group, open-label, and without randomized allocation. General statistical explanation: a single-group pre/post assessment can describe how measurements changed among observed participants, but it does not provide the same counterfactual comparison as a randomized control group. Changes may reflect the intervention, the course of the acute condition, other care, or measurement timing. Open-label status means masking was none; the record does not report additional safeguards or blinded assessment procedures.
The registry lists low-dose and high-dose groups for adverse event reporting, but does not report randomized allocation or a controlled comparison between these groups. Safety counts can describe the recorded events in each group, but a direct causal comparison would require design and analysis details not reported in the registry record. The registry does not report a prespecified statistical comparison of doses.
What is not available for statistical review?
The registry record does not report numerical primary endpoint estimates, confidence interval limits, or analysis results. It also does not report the detailed statistical plan, missing-data methods, interim analyses, adjustment for multiple outcomes, or the number of participants contributing to each endpoint analysis. General statistical explanation: these details matter because they clarify which observations contribute to an estimate, how uncertainty was calculated, and how conclusions account for multiple opportunities to find a result. Without them, the statistical analysis cannot be independently reconstructed from the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The registry record identifies a primary laboratory endpoint and a secondary outcome concerning percent change from baseline in anti-factor Xa activity by hemostatic efficacy. It also indicates three outcome measures. The record does not report a multiplicity procedure, such as an adjustment for evaluating more than one outcome, nor does it state how the primary and secondary outcomes were prioritized in a formal testing strategy. It does not report the statistical plan or interim analyses.
The registry does not report how missing baseline or follow-up measurements were handled, whether participants with incomplete measurements were excluded from a particular analysis, or whether any imputation method was used. The primary efficacy population is defined by receipt of any amount of andexanet, meeting clinical bleeding criteria, and reaching a drug-specific anti-factor Xa threshold. However, the record does not state the number of participants meeting that definition or the number included in the endpoint analysis. The total enrollment of 479 should not be assumed to be the denominator for every outcome.
General statistical explanation: missing measurements can affect an estimate when the participants with observed measurements differ from those without them. The handling method and reasons for missingness help readers judge the possible impact. Likewise, when several outcomes are examined, multiplicity procedures can affect how statistical evidence is interpreted. Since these details are not reported in the registry record, neither the consequences of missing data nor the handling of multiple outcomes can be evaluated. No inferential result for the primary endpoint is reported in the registry 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 |
|---|---|---|---|
| Andexanet: Low Dose | 157 | 382 | 41.1% |
| Andexanet: High Dose | 43 | 97 | 44.3% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Andexanet: Low Dose | 66 of 382 |
| Andexanet: High Dose | 15 of 97 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Andexanet: Low Dose | 40 of 382 |
| Andexanet: High Dose | 8 of 97 |
Most frequent serious adverse event terms
| Event term | Organ system | Andexanet: Low Dose | Andexanet: High Dose |
|---|---|---|---|
| Pneumonia | Infections and infestations | 14 of 382 | 6 of 97 |
| Respiratory Failure | Respiratory, thoracic and mediastinal disorders | 10 of 382 | 2 of 97 |
| Ischaemic Stroke | Nervous system disorders | 8 of 382 | 2 of 97 |
| Cerebrovascular Accident | Nervous system disorders | 4 of 382 | 4 of 97 |
| Pneumonia Aspiration | Respiratory, thoracic and mediastinal disorders | 7 of 382 | 1 of 97 |
| Pulmonary Embolism | Respiratory, thoracic and mediastinal disorders | 7 of 382 | 1 of 97 |
| Subdural Haematoma | Injury, poisoning and procedural complications | 6 of 382 | 2 of 97 |
| Haemorrhage Intracranial | Nervous system disorders | 7 of 382 | 0 of 97 |
| Sepsis | Infections and infestations | 4 of 382 | 3 of 97 |
| Cardiac Failure | Cardiac disorders | 3 of 382 | 3 of 97 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Andexanet: Low Dose | Andexanet: High Dose |
|---|---|---|---|
| Urinary Tract Infection | Infections and infestations | 40 of 382 | 8 of 97 |
Serious events with the highest arm-level rate: pneumonia (6.2%), cerebrovascular accident (4.1%), sepsis (3.1%), cardiac failure (3.1%), respiratory failure (2.6%).
The registry reports serious adverse events separately for the low-dose and high-dose andexanet groups. In the low-dose group, 157 of 382 participants at risk had a serious adverse event; in the high-dose group, 43 of 97 participants at risk had a serious adverse event. Other adverse events are listed for 40 of 382 participants in the low-dose group and 8 of 97 in the high-dose group. Deaths are listed as 66 and 15, respectively. These are descriptive counts as recorded, not comparative estimates of risk.
The registry lists pneumonia at 6.2%, cerebrovascular accident at 4.1%, sepsis at 3.1%, cardiac failure at 3.1%, respiratory failure at 2.6%, and ischaemic stroke at 2.1% among the top serious terms. These percentages describe the listed terms; the record does not provide further detail about timing, overlap between terms, or how event relatedness was assessed.
The two dose groups are not a randomized control comparison in the registry record. Their counts should not be used to infer that one dose caused more or fewer events than the other. The record also does not provide a comparison with participants receiving no andexanet or another treatment. Safety counts describe what was recorded in the study groups; they do not establish comparative safety or causation.
12. What the Result Does, and Does Not, Mean
The registry establishes the basic design and measurement framework: a completed, phase 3, open-label, single-group study of andexanet in participants with acute major bleeding while taking a factor Xa inhibitor. It defines a primary laboratory endpoint based on percent reduction in anti-factor Xa activity, along with the baseline and on-treatment measurement definitions. It also records adverse event counts for low-dose and high-dose groups.
Those details do not supply the primary endpoint result. The median percent reduction and its 95% confidence interval are not reported in the registry record. Numerical results for hemostatic efficacy are not reported either. As a result, the posted record does not establish how much anti-factor Xa activity changed, how precise an estimated change was, or how laboratory change corresponded to clinical hemostasis.
General statistical explanation: a before-and-after measurement can document a change within observed participants, but without a concurrent comparison group it cannot isolate the effect of treatment from other influences. This is particularly important in acute illness, where the condition and its management may change over time. The single-group design therefore limits causal interpretation, even if endpoint estimates were available.
The safety counts are useful as descriptive information about events recorded among participants in the listed dose groups. They do not establish that andexanet caused an event, or that an event rate differs from what would occur under another treatment. The registry record does not report randomized allocation between the dose groups or a control group.
Thus, the record can be read as documenting the intended efficacy measure, study structure, and observed safety reporting categories. It cannot, from the posted information, support a quantitative account of the primary endpoint or a controlled estimate of treatment effect. This absence of reported efficacy values is not evidence of no change or no effect; it means the numerical result is not reported in the registry record.
13. Why This Trial Matters Statistically
This study illustrates why the endpoint, population, and design must be considered together. The primary measure is a laboratory change in anti-factor Xa activity, while the study purpose also includes hemostatic efficacy and safety. A laboratory marker and a clinical outcome answer related but distinct questions. The registry describes the laboratory measure in detail, but does not report its numerical results or the numerical hemostatic efficacy findings.
The efficacy population is defined more narrowly than the enrolled population. Participants had to receive andexanet, meet clinical bleeding criteria, and meet the drug-specific anti-factor Xa threshold. This distinction matters when interpreting a result because the analyzed population may not include every enrolled participant. The number meeting the efficacy definition and the number contributing to the primary analysis are not reported in the registry record.
The study also demonstrates the limits of interpreting within-group change. General statistical explanation: a single-group design can describe changes observed after an intervention, but cannot by itself show how those changes compare with an alternative. Randomization and a control group are tools for addressing such comparisons; neither is recorded for this study. Low-dose and high-dose safety groups do not replace a randomized control group.
Finally, precision and transparency are essential to interpreting any estimate. The registry specifies a median and 95% confidence interval, but does not report the endpoint values or analysis details. Without the estimate and its uncertainty, statistical readers cannot assess the magnitude, precision, or robustness of the primary result. The record’s limitations therefore shape the conclusion as much as its stated design and outcomes do.
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 most immediate limitation for interpreting efficacy is that the numerical primary endpoint result is not reported in the registry record. Although the endpoint is defined as a median percent reduction with a 95% confidence interval, the median, interval limits, and analysis results are absent. Numerical hemostatic efficacy findings are also not reported. This prevents assessment of the observed effect size, uncertainty, and relationship between the laboratory endpoint and clinical bleeding outcomes.
The single-group design has no randomized control comparison. Accordingly, even if a change from baseline had been reported, the registry record would not establish how much of that change was attributable to andexanet rather than to other factors. The open-label design has no masking. The registry record does not report additional blinded assessment procedures or details about how outcome assessment was protected from knowledge of treatment.
The efficacy population has drug-specific laboratory thresholds and clinical criteria, but the record does not report the number of participants who met those criteria or the analysis denominator. Missing-data procedures, endpoint-specific participant counts, and reasons for missing measurements are not reported. The record also does not report the detailed statistical plan, multiplicity handling, or interim analyses.
For safety, the record lists counts by low-dose and high-dose groups but does not report randomized assignment or a controlled comparison. It does not provide enough detail to interpret the listed counts as causal effects or comparative risks. These limitations are specific to the information and design recorded; they do not determine what additional analyses or results may exist outside the registry record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study in Participants With Acute Major Bleeding to Evaluate the Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Direct and Indirect Oral Anticoagulants (Extension Study) — NCT02329327.
- Registry record last updated 2022-02-16; status last verified 2022-01.
- Results first posted 2022-02-16.
- 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
NCT02329327 is a completed phase 3, open-label, single-group study of andexanet alfa in participants receiving a factor Xa inhibitor who had acute major bleeding. Enrollment was 479. The registry records a start date of 2015-04-10 and a primary completion date of 2020-09-24. The intervention was an intravenous bolus followed by continuous infusion.
The primary endpoint was percent change from baseline in anti-factor Xa activity by factor Xa inhibitor, summarized as a median with a 95% confidence interval. The registry defines the baseline and on-treatment nadir but does not report numerical primary endpoint results. It also lists adverse event counts for low-dose and high-dose groups. Because allocation was not randomized and no control group is recorded, those groups do not constitute a like-for-like control comparison. The registry record does not report detailed statistical methods, missing-data handling, or multiplicity procedures.