The argatroban and tissue-type plasminogen activator stroke study: final results of a pilot safety study.
OBJECTIVE
Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tissue-type plasminogen activator (tPA) in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion.


METHODS
During standard-dose intravenous tPA, a 100-μg/kg bolus of Argatroban and infusion for 48 hours was adjusted to a target partial thromboplastin time of 1.75× baseline. The primary outcome was incidence of significant intracerebral hemorrhage defined as either symptomatic intracerebral hemorrhage or Parenchymal Hematoma Type 2. Recanalization was measured at 2 and 24 hours by transcranial Doppler or CT angiography.


RESULTS
Sixty-five patients were enrolled (45% men, mean age 63±14 years, median National Institutes of Health Stroke Scale=13). The median (interquartile range) time tPA to Argatroban bolus was 51 (38-60) minutes. Target anticoagulation was reached at a median (interquartile range) of 3 (2-7) hours. Significant intracerebral hemorrhage occurred in 4 patients (6.2%; 95% CI, 1.7-15.0). Of these, 3 were symptomatic (4.6%; 95% CI, 0.9-12.9). Seven patients (10%) died in the first 7 days. Within the 2-hour monitoring period, transcranial Doppler recanalization (n=47) occurred in 29 (61%) patients: complete in 19 (40%) and partial in another 10 (21%).


CONCLUSIONS
The combination of Argatroban and intravenous tPA is potentially safe in patients with moderate neurological deficits due to proximal intracranial arterial occlusions and may produce more complete recanalization than tPA alone. Continued evaluation of this treatment combination is warranted.


BACKGROUND
URL: www.clinicaltrials.gov. Unique identifier: NCT00268762.
Department of Neurology, University of Texas–Houston Medical School, Houston, TX, USA. andrew.d.barreto@uth.tmc.edu
Andrew D
AD
Barreto
Andrei V
AV
Alexandrov
Pat
P
Lyden
Jessica
J
Lee
Sheryl
S
Martin-Schild
Loren
L
Shen
Tzu-Ching
TC
Wu
April
A
Sisson
Renganayaki
R
Pandurengan
Zhongxue
Z
Chen
Mohammad H
MH
Rahbar
Clotilde
C
Balucani
Kristian
K
Barlinn
Rebecca M
RM
Sugg
Zsolt
Z
Garami
Georgios
G
Tsivgoulis
Nicole R
NR
Gonzales
Sean I
SI
Savitz
Robert
R
Mikulik
Andrew M
AM
Demchuk
James C
JC
Grotta
D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use*; D000991:Antithrombins / Q000009:adverse effects* / Q000627:therapeutic use*; D001120:Arginine / Q000031:analogs & derivatives; D002545:Brain Ischemia / Q000150:complications / Q000628:therapy; D002536:Cerebral Arteries / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D002550:Cerebral Veins / Q000473:pathology; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D010865:Pilot Projects; D010875:Pipecolic Acids / Q000009:adverse effects* / Q000627:therapeutic use*; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology; D013449:Sulfonamides; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000627:therapeutic use*; D016896:Treatment Outcome; D017585:Ultrasonography, Doppler, Transcranial
D000925:Anticoagulants; D000991:Antithrombins; D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; D010959:Tissue Plasminogen Activator; C031942:argatroban