Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial. Use of ancrod in acute or progressing ischemic cerebral infarction. Ancrod in acute ischemic stroke: results of 500 subjects beginning treatment within 6 hours of stroke onset in the ancrod stroke program. Controlled trial of ancrod in ischemic stroke. Ancrod for the treatment of acute ischemic brain infarction. The Ancrod Stroke Study Investigators. Intravenous ancrod for acute ischaemic stroke in the European Stroke Treatment with Ancrod Trial: a randomised controlled trial.
Approved treatment options for acute ischemic stroke in the United States and Canada are limited at present to intravenous tissue-type plasminogen activator, but bleeding complications, including intracranial hemorrhage, are a recognized complication.
                To evaluate the efficacy and safety of the defibrinogenating agent ancrod in patients with acute ischemic stroke.
                The Stroke Treatment with Ancrod Trial (STAT), a randomized, parallel-group, double-blind, placebo-controlled trial conducted between August 1993 and January 1998.
                Forty-eight centers, primarily community hospitals, in the United States and Canada.
                A total of 500 patients with an acute or progressing ischemic neurological deficit were enrolled and included in the intent-to-treat analysis.
                Patients were randomly assigned to receive ancrod (n=248) or placebo (n =252) as a continuous 72-hour intravenous infusion beginning within 3 hours of stroke onset, followed by infusions lasting approximately 1 hour at 96 and 120 hours. The ancrod regimen was designed to decrease plasma fibrinogen levels to 1.18 to 2.03 micromol/L.
                The primary efficacy end point was functional status, with favorable functional status defined as survival to day 90 with a Barthel Index of 95 or more or at least the prestroke value, compared by treatment group. Primary safety variables included symptomatic intracranial hemorrhage and mortality.
                Favorable functional status was achieved by more patients in the ancrod group (42.2%) than in the placebo group (34.4%; P=.04) by the prespecified covariate-adjusted analysis. Mortality was not different between treatment groups (at 90 days, 25.4% for the ancrod group and 23% for the placebo group; P=.62), and the proportion of severely disabled patients was less in the ancrod group than in the placebo group (11.8% vs 19.8%; P=.01). The favorable functional status observed with ancrod vs placebo was consistent in all subgroups defined for age, stroke severity, sex, prestroke disability, and time to treatment (< or = 3 or > 3 hours after stroke onset). There was a trend toward more symptomatic intracranial hemorrhages in the ancrod group vs placebo (5.2% vs 2.0%; P=.06), as well as a significant increase in asymptomatic intracranial hemorrhages (19.0% vs 10.7%; P=.01).
                In this study, ancrod had a favorable benefit-risk profile for patients with acute ischemic stroke. Ancrod has been used in Europe for over 15 years for peripheral vascular disease, deep vein thrombosis, and central retinal venous thrombosis, and in patients at risk for thromboembolism. In a double-blind, randomized, placebo-controlled study at University Hospitals in Cincinnati, 20 acute cerebral infarction patients received a series of IV infusions of ancrod (ten) or placebo (ten) for seven days. Early fibrinolysis with a small decrease in fibrinogen was observed, and d-dimers were elevated at four hours, indicating early clot lysis. At three months, patients with moderate to severe strokes (less than 40 on the Scandinavian Stroke Scale) in the ancrod group showed average improvement by a factor of 3 over the placebo group. No bleeding, abnormal laboratory results, or deaths occurred, but ancrod was discontinued in one patient who had seizures. As a result of this study, a double-blind multicenter international clinical trial to further assess the safety and effectiveness of ancrod is being planned. Previous studies of multiple-day dosing with the defibrinogenating agent, ancrod, in acute ischemic stroke yielded conflicting results but suggested that a brief dosing regimen might improve efficacy and safety. The Ancrod Stroke Program was designed to test this concept in subjects beginning ancrod or placebo within 6 hours of the onset of acute ischemic stroke.
                Five hundred subjects with acute ischemic stroke who could begin receiving study material within 6 hours of symptom onset were infused intravenously with either ancrod (0.167 IU/kg per hour) or placebo over 2 or 3 hours. The primary efficacy outcome was a dichotomized, modified Rankin score at 90 days with less stringent cut-points for higher prestroke modified Rankin score and pretreatment NIHSS total score ("responder analysis"). Safety variables included mortality, major bleeding, and intracranial hemorrhage.
                Although the desired changes in fibrinogen level were seen in >90% of ancrod subjects, interim analysis for futility led to the study being halted for lack of efficacy. Positive responder status in the interim dataset was seen in 39.6% of ancrod subjects and 37.2% of placebo subjects (P=0.47). Ninety-day mortality did not differ between the 2 groups (ancrod, 15.6%; placebo, 14.1%; P=0.32), and the incidence of symptomatic intracranial hemorrhage within the first 72 hours, although not significantly different in ancrod compared to placebo subjects (P=0.19), was approximately twice as high (3.9% vs 2.0%; P=0.19).
                These results demonstrate that intravenous ancrod starting within 6 hours after symptom onset in a broad selection of subjects with ischemic stroke did not improve their outcome and revealed a trend to increased bleeding despite successful efforts to achieve rapid initial defibrinogenation and avoid prolonged hypofibrinogenemia. In a randomized, single-blind study, 30 patients with acute ischemic stroke were treated with either low-molecular weight dextran and mannitol alone (group A, mean age, 63.3 +/- 11.8 years, n = 15) or in combination with the viper venom enzyme ancrod (group B, mean age, 67.9 +/- 7.6 years, n = 15). Lowering of plasma fibrinogen levels to 100-130 mg/dL with ancrod resulted in a significant reduction of the apparent blood viscosity, ie, of 37% at a shear rate of 0.03 s-1, compared with only 7% in group A. Fibrin degradation products increased considerably from 3.1 +/- 0.4 to 154.3 +/- 31.6 mg/L on day 3, while plasminogen decreased from 98.2% +/- 2.0% to 79.8% +/- 2.9% in group B. Global coagulation and platelet function tests were not influenced by either treatment. Neurological score improved by 1.1 arbitrary units (AU) in group A and by 2.6 AU in group B. Five patients in group A and two in group B died during the first two weeks. This preliminary study indicated a slightly better outcome in the ancrod treated patients. The beneficial effect may be due to the anticoagulative and fibrinolytic activity of ancrod rather than its effect on blood viscosity. There is no acute therapy proven to be of benefit for ischemic stroke. Ancrod is a potentially effective therapy because of the advantageous consequences of fibrinogen lowering.
                We studied the safety and efficacy of ancrod in patients with acute ischemic stroke administered within 6 hours of stroke onset. In a double-blind, randomized, placebo-controlled trial 64 patients received intravenous ancrod and 68 received placebo for 7 days. Neurological outcome, disability, and brain infarct volume were measured.
                There was no significant difference in overall mean scores on the Scandinavian Stroke Scale. No increase in bleeding occurred in the ancrod-treated patients. The target reduction of plasma fibrinogen levels of less than 100 mg/dL was achieved in only 15 (23%) of 64 ancrod-treated patients. Those patients with ancrod-induced 6-hour fibrinogen levels 130 mg/dL or less had a marginally significantly better neurological outcome on the Scandinavian Stroke Scale, mortality, and Barthel Index than ancrod-treated patients with higher fibrinogen levels.
                Ancrod appears safe and potentially effective when administered to patients within 6 hours of onset of ischemic stroke. Intravenous tissue plasminogen activator is the only approved specific treatment for acute ischaemic stroke. Ancrod, a natural defibrinogenating agent from snake venom, has proved to have a favourable effect when given within 3 h after an acute ischaemic stroke. The European Stroke Treatment with Ancrod Trial was undertaken to assess the effects of ancrod when given within 6 h.
                1222 patients with an acute ischaemic stroke were included in this randomised double-blind placebo-controlled trial. Brain CT scans were done to exclude intracranial haemorrhages and large evolving ischaemic infarctions. Patients were randomly assigned ancrod (n=604) or placebo (n=618). The primary outcome was functional success at 3 months (survival, Barthel Index of 95 or 100, or return to prestroke level). The analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, trial number NCT00343174.
                Functional success at 3 months did not differ between patients given ancrod (42%) and those given placebo (42%) (p=0.94, OR=0.99, 95% CI, 0.76-1.29).
                On the basis of our findings, ancrod should not be recommended for use in acute ischaemic stroke beyond 3 h.
The current evidence is promising but not yet sufficiently robust to support the routine use of fibrinogen depleting agents for the treatment of acute ischaemic stroke. Further trials are needed to determine whether there is worthwhile benefit, and if so, which categories of patients are most likely to benefit.