Argatroban tPA stroke study: study design and results in the first treated cohort.
BACKGROUND
The benefit of intravenous recombinant tissue plasminogen activator (rtPA) in acute stroke is linked to clot lysis and artery recanalization. Argatroban is a direct thrombin inhibitor that safely augments the benefit of rtPA in animal stroke models. There are no human data on this combination.


METHODS
We report the first phase of the Argatroban tPA Stroke Study, an ongoing prospective, open-label, dose-escalation, safety and activity study of argatroban and rtPA in patients with ischemic stroke. The primary outcome was incidence of intracerebral hemorrhage; secondary outcome, complete recanalization at 2 hours. After standard-dose intravenous rtPA administration, a 100-mug/kg bolus of argatroban followed by infusion of 1 mug/kg per minute for 48 hours was adjusted to a target partial thromboplastin time of 1.75 times that of the control group.


RESULTS
Fifteen patients (including 10 men) were enrolled, with a mean +/- SD age of 61 +/- 13 years. All patients had middle cerebral artery occlusions. Baseline median National Institute of Health Stroke Scale score was 14 (range, 4-25). The mean +/- SD time from symptom onset to argatroban bolus administration was 172 +/- 53 minutes. Symptomatic intracerebral hemorrhage occurred in 2 patients, including 1 with parenchymal hemorrhage type 2. Asymptomatic bleeding occurred in 1 patient and there was 1 death. Recanalization was complete in 6 patients and partial in another 4, and reocclusion occurred in 3 within 2 hours of rtPA bolus administration.


CONCLUSIONS
The safety of low-dose argatroban combined with intravenous rtPA may be within acceptable limits, and its efficacy for producing fast and complete recanalization is promising, but a larger cohort of patients is required to confirm these preliminary observations.
Sugg
Rebecca M
RM
Department of Neurology, University of Texas-Houston Medical School, 6431 Fannin, Houston, TX 77030, USA.
Pary
Jennifer K
JK
Uchino
Ken
K
Baraniuk
Sarah
S
Shaltoni
Hashem M
HM
Gonzales
Nicole R
NR
Mikulik
Robert
R
Garami
Zsolt
Z
Shaw
Sandi G
SG
Matherne
Dawn E
DE
Moyé
Lemuel A
LA
Alexandrov
Andrei V
AV
Grotta
James C
JC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000031:analogs & derivatives; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000473:pathology; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010875:Pipecolic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012107:Research Design; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
D010875:Pipecolic Acids; D011994:Recombinant Proteins; D013449:Sulfonamides; D001120:Arginine; D010959:Tissue Plasminogen Activator; C031942:argatroban