A Pilot Trial of Low-Dose Intravenous Abciximab and Unfractionated Heparin for Acute Ischemic Stroke: Translating GP IIb/IIIa Receptor Inhibition to Clinical Practice.

Thrombolysis remains a mainstay in the treatment of ischemic stroke. While not usually considered in the spectrum of clot lysis, experimental data show that inhibition of the platelet glycoprotein (GP) IIb/IIIa receptor can reduce as well as reverse thrombus formation and improve microvascular flow in stroke models. However, a recent clinical trial of GP IIb/IIIa inhibition in stroke did not demonstrate clinical benefit and was associated with increased hemorrhage. Based on an understanding of the relationship between GP IIb/IIIa receptor inhibition, efficacy and hemorrhage, we hypothesized that a lower dose of abciximab would achieve a favorable range of platelet inhibition and potentially good clinical outcomes. Forty-four patients with suspected large vessel occlusion, who were not eligible for rt-PA were offered treatment with approximately 30% lower total dose of intravenous abciximab if within 6 h for anterior circulation or 24 h for posterior circulation stroke (later modified to 12 h). Concomitant anticoagulation, usually with unfractionated heparin was employed. The extent of platelet inhibition was measured in 21 patients. Hemorrhage rate and 90-day functional outcomes and mortality were obtained. A matching algorithm involving finding the nearest neighbor from individual subjects in the control arm of the NINDS rt-PA database was used to compare outcomes at similar baseline characteristics and gender. Mean platelet inhibition was 92.1 ± 6.7% vs inhibition reported with percutaneous coronary intervention (PCI) of 96 ± 10; p = 0.08. Successful matching to NINDS controls was accomplished: after outlier elimination, median and mean NIHSS of the abciximab subjects compared to NINDS controls was 16.5 vs 15.5 (p = 0.92) and 16.3 vs 16.0 (p = 0.86). Mean age was 67.2 vs 67.1 (p = 0.97). Mean glucose was 141 vs 142 (p = 0.92). There was one symptomatic hemorrhage; minor hemorrhages occurred in 9%. The percent of patients who achieved an mRS 0-2 or died in the treated vs matched NINDS control patients was 63 vs 38 (p = .02) and 23 vs 23 (p = 1.0). Our pilot results indicated that a lower dose of abciximab results in platelet inhibition similar to that achieved in the coronary vascular bed during PCI. Comparison to matched historical controls suggests that this lower dose in combination therapy may be safe and effective therapy for thrombotic stroke and a randomized trial is warranted.

Thrombus burden is associated with clinical outcome after intra-arterial therapy for acute ischemic stroke.

BACKGROUND AND PURPOSE: Studies have established a relation between recanalization and improved clinical outcome in acute ischemic stroke patients; however, intra-arterial clot size has not been routinely assessed. The aim of the study was to determine the impact of intra-arterial thrombus burden on intra-arterial treatment (IAT) and clinical outcome. METHODS: A retrospective review of our IAT stroke database included procedure time, recanalization, symptomatic intracranial hemorrhage, poor outcome (modified Rankin Scale score >/=4 at discharge), and mortality. The modified Thrombolysis in Myocardial Infarction thrombus grade was dichotomized into grades 0 to 3 (no clot or moderate thrombus, <2 vessel diameters) versus grade 4 (large thrombus, >2 vessel diameters). RESULTS: Data were collected on 135 patients with thrombus grading. The baseline median National Institutes of Health Stroke Scale score was higher in patients of grade 4 compared with grades 0 to 3 (19 vs 17, P=0.012). Grade 4 thrombi required longer (median, range) times for IAT (113, 37 to 415 minutes vs 74, 22 to 215 minutes, respectively; P<0.001) and higher rates of mechanical clot disruption (wire, angioplasty, snare, stent, or Merci retriever) compared with grades 0 to 3 (76% vs 53%, P=0.005). There were no differences in rates of symptomatic intracranial hemorrhage (6.6% vs 4.1%, P=0.701) or recanalization (50% vs 61%, P=0.216) in grade 4 versus grades 0 to 3. Multivariate analysis adjusted for age, baseline National Institutes of Health Stroke Scale score, and artery of involvement showed that grade 4 thrombi were independently associated with poor outcome (odds ratio=2.4; 95% CI, 1.06 to 5.57; P=0.036) and mortality (odds ratio=4.0; 95% CI, 1.2 to 13.2; P=0.023). CONCLUSIONS: High thrombus grade as measured by the modified Thrombolysis in Myocardial Infarction criteria may be a risk factor that contributes to poor clinical outcome.

Is intra-arterial thrombolysis safe after full-dose intravenous recombinant tissue plasminogen activator for acute ischemic stroke?

BACKGROUND AND PURPOSE: The optimal approach for acute ischemic stroke patients who do not respond to intravenous recombinant tissue plasminogen activator (IV rt-PA) is uncertain. This study evaluated the safety and response to intra-arterial thrombolytics (IATs) in patients unresponsive to full-dose IV rt-PA. METHODS: A case series from a prospectively collected database on consecutive acute ischemic stroke patients treated with IATs after 0.9 mg/kg IV rt-PA during a 7-year interval was collected. Primary outcome measures included symptomatic intracranial hemorrhage and mortality. As indicators of response, secondary outcome measures were recanalization and discharge disposition. RESULTS: Sixty-nine patients (mean+/-SD age, 60+/-13 years; range, 26 to 85 years; 55% male) with a median pretreatment National Institutes of Health Stroke Scale score of 18 (range, 6 to 39) were included. IV rt-PA was started at 124+/-32 minutes (median, 120 minutes) and IAT, at 288+/-57 minutes (median, 285 minutes). IATs consisted of reteplase (n=56), alteplase (n=7), and urokinase (n=6), with an average total dosage of 2.8 U, 8.6 mg, and 700 000 U, respectively. Symptomatic intracranial hemorrhage occurred in 4 of 69 (5.8%) patients; 3 cases were fatal. Recanalization was achieved in 50 (72.5%) and a favorable outcome (home or inpatient rehabilitation) in 38 (55%). CONCLUSIONS: IAT therapy after full-dose IV rt-PA in patients with persisting occlusion and/or lack of clinical improvement appears safe compared with IV rt-PA alone or low-dose IV rt-PA followed by IAT. A high rate of recanalization and favorable outcome can be achieved.

Aneurysmal subarachnoid hemorrhage in patients with Hunt and Hess grade 4 or 5: treatment using the Guglielmi detachable coil system.

BACKGROUND AND PURPOSE: Patients in poor clinical condition (Hunt and Hess grade 4 or 5) after subarachnoid hemorrhage (SAH) have historically fared poorly and many often were excluded from aggressive treatment. Early aggressive surgical treatment of SAH can produce good-quality survival for a higher percentage of patients than previously reported. We assessed the outcome of patients with Hunt and Hess grade 4 or 5 who were treated with Guglielmi detachable coil (GDC) embolization. METHODS: We retrospectively evaluated the records of 27 consecutive grade 4 and 5 patients with 29 aneurysms treated within 72 hours of SAH by using GDCs. Percentage aneurysm occlusion after embolization, perioperative complications, and symptoms of vasospasm were evaluated. Outcome was assessed with the Glasgow Outcome Scale. RESULTS: Sixteen patients (59%) were grade 4, and 11 (41%) were grade 5. Eighteen (67%) had one aneurysm, six (22%) had two aneurysms, and three (11%) had three aneurysms. Twenty-nine aneurysms were treated. Fourteen (48%) were completely occluded, and four (14%) were nearly completely occluded (>/=95% occlusion) at embolization. Eleven aneurysms (38%) had partial coiling (<95% occlusion). In the 27 patients, one technical (4%) and one clinical (4%) complication occurred at embolization. No rehemorrhage occurred in any patients (follow-up, 6-44 months; mean, 23 months). Twenty-five (92%) had vasospasm, and seven required endovascular treatment because of worsening clinical status. Sixteen patients (59%) died within 30 days of SAH. Eight patients (30%) had a good clinical outcome at a mean follow-up of 23 months. CONCLUSION: Patients with Hunt and Hess grade 4 or 5 after SAH can undergo successful coil embolization of the aneurysms despite their poor medical condition and a high frequency of vasospasm at the time of treatment. Morbidity and mortality rates with this disease are still high. These findings compare favorably with those published in surgical series for aggressively treated patients with Hunt and Hess grade 4 or 5.