Ischemic Stroke
Conditions
Keywords
stroke, thrombin inhibition, thrombolysis, bleeding, outcome
Brief summary
Is the combination of low doses of argatroban in combination with rt-PA safe, and does it increase recanalization in patients with acute ischemic stroke.
Detailed description
All patients with acute ischemic stroke who qualify for IV rt-PA under accepted guidelines, and who have an occluded middle cerebral artery documented on TCD, receive standard dose IV rt-PA and a bolus and 48 hour infusion of argatroban aimed at prolonging the aPTT 1.75 X baseline. Follow up CT scanning and TCD every 30 minutes for 2 hours and then daily will determine the incidence of hemorrhage, recanalization and reocclusion, and serial neurological exam will determine the clinical outcome. For patients without temporal windows, a baseline CT-Angiogram (CTA) demonstrating arterial occlusion can also be enrolled. In those patients, a follow-up CTA (24-36 hours) will be performed.
Interventions
DRUGargatroban
Argatroban IV Infusion at 1mcg/kg/min for 48 hours.
Sponsors
The University of Texas Health Science Center, Houston
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Ischemic stroke symptoms with onset ≤ 3 hours\*. * \*or\<4.5 hours according to local standard of care. Symptoms must be distinguished from another ischemic event such as syncope, seizure, migraine, and hypoglycemia. If the patient reports awakening with the event, the time of onset should be considered as last time the patient (or a witness to the patient's condition) considered herself/himself normal. * 18-85 years of age. * A clot causing complete or partial occlusion (TIBI 0, 1, 2, or 3) via TCD in any one of the following areas: distal iternal carotid artery (ICA), Meddle cerebral artery (MCA - M1 or M2), posterior cerebral arteral (ICA - P1 or P2), distal vertebral or basilar occlusions. TCD must be abnormal prior to the start of Argatroban. For patients without temporal windows (or in centers without emergent access to TCD), an abnormal CTA is required for enrollment (TIMI 0 or 1). * Females of childbearing potential must have a negative serum pregnancy test prior administration of argatroban. * Signed informed consent by the patient or the patient's legal representative. * Meet criteria for rt-PA therapy.
Exclusion criteria
* Evidence of intracranial hemorrhage on baseline CT scan or non-vascular cause of neurologic deficit. * National institute health stroke scale (NIHSS) Level of Consciousness score ≥2. * Baseline (immediately pre-Argatroban) NIHSS ≤ 5 or patient with rapidly resolving deficit or rapidly improving symptoms consistent with TPA. * Baseline NIHSS ≥15 for right hemisphere strokes and ≥20 for left hemisphere strokes. * Pre-existing disability with modified rankin scale (mRS) ≥ 2. * CT scan findings of hypoattenuation of the x-ray signal (hypodensity)involving ≥ 1/2 of the MCA territory. * Any evidence of clinically significant bleeding, or known coagulopathy. * Patients currently on warfarin, with an elevated INR ≥ 1.5. * Patients currently or within previous 48 hrs. on heparin with an elevated aPTT greater than the upper limit of normal. * Heparin flush required for an IV line. Line flushes with saline only. * History of ICH or significant bleeding episode within the 3 months before study enrollment. * Major surgery or serious trauma within the last 6 weeks. * Patients who have had an arterial puncture at a non-compressible site, biopsy of parenchymal organ, or lumbar puncture within the last 2 weeks. * Previous stroke, myocardial infarction, post myocardial infarction pericarditis, intracranial surgery, or significant head trauma within 3 months of baseline. * Uncontrolled hypertension. * Alcohol and/or substance abuse that would increase the risk of hemorrhage in the opinion of the investigator. * Surgical intervention anticipated within the next 7 days. * Hepatic dysfunction, defined by liver function tests greater than 3 times upper limit of normal at baseline, specifically serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT). * Abnormal blood glucose * History of primary or metastatic brain tumor. * Severe mental deficit prior to onset of stroke such as organic brain disorder, schizophrenia, etc. * Concurrent severe neurologic disorder, such as seizure at onset of stroke or uncontrolled seizure disorder that complicates diagnosis of acute ischemic stroke. * Current platelet count\< 100,000/mm3. * Life expectancy \<3 months in the opinion of the investigator. * Need to be on concomitant (i.e, during the Argatroban infusion) anticoagulants other than Argatroban, including any form of heparin, unfractionated heparin (UFH), low molecular weight heparin (LMWH), defibrinogenating agent, dextran, other direct thrombin inhibitors or thrombolytic agents, glycoprotein llb/llla (GPIIb/IIIa) or warfarin.(Caveat: If these anticoagulants can be deferred for 48 hours, then they can be included). * Participated in investigational study within 30 days before the first dose of study medication. * Hypersensitivity to Argatroban or its agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Symptomatic and Radiographic Intracerebral Hemorrhage | Within 7 days of enrollment | Significant intracerebral hemorrhage as defined by either: 1. Symptomatic intracerebral hemorrhage or 2. Parenchymal hematoma type 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Arterial Complete Recanalization at 2 Hours Post tPA Bolus | 2 hours complete recanalization post tPA bolus | Complete Recanalization as measured by either transcranial Doppler Ultrasound at 2 hours post tPA bolus. |
| Arterial Complete Recanalization at 24 Hours Post tPA Bolus | 24 hours from tPA bolus | Complete recanalization at 24 hours post tPA bolus as measured by either transcranial Doppler ultrasound or CT-Angiography. |
Countries
United States
Participant flow
Recruitment details
Date of first enrollment: May 6, 2003 Date of last enrollment: August 20, 2010 All patients enrolled through hospital emergency departments
Participants by arm
| Arm | Count |
|---|---|
| Intervention Argatroban IV bolus 100 mcg/kg bolus, followed by Argatroban IV Infusion 1 mcg/kg/min for 48 hours. Dose adjusted for target PTT of 1.75 times the patient's baseline. | 65 |
| Total | 65 |
Baseline characteristics
| Characteristic | Intervention |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 31 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants |
| Age, Continuous | 63 years STANDARD_DEVIATION 14 |
| Region of Enrollment United States | 65 participants |
| Sex: Female, Male Female | 36 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 55 / 65 |
| serious Total, serious adverse events | 21 / 65 |
Outcome results
Primary
Symptomatic and Radiographic Intracerebral Hemorrhage
Significant intracerebral hemorrhage as defined by either: 1. Symptomatic intracerebral hemorrhage or 2. Parenchymal hematoma type 2.
Time frame: Within 7 days of enrollment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intervention | Symptomatic and Radiographic Intracerebral Hemorrhage | 6.2 percentage of patients |
Secondary
Arterial Complete Recanalization at 24 Hours Post tPA Bolus
Complete recanalization at 24 hours post tPA bolus as measured by either transcranial Doppler ultrasound or CT-Angiography.
Time frame: 24 hours from tPA bolus
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intervention | Arterial Complete Recanalization at 24 Hours Post tPA Bolus | 63 percent of patients |
Secondary
Arterial Complete Recanalization at 2 Hours Post tPA Bolus
Complete Recanalization as measured by either transcranial Doppler Ultrasound at 2 hours post tPA bolus.
Time frame: 2 hours complete recanalization post tPA bolus
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intervention | Arterial Complete Recanalization at 2 Hours Post tPA Bolus | 40 percent of patients |