ESTAT: Snake-venom drug ineffective in stroke beyond standard three-hour treatment window
November 23, 2006
Caroline Cassels
From Medscape Medical News-a professional news service of WebMD
Heidelberg, Germany - Ancrod, a natural defibrinogenating agent derived from snake venom, should not be used to treat ischemic stroke more than three hours after symptom onset, a new study has found [1].
The European Stroke Treatment with Ancrod Trial (ESTAT) found that attempting to extend the standard ischemic-stroke treatment window from three to six hours using this agent increased the rate of intracerebral hemorrhage (ICH) and three-month mortality, compared with placebo.
The study is published in the November 23, 2006 issue of the Lancet.
"On the basis of our findings, ancrod should not be recommended for use in acute ischemic stroke beyond three hours," the authors write.
Widening the treatment window
Investigators were encouraged by the results of the North American Stroke Treatment with Ancrod Trial (STAT). Published in 2000 in JAMA [2], it included 500 patients and had an almost identical design to ESTAT. STAT found when ancrod was given within three hours after acute ischemic stroke, outcomes were better than they were in the control group.
"Our aim [with the ESTAT study] was to see whether ancrod was effective with a six-hour window rather than a three-hour window, as was used in STAT," the authors write.
Led by Dr Michael Hennerici (University of Heidelberg, Germany), the multicenter, randomized, double-blind, placebo controlled phase 3 study included 1222 patients from Europe, Australia, and Israel. Of these, 604 subjects were randomly assigned to receive ancrod and the remaining 618 received placebo.
Patients over age 18 with an acute moderate or severe neurological deficit suggestive of an ischemic event were eligible for the study. Treatment was started within six hours of symptom onset. Those with evidence of parenchymal hemorrhage and hemorrhagic transformation on CT imaging, or with major signs of developing infarction, were excluded from the study.
Higher mortality
Patients received ancrod or placebo as a continuous 72-hour intravenous infusion, followed by daily single infusions lasting approximately one hour for two days, to reach and maintain a target fibrinogen concentration of 1.2-2.1 µmol/L.
Ancrod was given at initial infusion rates of 1.00, 0.75, and 0.50 IU/kg, per six hours, based on pretreatment fibrinogen concentrations of >13.2 µmol/L, 10.3-13.2 µmol/L, or <10.3 µmol/L, respectively.
Patients were not allowed to receive antiplatelet agents, oral anticoagulants, thrombolytics, heparin, or other drugs that might affect the fibrinolytic system.
Functional success at three months was the study's primary outcome, which was defined as survival to follow-up with a Barthel index score of 95 to 100, or at least equal to prestroke value. Secondary outcomes included the modified Scandinavian Stroke Scale, the modified Rankin Scale, death rates at three and 12 months, and CT infarct-volume at day seven.
At three-month follow-up, functional outcomes in the ancrod and placebo groups were the same. The authors report that 42% of patients in both groups had a Barthel index score >95 or had returned to prestroke values. However, neurological recovery was worse in the placebo group.
At 20%, 90-day mortality was worse in the ancrod group than in the placebo group (14%). However, the authors report that 12-month mortality did not differ significantly between the two groups.
Timing (still) matters
Symptomatic and asymptomatic ICH at day 28 occurred in 13% of patients in the ancrod group and 4% in the placebo group. However, neurological recovery was worse in the placebo group.
"Symptomatic intracranial hemorrhage occurred significantly more often in patients given ancrod, compared with those given placebo, and mainly arose within seven days. Asymptomatic intracranial hemorrhage also occurred more often in the ancrod group than the placebo group," the authors write.
However, the authors note that despite the discouraging differences in death and intracranial hemorrhage rates between the two groups, the overall death rate in ESTAT was lower than in the control groups of earlier controlled trials, including the Neurological Disorders and Stroke (NINDS) tPA trial, which reported a death rate of 21% among controls, and STAT's 23% death rate.
In an accompanying editorial, Dr Markku Kaste (Helsinki University Central Hospital, Finland), notes that "although the study was unsuccessful, it delivers an important message: that time from onset of symptoms to treatment matters, and in ESTAT it was too long."
Accentuate the negative
As an addendum to the study, the authors note that it is just as important to report negative results as it is positive results. They cite the struggle they had to publish the ESTAT trial results, the preliminary findings of which were originally reported in 2001 at the World Federation of Neurology Congress in London.
After this conference, they write, the pharmaceutical company that supported the trial (Knoll AG) was sold. Thereafter, the data from the study were not fully available to the investigators, making further analysis difficult.
According to the authors, "only with the support of many dedicated investigators and after careful reassessment of the material finally provided" were they able to prepare the current report.
"This situation illustrates the understandable, but often regrettable divergences between sponsor and investigators' interest, leading to scientific losses and unethical waste of patients' and investigators' efforts. The bias towards easier publication of successful trials, sometimes at too early a stage, is another important issue to consider: the publication of this report is therefore an important recognition of the scientific and medical value of all clinical trials," they write. |
