FAST
(2008)Objective
To determine whether recombinant activated factor VII (rFVIIa) given within 4 hours of acute spontaneous intracerebral hemorrhage reduces death or severe disability at 90 days.
Study Summary
• Hematoma growth WAS reduced by rFVIIa 80 μg/kg (mean ICH volume increase 11% vs 26% placebo; absolute -3.8 mL, 95% CI 0.9-6.7, P=0.009), confirming the hemostatic effect from the phase 2b trial.
• 90-day mortality was similar (~20%) in all three groups; NIHSS scores at 90 days were slightly but significantly lower with 80 μg/kg (small effect).
• Safety signal: arterial thromboembolic serious adverse events were more frequent with rFVIIa 80 μg/kg than placebo (9% vs 4%, P=0.04); overall thromboembolic SAEs and venous events were similar across groups.
Intervention
Single IV dose of recombinant activated factor VII (rFVIIa, NovoSeven) 20 μg/kg or 80 μg/kg vs matching placebo, given within 4 hours of ICH onset (within 1 hour of baseline CT).
Inclusion Criteria
Adults ≥18 years with spontaneous intracerebral hemorrhage documented by CT within 3 hours of symptom onset; treatment feasible within 4 hours of onset.
Study Design
Arms: Placebo vs rFVIIa 20 μg/kg vs rFVIIa 80 μg/kg (single IV dose)
Patients per Arm: 268 placebo / 276 rFVIIa 20 μg/kg / 297 rFVIIa 80 μg/kg (total N=841 randomized, 821 dosed)
Outcome
• Radiographic (positive): mean 24-hour ICH volume increase 26% placebo vs 18% (20 μg/kg, P=0.09) vs 11% (80 μg/kg, P<0.001); absolute volume growth -3.8 mL with 80 μg/kg vs placebo (95% CI 0.9-6.7, P=0.009).
• Mortality at 90 days ~20% in all three groups (no benefit).
• Safety: arterial thromboembolic SAEs 4% placebo vs 9% with 80 μg/kg (P=0.04); troponin elevation 15% / 13% / 22%; STEMI 1.5% / 0.4% / 2.0%; CT-defined cerebral infarction 2.2% / 3.3% / 4.7%.
• Exploratory subgroup (age ≤70, ICH ≤60 mL, IVH ≤5 mL, treated ≤2.5 h; ~19% of cohort): adjusted OR for poor 90-day outcome 0.28 (95% CI 0.08-1.06, P=0.03).
Clinical Question
In adults with spontaneous intracerebral hemorrhage treated within 4 hours of onset, does recombinant activated factor VII (rFVIIa) at 20 or 80 μg/kg, compared with placebo, reduce the proportion with severe disability or death (mRS 5-6) at 90 days?
Bottom Line
In this phase 3 trial (FAST), hemostatic therapy with rFVIIa within 4 hours of ICH reduced 24-hour hematoma growth (11% vs 26% with 80 μg/kg) but did NOT reduce 90-day death or severe disability, and 80 μg/kg increased arterial thromboembolic events (9% vs 4%, P=0.04).
Major Points
- Primary outcome (mRS 5 or 6 at 90 days) was not different across groups: 24% placebo, 26% rFVIIa 20 μg/kg, 29% rFVIIa 80 μg/kg — clearly negative for clinical benefit.
- Hemostatic effect confirmed: mean 24-h ICH volume increase 26% (placebo), 18% (20 μg/kg), 11% (80 μg/kg, P<0.001 vs placebo); absolute reduction 3.8 mL with 80 μg/kg (95% CI 0.9-6.7, P=0.009).
- Mortality at 90 days ~20% across all three arms; no survival benefit from rFVIIa.
- Arterial thromboembolic serious adverse events were increased with 80 μg/kg vs placebo (9% vs 4%, P=0.04); troponin elevation 22% vs 15%; CT-defined cerebral infarction 4.7% vs 2.2%.
- Randomization imbalances (more intraventricular hemorrhage, coma, and left ventricular hypertrophy in 80 μg/kg arm) and unexpectedly good placebo-group outcomes (mortality 19%, poor outcome 24%) may partly explain the discordance with the earlier phase 2b trial.
- Post-hoc subgroup (age ≤70, ICH ≤60 mL, IVH ≤5 mL, treated ≤2.5 h; 19% of cohort): adjusted OR for poor 90-day outcome 0.28 (95% CI 0.08-1.06, P=0.03) — hypothesis-generating and motivated later spot-sign / early-treatment trials.
- Findings largely ended routine consideration of rFVIIa for unselected ICH; interest continued only in ultra-early / spot-sign-positive subgroups (later tested by SPOTLIGHT, STOP-IT, TRAIGE, and FASTEST).
Study Design
- Study Type
- Phase 3 Randomized Controlled Trial
- Randomization
- Yes
- Blinding
- Double-blind, placebo-controlled (block randomization by site)
- Sample Size
- 841
- Follow-up
- 90 days
- Centers
- 122
- Countries
- Multinational (22 countries; sites in North America, Europe, Australia, Asia, South America, and the Middle East)
Primary Outcome
Definition: Poor outcome — severe disability or death (modified Rankin scale 5 or 6) at 90 days
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | - |
Limitations & Criticisms
- Baseline randomization imbalances disadvantaged the 80 μg/kg arm — higher rates of intraventricular hemorrhage (41% vs 29% placebo), coma (GCS 6-8), left ventricular hypertrophy, and larger total lesion volume — which likely biased the primary outcome against active treatment.
- The placebo group had unexpectedly favorable outcomes (mortality 19%, poor outcome 24%) compared with the earlier phase 2b trial (mortality 29%, poor outcome 45%), reducing the absolute effect size rFVIIa could achieve.
- Sponsor (Novo Nordisk) responsible for trial operations and initial data analysis; multiple author financial ties (consulting, lecture fees, employment, stock ownership).
- Trial did not require CT-angiographic 'spot sign' or other markers of active bleeding to enrich for patients most likely to benefit from hemostatic therapy.
- 4-hour treatment window may have been too long — only 17% treated within 2 hours; hemostatic effect and possible clinical benefit were largest with earliest treatment.
- Broad inclusion allowed elderly patients (up to 97 years) at high risk of non-neurologic death, diluting any neurologic benefit.
- Reliance on modified Rankin 5-6 as primary endpoint (rather than shift analysis across full mRS) may have missed smaller functional gains; NIHSS did show a small significant improvement with 80 μg/kg.
- Post-hoc subgroup analyses (young, small ICH, minimal IVH, treated ≤2.5 h) are hypothesis-generating only and were not prespecified.
Citation
N Engl J Med 2008;358(20):2127-2137. DOI: 10.1056/NEJMoa0707534