Ancrod for the Treatment of Acute CVA

abstract & commentary

Source: Sherman DG, et al for the STAT participants. Intravenous ancrod for treatment of acute ischemic stroke — the STAT study: A randomized controlled trial. JAMA 2000;283:2395-2403.

Extracted from malaysian pit viper venom, ancrod has been used outside the United States for thrombosis treatment because of its ability to accelerate fibrinogen cleavage and induce rapid defibrinogenation. Because elevated fibrinogen has been associated with poor outcomes in stroke, some have suggested ancrod for emergent treatment. Possible mechanisms include depletion of fibrinogen for thrombosis, accelerated spontaneous fibrinolysis, decreased blood viscosity, and improved circulation.

This study reports the findings of the Stroke Treatment with Ancrod Trial (STAT), a four-year multicenter, double-blind, controlled trial in which 500 ischemic stroke patients were andomized to receive either ancrod or placebo. Eligible patients included those presenting within three hours of symptom onset who did not meet exclusion criteria (e.g., intracranial hemorrhage [ICH], mass lesion, bleeding disorder, elevated blood pressure). Ancrod was administered as a 72-hour initial infusion (doses of 0.167, 0.125, or 0.082 IU/kg/hr based on initial fibrinogen levels), followed by one-hour infusions on days four and five, with target fibrinogen levels of 1.18-2.03 µmol/L.

Patients were followed for 90 days with a primary outcome measure of favorable functional status, defined as a Barthel Index (BI) score of 95 (indicating little or no need for help with activities of daily living or return to at least baseline prestroke status). Safety monitors included patient mortality, adverse events, and ICH incidence.

The ancrod group had a higher rate of favorable outcomes vs. placebo (41.1% vs 35.3%, respectively) and a higher rate of complete recovery (a BI score of 100) or return to baseline prestroke status (36.1% vs 26.4%, respectively). This better outcome was consistent regardless of age, prestroke disability, or time to treatment (within the 3-hour treatment period, though some patients were outside this window). Mortality and adverse event rates were similar for both groups. There was a trend toward more symptomatic ICHs for ancrod (5.2% vs 2.0%, P = 0.06), all occurring within 72 hours of treatment onset. Rapid initial defibrinogenation was associated with treatment success (favorable outcome of 45.8% vs 34.6% when 6-hour levels were within therapeutic range) and with less risk for adverse events. Conversely, subsequent serial low fibrinogen levels appeared associated with greater risk for ICH and less treatment success. The investigators concluded that ancrod has a favorable risk/benefit profile in the setting of acute ischemic stroke.

Comment by Theodore C. Chan, MD, FACEP

The STAT study adds to the growing literature supporting acute stroke therapy, along with the National Institute of Neurological Disorders and Stroke (NINDS) trial assessing tPA and the second Prolyse in Acute Cerebral Thromboembolism (PROACT II) trial assessing intra-arterial thrombolysis.1,2

This study is remarkable from a number of standpoints. First, the study was conducted primarily in community hospitals, indicating that both research on stroke and actual acute treatment of it are feasible and applicable in this setting, where the large majority of stroke patients receive care. Second, while only 500 of 2613 patients screened were eligible, only a small number (383) were excluded because they presented outside the three-hour window. Third, rapid initial defibrinogenation was associated with favorable outcome, whereas subsequent levels were related to increased ICH risk, suggesting that control of fibrinogen levels may improve outcome without necessarily increasing risk. The results of STAT must be interpreted cautiously. The investigators used only the BI as their measure of functional status. Other studies, such as NINDS, used multiple measurements to assess neurologic status. Also, tPA had a much easier dosing regimen in NINDS, and results were as favorable as the STAT findings for ancrod. Third, a recent European Stroke Treatment with Ancrod Trial (ESTAT) has been prematurely terminated because of increased 90-day mortality. Assessment of ancrod for acute ischemic stroke should await the analysis of this trial.

References

1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581-1587.

2. Furlan A, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II Study: A randomized controlled trial. JAMA 1999;282:2003-2011.