Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial.
ABSTRACT NXY-059 is a free radical-trapping neuroprotectant demonstrated to reduce disability from ischemic stroke. We conducted analyses on additional end points and sensitivity analyses to confirm our findings.
We randomized 1722 patients with acute ischemic stroke to a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours of stroke onset. The primary outcome was disability at 90 days, as measured by the modified Rankin Scale (mRS), a 6-point scale ranging from 0 (no residual symptoms) to 5 (bed-bound, requiring constant care). Additional and exploratory analyses included mRS at 7 and 30 days; subgroup interactions with final mRS; assessments of activities of daily living by Barthel index; and National Institutes of Health Stroke Scale (NIHSS) neurological scores at 7 and 90 days.
NXY-059 significantly improved the distribution of the mRS disability score compared with placebo at 7, 30, and 90 days (Cochran-Mantel-Haenszel test P=0.002, 0.004, 0.038, respectively; 90-day common odds ratio 1.20; 95% CI, 1.01 to 1.42). The benefit was not attributable to any specific baseline characteristic, stratification variable or subgroup interaction. Neurological scores were improved at 7 days (odds ratio [OR], 1.46; 95% CI, 1.13, 1.89; P=0.003) and the Barthel index was improved at 7 and 30 days (OR, 1.55; 95% CI, 1.22, 1.98; P<0.0001; OR, 1.27; 95% CI, 1.01, 1.59; P=0.02).
NXY-059 within 6 hours of acute ischemic stroke significantly reduced disability. Benefit on neurological scores and activities of daily living was detectable early but not significant at 90 days; however, our trial was underpowered to measure effects on the neurological examination. The benefit on disability is not confounded by interactions and is supported by other outcome measures.
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ABSTRACT: BACKGROUND: The neurotrophic drug Cerebrolysin accelerated recovery and prevented acute neuronal damage in preclinical models of ischaemia. Previous clinical trials support therapeutic effects in stroke patients. The study investigated whether the combination with alteplase and Cerebrolysin is safe and can further reduce disability after acute ischaemic stroke. METHODS: This placebo-controlled, double-blind trial involved 119 patients with acute ischaemic hemispheric stroke, randomly assigned to a combined treatment with alteplase plus Cerebrolysin or placebo (administered 1 h after thrombolytic treatment) starting within three-hours after onset of symptoms. A daily i.v. infusion of 30 ml Cerebrolysin or placebo was given for 10 consecutive days. Primary outcome was the modified Rankin Scale at day 90. A sequential design with interim analyses was applied. RESULTS: The third interim analysis did not show a benefit in the modified Rankin Scale for Cerebrolysin on day 90 compared to placebo and the study was stopped. The National Institutes of Health Stroke Scale responder analysis (secondary outcome measure) showed significantly more patients with an improvement of 6 or more points (or a total score of 0 or 1) after two-, five-, 10, and 30 days in the Cerebrolysin group. Similar trends were observed for the modified Rankin Scale responder analysis without achieving statistical significance. There was no difference between treatment groups regarding adverse events. CONCLUSIONS: The combination of Cerebrolysin with recombinant tissue-Plasminogen Activator is safe for treatment of acute ischaemic stroke but did not improve outcome at day 90. During the treatment period with Cerebrolysin (10 days), significantly more patients had a favourable response in neurological outcome measures (National Institutes of Health Stroke Scale) as compared to the placebo group.International Journal of Stroke 09/2012; · 2.75 Impact Factor
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ABSTRACT: The use of alteplase in patients who have had a prior stroke and concomitant diabetes is not approved in Europe. To examine the influence of diabetes and prior stroke on outcomes, we compared data on thrombolysed patients with nonthrombolysed comparators. We selected patients with ischemic stroke on whom we had data on age, pretreatment baseline National Institutes of Health Stroke Scale (b-NIHSS), and 90-day outcome measures (functional modified Rankin score [mRS]) and neurological measures [NIHSS]) in the Virtual International Stroke Trials Archive. We compared outcomes between thrombolysed patients and nonthrombolysed comparators in those with and without diabetes, those who have had a prior stroke, or both and report findings using the Cochran-Mantel-Haenszel (CMH) test and proportional odds logistic regression analyses. We report an age-adjusted and b-NIHSS-adjusted CMH P value and odds ratio (OR). Rankin data were available for 5,817 patients: 1,585 thrombolysed patients and 4,232 nonthrombolysed comparators. A total 1,334 (24.1%) patients had diabetes, 1,898 (33.7%) patients have had a prior stroke, and 491 (8%) patients had both. Diabetes and nondiabetes had equal b-NIHSS (median 13; P = 0.3), but patients who have had a prior stroke had higher b-NIHSS than patients who have not had a prior stroke (median 13 vs. 12; P < 0.0001). Functional outcomes were better for thrombolysed patients versus nonthrombolysed comparators among both nondiabetic (P < 0.0001; OR 1.4 [95% CI 1.3-1.6]) and diabetic (P = 0.1; 1.3 [1.05-1.6 ]) subjects. Similarly, outcomes were better for thrombolysed patients versus nonthrombolysed comparators among who have not had a prior stroke (P < 0.0001; 1.4 [1.2-1.6 ]) and those who have (P = 0.02; 1.3 [1.04-1.6 ]). There was no interaction of diabetes and prior stroke with treatment (P = 0.8). Neurological outcomes were consistent with the mRS. Outcomes from thrombolysis are better among patients with diabetes and/or those who have had a prior stroke than in control subjects. Withholding thrombolytic treatment from otherwise-eligible patients may not be justified.Diabetes care 12/2010; 33(12):2531-7. · 7.74 Impact Factor
Article: Stroke management[Show abstract] [Hide abstract]
ABSTRACT: Stroke is the third most common cause of death in most developed countries. It is a worldwide problem; about 4.5 million people die from stroke each year. Stroke can occur at any age, but half of all strokes occur in people aged over 70 years. About 80% of all acute strokes are ischaemic, usually resulting from thrombotic or embolic occlusion of a cerebral artery. The remainder are caused either by intracerebral or subarachnoid haemorrhage. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of specialised care in people with acute stroke? What are the effects of medical treatment in people with acute ischaemic stroke? What are the effects of decompressive hemicraniectomy in acute ischaemic stroke? What are the effects of surgical evacuation for intracerebral haematomas? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 41 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: acute reduction in blood pressure, aspirin, evacuation (early surgical evacuation, or conservative treatment), decompressive hemicraniectomy, neuroprotective agents (calcium channel blockers, citicoline, gamma-aminobutyric acid agonists, glycine antagonists, lubeluzole, magnesium, N-methyl-D-aspartate antagonists), specialised stroke care, systemic anticoagulation (heparinoids, specific thrombin inhibitors, low molecular weight heparin, oral anticoagulants, unfractionated heparin), and thrombolysis.Clinical evidence 01/2011;