ANNEXA-I

Clinical Context

Oral factor Xa inhibitors (e.g., apixaban, rivaroxaban, edoxaban) are widely prescribed for the prevention and treatment of thromboembolic disorders. While they offer advantages over vitamin K antagonists, managing acute major bleeding, including life-threatening intracerebral hemorrhage (ICH), in patients receiving these agents is a critical challenge. Unlike VKAs, for which specific reversal strategies like PCCs exist, options for rapidly and effectively reversing factor Xa inhibitors were limited until the development of andexanet alfa.

Andexanet alfa is a modified, recombinant human factor Xa decoy protein that binds and sequesters factor Xa inhibitors, thereby restoring the activity of endogenous factor Xa. An earlier single-group study (ANNEXA-4) suggested that andexanet alfa could rapidly reverse anti-factor Xa activity and was associated with good or excellent hemostatic efficacy in patients with major bleeding. However, randomized controlled data comparing andexanet alfa to usual care (which often includes off-label use of PCCs or supportive care alone) were needed.

The ANNEXA-I trial was designed to definitively assess the efficacy and safety of andexanet alfa compared with usual care in patients with acute major bleeding associated with the use of factor Xa inhibitors.

Patient Population

ANNEXA-I was an international, multicenter trial that enrolled 530 adult patients (≥18 years) who presented with acute major bleeding. Major bleeding could be:

• Life-threatening intracranial hemorrhage (ICH was the most common type, accounting for about 67% of patients).
• Severe acute gastrointestinal bleeding.
• Other types of major bleeding (e.g., retroperitoneal, intramuscular with compartment syndrome).

Eligible patients had received an oral factor Xa inhibitor (apixaban, rivaroxaban, or edoxaban) or outpatient enoxaparin within a specified timeframe (generally within 15 hours, or longer with renal impairment) prior to presentation and required urgent reversal of anticoagulation. Specific criteria for ICH included estimated hematoma volume not exceeding 60 mL and GCS ≥7.

Exclusions included planned surgery within 12 hours, severe ICH deemed non-survivable, recent thrombotic events, or other conditions that would confound the assessment or increase risk.

The median age of participants was approximately 78-79 years. Atrial fibrillation was the most common indication for anticoagulation.

Study Design

ANNEXA-I was a prospective, randomized, open-label, multicenter trial with blinded endpoint adjudication.

Protocol Details

Patients were randomized 1:1 to receive either:

• Intervention Group (Andexanet Alfa): An intravenous bolus of andexanet alfa followed by a 2-hour continuous infusion. The specific dose (low dose: 400 mg bolus + 480 mg infusion; high dose: 800 mg bolus + 960 mg infusion) was determined by the type of factor Xa inhibitor, its dose, and the time since the last intake, according to the drug’s labeling. Patients also received standard supportive care.
• Control Group (Usual Care): Standard treatment for bleeding management as per local institutional guidelines. This could include supportive care, blood products, and specific hemostatic agents like 4-factor prothrombin complex concentrates (PCCs were used in about 68% of usual-care patients with ICH). Andexanet alfa was not permitted in this group.

Outcome Assessment

The primary outcome was hemostatic efficacy, a composite endpoint assessed from randomization through 12 hours. Secondary outcomes, including clinical events like mortality and thrombotic events, were assessed at 30 days. All major outcomes were adjudicated by a clinical events committee blinded to treatment assignment.

Power Analysis & Statistical Approach

The primary outcome was hemostatic efficacy. The trial was designed to have approximately 90% power to detect a significant difference in hemostatic efficacy between the andexanet alfa and usual-care groups, assuming specific event rates.

Risk of Bias Analysis

(Content for this section needs to be added. Considerations: Open-label design for intervention (unavoidable), but blinded adjudication of outcomes is a major strength. Heterogeneity of “usual care” interventions. Industry sponsorship.)

Results

A total of 530 patients underwent randomization: 263 to andexanet alfa and 267 to usual care. Baseline characteristics were generally well-balanced. ICH was the qualifying bleeding event in 67% of patients in both groups.

Primary Outcome: Hemostatic Efficacy

Andexanet alfa was superior to usual care in achieving hemostatic efficacy:

• Andexanet Alfa group: 69.8% (174 of 249 evaluable patients) achieved hemostatic efficacy.
• Usual-Care group: 57.0% (131 of 230 evaluable patients) achieved hemostatic efficacy.
  The adjusted risk difference was 13.4 percentage points (95% CI, 4.6 to 22.2; p=0.003).

For the subgroup of patients with ICH, good or excellent hemostatic efficacy (based on limited hematoma expansion) was observed in:

• Andexanet Alfa group: 78.5%
• Usual-Care group: 60.0%

Secondary Outcomes

• Change in Anti-Factor Xa Activity: Andexanet alfa rapidly and substantially reduced anti-factor Xa activity from baseline compared with usual care.
• Mortality at 30 days:
  • Andexanet Alfa group: 15.2%
  • Usual-Care group: 15.4%
    (No significant difference).
• Functional Outcome (mRS) at 30 days (ICH patients): While not a primary or major secondary endpoint for the overall trial, descriptive data for ICH patients did not show a significant difference in functional outcomes.
• Thrombotic Events within 30 days:
  • Andexanet Alfa group: 10.3%
  • Usual-Care group: 6.0%
    (Adjusted risk difference, 4.6 percentage points; 95% CI, -0.1 to 9.4). This numerical increase with andexanet alfa is an important safety consideration.

Final Thoughts & Critical Appraisal

The ANNEXA-I trial provides the first randomized controlled evidence for andexanet alfa in patients with acute major bleeding associated with factor Xa inhibitor use.

Key takeaways:

• Superior Hemostatic Efficacy: Andexanet alfa was more effective than usual care (which often included PCCs) in achieving the composite primary endpoint of hemostatic efficacy, driven by both control of bleeding and rapid reduction of anti-factor Xa activity. This was also observed in the ICH subgroup regarding hematoma stability.
• No Clear Impact on Clinical Outcomes (Mortality/Function): Despite better hemostatic efficacy, andexanet alfa did not demonstrate a significant improvement in 30-day mortality or functional outcomes in the overall population or the ICH subgroup within the 30-day timeframe of this trial’s primary clinical safety endpoints. Longer-term clinical outcomes are still awaited.
• Increased Thrombotic Risk: Andexanet alfa was associated with a numerically higher incidence of thrombotic events within 30 days compared to usual care. This is a critical safety concern, as factor Xa inhibitors are often prescribed to patients at high underlying thrombotic risk.
• Comparison to Usual Care (including PCCs): A significant proportion of patients in the usual-care arm received PCCs. The superiority of andexanet alfa in hemostatic efficacy over a usual-care strategy that frequently included PCCs is noteworthy.
• Implications for Practice: Andexanet alfa is an effective reversal agent for factor Xa inhibitors based on laboratory markers and hemostatic control. However, the lack of clear benefit on short-term clinical outcomes like mortality or function, coupled with a signal for increased thrombotic events, means its role needs careful consideration. Decisions to use andexanet alfa will involve weighing its proven ability to control bleeding against the potential thrombotic risk and the current absence of definitive evidence for improved patient-centered clinical outcomes from this trial.

ANNEXA-I is a landmark trial that confirms the biological efficacy of andexanet alfa but also highlights the complexities of translating improved hemostasis into better clinical outcomes in critically ill bleeding patients, especially concerning the balance of bleeding and thrombotic risks.

How do we reconcile the results with other studies?

(Content for this section needs to be added, comparing ANNEXA-I with ANNEXA-4, observational studies of PCCs for FXa inhibitor reversal, and discussing the challenges of demonstrating clinical outcome benefits with reversal agents when underlying patient conditions are severe.)

Found an error or want to suggest an improvement? Edit this page on GitHub.