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

Abstract

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.

Explicit Consideration of Baseline Factors to Assess Recombinant Tissue-Type Plasminogen Activator Response With Respect to Race and Sex

“…18,20,21 A matching method based on weighted Euclidean distances was adapted to obtain a pair of subjects considered to be the nearest neighbors in an 3D space of NIHSS, age, and glucose. 18,23,24 Because there were fewer blacks relative to whites available to match, we were able to find a suitable white subject for each black subject.…”

“…19 pPAIRS can be applied to smaller populations, as long as there is sufficient overlap of subject characteristics for matching. 18,20,21 Despite being completed nearly 2 decades ago, the NINDS rtPA dataset remains one of the best characterized datasets, and the only randomized controlled clinical trial of rtPA with a reasonably proportionate enrollment of blacks. Therefore, we used this dataset to investigate potential race, sex, and race-plus-sex outcome differences after rigorous consideration of baseline variables.…”

Exploratory Analysis of Glyburide as a Novel Therapy for Preventing Brain Swelling

“…The K-nn algorithm used here guarantees in identifying the nearest-neighbor matches considering all variables simultaneously [27, 28] and has been demonstrated to provide good matching in relatively small samples [29]. Weighting minimizes the influence of factors that are scaled across wide ranges.…”

Influence of Racial Differences on Outcomes after Thrombolytic Therapy in Acute Ischemic Stroke

“…race ethnicity) and continuous (e.g. NIHSS, age) variables (16–18). The software weights individual variables so that their influence on the final match is not skewed by a larger range, and it considers poorly matched patients as outliers, excluding them using Tukey's method (16,19).…”