Ancrod in acute ischemic stroke: results of 500 subjects beginning treatment within 6 hours of stroke onset in the ancrod stroke program.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Levy
David E
DE
Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY, USA. delmd@nyc.rr.com
del Zoppo
Gregory J
GJ
Demaerschalk
Bart M
BM
Demchuk
Andrew M
AM
Diener
Hans-Christoph
HC
Howard
George
G
Kaste
Markku
M
Pancioli
Arthur M
AM
Ringelstein
E Bernd
EB
Spatareanu
Carmen
C
Wasiewski
Warren W
WW
D000208:Acute Disease; D000368:Aged; D000721:Ancrod / Q000008:administration & dosage* / Q000009:adverse effects; D002543:Cerebral Hemorrhage / Q000139:chemically induced; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010919:Placebos; D020521:Stroke / Q000188:drug therapy*; D013997:Time Factors; D017211:Treatment Failure
D005343:Fibrinolytic Agents; D010919:Placebos; D000721:Ancrod