Targeting Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke Based on Risk of Intracranial Hemorrhage or Poor Functional Outcome An Analysis of the Third International Stroke Trial

ArticleinStroke 45(4) · March 2014with16 Reads
DOI: 10.1161/STROKEAHA.113.004362 · Source: PubMed
Abstract
Intravenous recombinant tissue-type plasminogen activator (rtPA), despite a risk of early symptomatic intracranial hemorrhage (sICH), is of net clinical benefit to acute stroke patients. We tested if predictive models could identify patients least likely to be harmed by sICH or those who gained no net benefit. We used the Third International Stroke Trial (IST-3) trial data set, an international, multicenter, open treatment randomized trial of 0.9 mg/kg rtPA versus control in 3035 patients with acute ischemic stroke. We compared the discrimination and calibration of previously developed predictive models for ICH and poststroke poor outcome and developed a new model using variables selected by systematic review. We calculated the absolute and relative risk reduction of death or dependency with rtPA in patients at a low, medium, or high predicted risk of sICH or poor functional outcome. Prediction models for sICH or poor outcome (Hemorrhage After Thrombolysis [HAT]; Sugar, Early Infarct Signs, Dense Artery, Age, National Institutes of Health (NIH) Stroke Score (SEDAN); Glucose Race Age Sex Pressure Stroke Severity [GRASPS]; Stroke Thrombolytic Predictive Instrument; Dense Artery, Rankin Score, Age, Glucose, Onset to Treatment Time, NIHSS [DRAGON]; Totaled Health Risk in Vascular Events [THRIVE]; our new model; and a model with National Institutes of Health Stroke Scale and age) had similar area under receiver operator characteristic curves (AUROCC) to predict sICH (P for difference >0.05). The simplest model (with covariates National Institutes of Health Stroke Scale and age) predicted both sICH (AUROCC, 0.63; 95% CI, 0.58-0.68) and poststroke poor functional outcome (AUROCC, 0.80; 95% CI, 0.77-0.82) similarly to complex models. There was no evidence that the effect of rtPA in patients at high predicted risk of sICH or poor functional outcome after stroke was less than in those at lower risk. There is a clinically relevant net positive effect of rtPA in patients with acute stroke at a high predicted risk of sICH or poor functional outcome. http://www.controlled-trials.com. Unique identifier: ISRCTN25765518.
    • "A low NIHSS score generally corresponds to patients with neurological deficit that is only slightly disabling, and is one of the exclusion criteria in summaries of product characteristics to avoid the risk of bleeding. However, these results and those from a recent clinical trial have led to a rethink, as it is known that not all cases with low NIHSS have a good outcome [33]. In the analysis of factors influencing prognosis, as in other studies, the NIH stroke severity scale stands out [34]. "
    [Show abstract] [Hide abstract] ABSTRACT: The primary objective of this sub analysis of the CONOCES study was to analyse outcomes in terms of mortality rates, quality of life and degree of autonomy over the first year in patients admitted to stroke units in Spain. The secondary objective was to identify the factors determining good prognosis. We studied a sample of patients who had suffered a confirmed stroke and been admitted to a Stroke Unit in the Spanish healthcare system. Socio-demographic and clinical variables and variables related to the level of severity (NIHSS), the level of autonomy (Barthel, modified Rankin) and quality of life (EQ-5D) were recorded at the time of admission and then three months and one year after the event. Factors determining prognosis were analysed using logistic regression and ROC curves. A total of 321 patients were recruited, 33% of whom received thrombolytic treatment, which was associated with better results on the Barthel and the modified Rankin scales and in terms of the risk of death. Mean quality of life measured through EQ-5D improved from 0.57 at discharge to 0.65 one year later. Full autonomy level measured by Barthel index increased from 30.1% at discharge to 52.8% at one year and by the modified Rankin scale from 51% to 71%. The rates for in-hospital and 1-year mortality were 5.9% and 17.4% respectively. Low NIHSS scores were associated with a good prognosis with all the outcome variables. The three instruments applied (NIHSS, Barthel and modified Rankin scales) on admission showed good discriminative ability for patient prognosis in the ROC curves. There has been a change in the prognosis for stroke in Spain in recent years as the quality of life at 1 year observed in our study is clearly higher than that obtained in other Spanish studies conducted previously. Moreover, survival and functional outcome have also improved following the introduction of a new model of care. These results clearly promote extension of the model based on stroke units and reinforced rehabilitation to the majority of the more than 100,000 strokes that occur annually in Spain.
    Full-text · Article · Dec 2015
    • "Intravenous administration of recombinant tPA remains the most commonly used proven beneficial intervention for acute ischemic stroke by stimulating thrombolysis and rescues the ischemic brain via restoring blood flow. However, the short therapeutic time window, ICH transformation, poor thrombolytic perfusion rate, and neurotoxicity comprise major limitations to its use [1][2][3]. Annexin A2 is a cell-surface protein that can forma triple complex with tPA and plasminogen, which increases the catalytic efficiency of tPA, enabling it to convert plasminogen to plasmin more efficiently in about 60 fold than same amount of tPA alone in vitro [4]. However, clinically giving large amount of tPA alone but without fibrinolytic assembly of the tPA-annexin A2-plasminogen complex formation, makes tPA converting plasminogen to plasmin inefficiently, which may be partially responsible for the shortcomings of tPA reperfusion therapy[4]. "
    [Show abstract] [Hide abstract] ABSTRACT: We previously have shown that tissue type plasminogen activator (tPA) in combination with its receptor annexin A2 (rA2) protein significantly improved tPA thrombolytic efficacy. In this study we aimed to examine the therapeutic effects of the combination when treated at delayed 4-hourwindow after stroke compared to standard conventional tPA alone in an embolic focal stroke rat model. We compared effects of intravenous tPA alone (10mg/kg) versus a combination of low-dose tPA (5mg/kg) plus 10 mg/kg rA2. Totally 152 rats were used. Our results showed that: (1) at 24 hours after stroke, the combination slightly reducedbrain infarction compared to saline (9.2% reduction), and tPA (7.4% reduction), although the reductions did not reach statistical significance;while the combinationsignificantly reduced (22.2% reduction) the conventional tPA-elevated intracerebral hemorrhagic (ICH) transformation; (2) at 7 days after stroke, the combination significantly attenuated conventional tPA alone-elevated iron deposition at peri-lesion area (68.2% reduction); (3) at 28 days after stroke, the combination significantly improved performance ofadhesive tape-removal test, which was accompanied by asignificantly higher microvessel density at peri-infarct areas compared to conventional tPA alone group.In conclusion, compared to conventional tPA alone, when treated at delayed 4-hour after stroke, the combination of low-dose tPA plus rA2 therapy provides a saferprofile by loweringrisk of ICH transformation and improvesneurological function recovery after stroke. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Full-text · Article · Jul 2015
    • "There is a knowledge gap in understanding the increased damage of BBB integrity-associated hemorrhagic transformation in patients with diabetes/poststroke hyperglycemia after receiving tPA, and lack of effective therapeutics targeting the severe complication (Desilles et al., 2013; Hafez et al., 2014; Whiteley et al., 2014). Although clinical evidence is lacking, accumulating experimental findings suggest that there are interactions of multiple pathogenic factors including hyperglycemia-mediated vascular oxidative stress and inflammation, ischemic insult, and tPA neurovascular toxicity in concert contribute to the BBB disruption–intracerebral hemorrhagic transformation process (Adibhatla & Hatcher, 2008; Ishrat et al., 2012; Wang et al., 2008 ). "
    [Show abstract] [Hide abstract] ABSTRACT: To date, tissue type plasminogen activator (tPA)-based thrombolytic stroke therapy is the only FDA-approved treatment for achieving vascular reperfusion and clinical benefit, but this agent is given to only about 5% of stroke patients in the USA. This may be related, in part, to the elevated risk of symptomatic intracranial hemorrhage, and consequently limited therapeutic time window. Clinical investigations demonstrate that poststroke hyperglycemia is one of the most important risk factors that cause intracerebral hemorrhage and worsen neurological outcomes. There is a knowledge gap in understanding the underlying molecular mechanisms, and lack of effective therapeutics targeting the severe complication. This short review summarizes clinical observations and experimental investigations in preclinical stroke models of the field. The data strongly suggest that interactions of multiple pathogenic factors including hyperglycemia-mediated vascular oxidative stress and inflammation, ischemic insult, and tPA neurovascular toxicity in concert contribute to the BBB damage-intracerebral hemorrhagic transformation process. Development of combination approaches targeting the multiple pathological cascades may help to attenuate the hemorrhagic complication.
    Full-text · Article · Oct 2014
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