FAST

Clinical Context

Limiting hematoma expansion is a key therapeutic target in the acute phase of intracerebral hemorrhage (ICH), as ongoing bleeding is associated with neurological deterioration and worse outcomes. Recombinant activated factor VII (rFVIIa) is a pro-hemostatic agent that promotes thrombin generation and fibrin clot formation at the site of bleeding. Promising results from a phase 2b trial suggested that early administration of rFVIIa could reduce hematoma growth and might improve clinical outcomes in patients with ICH.

The FAST (Factor Seven for Acute Hemorrhagic Stroke Trial) was a large, international phase 3 trial designed to definitively evaluate the efficacy and safety of rFVIIa in patients with acute ICH. The hope was that by rapidly achieving hemostasis, rFVIIa would limit the extent of the initial bleed and thereby reduce subsequent death and disability.

Patient Population

The FAST trial enrolled 841 adult patients (≥18 years) from multiple centers worldwide. Eligible patients had:

• Spontaneous intracerebral hemorrhage confirmed by CT scan.
• Ability to receive treatment within 4 hours of symptom onset (the initial protocol specified 3 hours but was amended to 4 hours to improve recruitment).
• A Glasgow Coma Scale (GCS) score of ≥5.
• Hematoma volume <60 mL (with some variations in initial criteria based on location).

Key exclusion criteria included infratentorial hemorrhage, purely intraventricular hemorrhage, known secondary causes of ICH, significant pre-existing coagulopathy (e.g., INR >1.5), thrombocytopenia, a history of recent (within 30 days) or high ongoing risk of thromboembolic events, or planned surgical evacuation of the hematoma within 24 hours.

The median age of participants was approximately 65-67 years. About 60% were male. The median GCS at baseline was 13-14. The median time from symptom onset to treatment was around 3 hours.

Study Design

FAST was an international, multicenter, prospective, randomized, double-blind, placebo-controlled, phase 3 trial.

Protocol Details

Eligible patients were randomized in a 1:1:1 ratio to one of three treatment groups, with the study drug administered as a single intravenous bolus within 4 hours of symptom onset:

• Placebo Group: Received an intravenous placebo infusion.
• rFVIIa 20 μg/kg Group: Received rFVIIa at a dose of 20 micrograms per kilogram of body weight.
• rFVIIa 80 μg/kg Group: Received rFVIIa at a dose of 80 micrograms per kilogram of body weight.

All patients also received standard medical care according to local guidelines, including blood pressure management and other supportive therapies.

Outcome Assessment

The primary outcome was assessed at 90 days. Assessment of the modified Rankin Scale (mRS) was performed by trained assessors who were blinded to the treatment allocation. Hematoma volume was assessed by CT scans at baseline and 24 hours.

Power Analysis & Statistical Approach

The primary outcome was the proportion of patients dead or severely disabled (mRS 5 or 6) at 90 days. The trial was powered to detect a clinically meaningful reduction in this outcome with rFVIIa compared to placebo. The primary comparison was between the 80 μg/kg rFVIIa group and the placebo group.

Risk of Bias Analysis

(Content for this section needs to be added. Considerations: double-blind, placebo-controlled design is a major strength, potential unblinding if thromboembolic events were very different, industry sponsorship.)

Results

A total of 841 patients were randomized: 268 to placebo, 276 to rFVIIa 20 μg/kg, and 297 to rFVIIa 80 μg/kg. Baseline characteristics were well-balanced across the groups.

Effect on Hematoma Growth (A Key Mechanistic Outcome)

Administration of rFVIIa resulted in a significant reduction in the increase in hematoma volume from baseline to 24 hours compared with placebo. The mean increase in volume was:

• Placebo: 10.7 mL
• rFVIIa 20 μg/kg: 7.2 mL (p=0.02 vs. placebo)
• rFVIIa 80 μg/kg: 5.8 mL (p<0.001 vs. placebo)
  The 80 μg/kg dose showed the most pronounced effect on limiting hematoma expansion.

Primary Outcome: Death or Severe Disability (mRS 5–6) at 90 Days

Despite the positive effect on hematoma growth, rFVIIa did not lead to a statistically significant improvement in the primary clinical outcome. The proportion of patients who died or were severely disabled (mRS 5 or 6) at 90 days was:

• Placebo: 29%
• rFVIIa 20 μg/kg: 26% (Absolute difference vs. placebo: -3.2%; 95% CI, -11.3 to 4.8; p=0.42)
• rFVIIa 80 μg/kg: 24% (Absolute difference vs. placebo: -5.5%; 95% CI, -13.4 to 2.4; p=0.10 for the primary comparison)

Secondary Clinical Outcomes

• Ordinal analysis of mRS scores: Showed a trend towards benefit with the 80 μg/kg dose of rFVIIa (OR for improved outcome 1.3, 95% CI 0.9–1.7; p=0.08) but did not reach statistical significance.
• Mortality at 90 days: Was similar across groups (Placebo: 18%; rFVIIa 20 μg/kg: 16%; rFVIIa 80 μg/kg: 18%).

Safety Outcomes (Thromboembolic Events)

The use of rFVIIa, particularly at the 80 μg/kg dose, was associated with an increased risk of arterial thromboembolic serious adverse events:

• Placebo: 2%
• rFVIIa 20 μg/kg: 4%
• rFVIIa 80 μg/kg: 7% (p=0.02 for trend; p=0.04 for 80 μg/kg vs. placebo)
  Myocardial infarction was the most common arterial thromboembolic event. Rates of venous thromboembolic events were similar across groups.

Final Thoughts & Critical Appraisal

The FAST trial was a large, well-designed study that provided crucial insights into the potential role of rFVIIa in acute ICH. While rFVIIa effectively limited hematoma expansion, this did not translate into a significant improvement in clinical outcomes (death or severe disability) and was associated with an increased risk of arterial thromboembolic events at the higher dose tested.

Key takeaways:

• Dissociation between Hematoma Growth and Clinical Outcome: FAST demonstrated that simply reducing hematoma expansion does not automatically lead to better functional outcomes. This highlights the complex pathophysiology of ICH, where factors beyond initial hematoma size (e.g., secondary injury, edema, location) play significant roles.
• No Clear Clinical Benefit: Neither dose of rFVIIa significantly reduced the rate of death or severe disability compared to placebo.
• Increased Thromboembolic Risk: The higher dose of rFVIIa (80 μg/kg) was associated with a concerning increase in arterial thromboembolic events, raising safety concerns that likely outweighed any marginal trend towards clinical benefit.
• Impact on Practice: The results of the FAST trial, along with other studies and the associated thromboembolic risks, led to a significant decline in the off-label use of rFVIIa for acute ICH. It is generally not recommended for this indication outside of specific situations (e.g., known factor VII deficiency or in patients with coagulopathy where other reversal agents are contraindicated or unavailable, and even then with extreme caution).

The FAST trial was pivotal in shaping our understanding of hemostatic therapy in ICH. It emphasized that interventions must not only affect surrogate markers like hematoma volume but also demonstrate clear clinical benefit and acceptable safety before being adopted into routine practice. It also paved the way for research into other hemostatic agents and strategies.

How do we reconcile the results with other studies?

(Content for this section needs to be added, particularly discussing the earlier promising phase 2b rFVIIa trial and why the phase 3 results differed, and the broader implications for hemostatic therapy research in ICH.)

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