n ANCROD FOR THE TREATMENT OF ACUTE ISCHAEMIC BRAIN INFARCTION

The Ancrod Stroke Study

The clinical use of Ancrod for the early treatment of acute ischaemic stroke, based on its fibrinogen-lowering effect, was first supported by two small trials conducted by Hossman et al in 1983 and by Olinger et al in 1988 which showed an apparent clinical benefit with Ancrod.1,2

This led to a multi-institutional, double-blind, randomized placebo-controlled trial of the efficacy and safety of Ancrod in patients with acute ischaemic stroke.3 The Ancrod Stroke Study enrolled 132 patients between the ages of 35 and 80 who were given either intravenous Ancrod (n=64) or placebo (n=68) within 6 hours of onset of acute ischaemic stroke for 7 days. The dosing protocol aimed to achieve a plasma fibrinogen level between 70-100 mg/dl.

Efficacy results
The baseline-corrected 3-month SSS score was higher in the Ancrod-treated group than in the placebo group although this difference was not significant; a higher proportion of Ancrod-treated patients also made meaningful neurological responses (78%) than in the placebo group (57%) (p=0.018). The median brain infarct volume determined by CT scan in the patients surviving was 13.3 cm3 in the Ancrod-treated group compared to 30.6 cm3 in the placebo-treated group (p=0.0476). Mortality at one year was also lower in the Ancrod group and mortality at one month just missed significance. Other neurological outcome measures favoured the Ancrod group but were not significant (Table 1).3

Table 1. Outcomes of patients according to treatment group

*A meaningful response on the SSS was defined as survival beyond 10 days with a motor score that improved by at least one grade and by two if the baseline score was the worst possible.
**The Barthel index score used in this study had a maximum possible score of 95 rather than the more typical 100. A meaningful response was defined as present if the total score was 90 greater or as high as the estimated prestroke score.

Subgroups analysis
An analysis was also undertaken of the Ancrod patients whose 6-hour fibrinogen levels were below or above the median value of 130 mg/dl (Table 2). Patients achieving the 6-hour fibrinogen levels at or below the median value of 130 mg/dl had a perfect median Barthel Index score (95) at 3 months compared with a score of 75 in those with fibrinogen levels above 130 mg/dl. The improvement in 3-month SSS score with patients achieving the lower fibrinogen levels was greater than in those with higher levels and this difference just missed significance (42 vs 36, p=0.53) .3 No patient in either group developed a symptomatic intracerebral haemorrhage and, in comparison to placebo, clinically important bleeding complications were not increased in the Ancrod-treated patients.3

Although there were no statistically significant differences in neurological outcome scores there was a trend in this study favouring Ancrod treatment. This was more evident in those Ancrod patients with lower fibrinogen levels. Overall, however, the results of this study do indicate that Ancrod may be a safe and potentially beneficial therapy for acute ischaemic stroke.

Table 2. Subgroup analysis of outcome scores for patients with plasma fibrinogen less than 130 mg/dl.

References
1. Hossman V, Heiss W-D, Bewermeyer H, Wiedemann G. Controlled trial of Ancrod in ischemic stroke. Arch Neurol 1983; 40: 803-808.
2. Olinger CP, Brott TG, Barsan WG et al. Use of Ancrod in acute or progressing ischemic cerebral infarction. Ann Emergency Med 1988; 17 (11): 1208-1209.
3. Ancrod Stroke Study Investigators. Ancrod for the treatment of acute ischemic brain infarction. Stroke 1994; 25: 1755-1759.

n STROKE TREATMENT with ANCROD TRIAL (STAT)

The efficacy of Ancrod in the treatment of acute ischaemic stroke has yet to be conclusively demonstrated in a large-scale, randomized, double-blind trial. However, a large-scale trial is currently underway in the United States which aims to confirm the efficacy and safety of Ancrod administered within 3 hours from onset of symptoms in the early treatment of acute ischaemic stroke.

Since the earlier Ancrod Stroke Study results suggested that lower fibrinogen levels are associated with greater therapeutic benefit, this study has target fibrinogen target levels of 40-70 mg/dl compared with the target of 70-100 mg/dl in the Ancrod Stroke Study. Continuous infusion of Ancrod enables adjustment of the infusion rate based on initially frequent fibrinogen level determinations.

The study, which plans to enrol 470 patients in 25-30 centres with 235 patients in each treatment group, was begun in August 1993 and is due for completion in 1997. As of January 1997, 407 of the 470 patients planned for the study have been enrolled.

The primary efficacy parameter is activities of daily living and level of physical performance measured by the Barthel Index. Secondary efficacy parameters include neurological deficit measured by the Scandinavian Stroke Scale (SSS).

Interim results from the study show that mean fibrinogen levels are within the target range approximately nine hours after beginning treatment with Ancrod and then remain generally within range at least through the continuous infusion period of 72 hours (Figure 1).

Figure 1. Mean fibrinogen levels in patients receiving Ancrod.

In the total patient population enrolled to date, important variables are mean age (72 years, older than the generally-accepted mean of 67) and mean interval from stroke onset to treatment of 2.2 hours.

Although it is too early to evaluate efficacy results, the safety/monitoring committee has been reviewing safety issues on a continuing basis and completed the second pre-planned, interim analysis in the autumn of 1996. Up to January 1997, there have been altogether 85 deaths (21%) within 3 months of stroke onset. Ten patients have had symptomatic intracranial haematomas.

The blinded safety analysis in October 1996 identified no safety problems and recommended study continuation to completion.

n EUROPEAN STROKE TREATMENT with ANCROD TRIAL (ESTAT)

The European based Ancrod trial is a multicentre, randomised, double-blind placebo controlled study of the efficacy and safety of i.v. Ancrod administered within 6 hours after the onset of acute ischaemic stroke symptoms.

600 patients (300 per treatment group) are planned to be enrolled in at least 30 centres. Patient enrolment was begun in the second half of 1996 and 19 centres have initiated recruiting patients. The trial is expected to run through to 1999.

As in STAT, this study is also evaluating lower fibrinogen target levels of 40-70 mg/dl. These target levels have previously been shown to be safe and, as suggested by the investigators of the Ancrod Stroke Study, may be associated with greater therapeutic benefit.1 The treatment period involves continuous intravenous infusion of Ancrod for 72 hours to maintain plasma fibrinogen in the target range of 40-70 mg/dl followed by 2 days of intermittent i.v. dosing. Follow up will be at 3 months to evaluate the main efficacy parameter, with long-term follow-up continued over 12 months (Figure 1).

The primary efficacy parameter is the Barthel Index of functional status at three months. Secondary efficacy parameters include improvement in neurological deficit measured by the Scandinavian Stroke Scale (SSS), success in the Rankin Scale, death rates and CT infarct volume data at month 3.

* Pre-stroke information

Safety variables include death, intracerebral haematoma, thrombotic complications and clinical adverse events.

In addition, the health economic costs of each therapeutic alternative will be evaluated and will include costs of patients' stay in intensive care unit and of total hospitalisation.

Principal investigator
Prof. Dr. Michael G. Hennerici Department of Neurology - University of Heidelberg - Klinicu Mannheim Theodor-Kutzer-Ufer 1 - D-68135 Mannheim (Germany)

Reference
1. Ancrod Stroke Study Investigators. Ancrod for the treatment of acute ischemic brain infarction. Stroke 1994; 25: 1755-1759.

Ancrod administration produces rapid and effective defibrinogenation.1

Reduction in fibrinogen levels with Ancrod results in a progressive reduction in blood viscosity.2

Ancrod also shows a fibrinolytic effect and locally enhances fibrinolysis and clot-specific thrombolysis.2,3

A close linear relationship between blood fibrinogen levels and thrombus score or weight has been shown in animal models.4

In animal models, Ancrod has been shown to cause a significant brain lesion reduction even if Ancrod therapy is delayed up to 3 hours.4

In a double-blind, randomised study of intravenous Ancrod or placebo given within 6 hours of stroke onset, patients with Ancrod-induced 6-hour fibrinogen levels of 130 mg/dl or less had a marginally significantly better neurological outcome on the Scandinavian Stroke Scale and improvements in mortality and volume of infarct size.5

In clinical trials of Ancrod, it has been shown to be remarkably safe, and is not associated with increased bleeding.2

The safety and efficacy of Ancrod in the early treatment of acute stroke is currently being evaluated in two large multicentre, double-blind, placebo-controlled trials in the US (STAT) and in Europe (ESTAT).

References
1. Wright JG, Geroulakos G. Semin Vasc Surg 1996; 9: 315-328.
2. Illig KA, Ouriel K. Semin Vasc Surg 1996; 9: 303-314.
3. Glas-Greenwalt P, Levy DE. Thrombosis Haemostasis 1995; 73: 1151.
4. Elger B et al Eur J Neurol 1995; 2 (Suppl 2): 58.
5. The Ancrod Stroke Study Investigators. Stroke 1994; 25: 1755-1759.

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