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James Grotta
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ABSTRACT: It is indisputable that in the first 2 to 3 hours of an acute ischemic, the best strategy to maximize recovery is robustly time-based and depends on getting the artery open as soon as possible. The second law of thermodynamics and the underappreciated effect of clot consistency and size must be accounted for in our efforts to minimize time to recanalization within the first 2 to 3 hours. It is also clear that at later time intervals, beyond 4.5 hours, few patients completely recover even with sustained complete recanalization, and that the ability to recover depends more on physiologic tissue issues than on the duration of the occlusion. Clinical factors as well as imaging should be used to select patients who may benefit from delayed attempts at reperfusion.
Annals of the New York Academy of Sciences 09/2012; 1268(1):141-4. · 3.15 Impact Factor
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James Grotta
Journal of the American Society for Experimental NeuroTherapeutics 06/2011; 8(3):317-8. · 5.38 Impact Factor
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ABSTRACT: "Home time" (HT) refers to the number of days over the first 90 after stroke onset that a patient spends residing in their own home or a relative's home versus any institutional care. It is an accessible and objective parameter, free from subjective bias, with potential as an outcome measure in acute stroke trials. We sought to validate HT and assess treatment responsiveness using independent data.
We estimated HT in the Stroke Acute Ischemic NXY Treatment (SAINT) I neuroprotection trial. We compared outcomes between thrombolyzed (T) and nonthrombolyzed comparators (C) using HT and the modified Rankin Scale. For our primary analysis, we adjusted for baseline covariates that significantly influence HT and in sensitivity analyses considered all variables that differed between groups at baseline. We report ordinal logistic regression and analysis of covariance with 95% CIs. We describe the relationship of HT with baseline National Institutes of Health Stroke Scale and its components and with Day 90 modified Rankin Scale and Barthel Index.
SAINT I included 1699 patients from 23 countries, of whom 28.7% received alteplase. HT correlated with age, baseline severity, alteplase use, side of ischemic lesion, presence of diabetes, and country of patient enrollment (each P<0.05). We found an association between use of alteplase with better adjusted outcomes by either measure (OR for extended HT, 1.36; 95% CI, 1.08 to 1.72; P=0.009; analysis of covariance P=0.007 with a 5.5-day advantage; OR for more favorable modified Rankin Scale, 1.6; 95% CI, 1.28 to 2.00; P<0.0001; Cochran-Mantel-Haenszel P=0.046). HT was significantly associated with baseline National Institutes of Health Stroke Scale and each component of the National Institutes of Health Stroke Scale except level of consciousness, dysarthria, and ataxia. HT was significantly associated with Day 90 modified Rankin Scale and Barthel Index.
HT is a responsive measure for use in multinational acute stroke trials. Its inclusion as a complementary outcome is reasonable. We propose treatment effects are adjusted for age, baseline National Institutes of Health Stroke Scale, side of stroke lesion, country of enrollment, and the presence of diabetes.
Stroke 02/2011; 42(4):1046-50. · 5.73 Impact Factor
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Stroke 02/2010; 41(4):e189; author reply e190. · 5.73 Impact Factor
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ABSTRACT: Measures of a therapy's effect size are important guides to clinicians, patients, and policy-makers on treatment decisions in clinical practice. The ECASS 3 trial demonstrated a statistically significant benefit of intravenous tissue plasminogen activator for acute cerebral ischemia in the 3- to 4.5-hour window, but an effect size estimate incorporating benefit and harm across all levels of poststroke disability has not previously been derived.
Joint outcome table specification was used to derive number needed to treat to benefit (NNTB) and number needed to treat to harm (NNTH) values summarizing treatment impact over the entire outcome range on the modified Rankin scale of global disability, including both expert-dependent and expert-independent (algorithmic and repeated random sampling) array generation.
For the full 7-category modified Rankin scale, algorithmic analysis demonstrated that the NNTB for 1 additional patient to have a better outcome by >or=1 grades than with placebo must lie between 4.0 and 13.0. In bootstrap simulations, the mean NNTB was 7.1. Expert joint outcome table analyses indicated that the NNTB for improved final outcome was 6.1 (95% CI, 5.6-6.7) and the NNTH 37.5 (95% CI, 34.6-40.5). Benefit per 100 patients treated was 16.3 and harm per 100 was 2.7. The likelihood of help to harm ratio was 6.0.
Treatment with tissue plasminogen activator in the 3- to 4.5-hour window confers benefit on approximately half as many patients as treatment <3 hours, with no increase in the conferral of harm. Approximately 1 in 6 patients has a better and 1 in 35 has a worse outcome as a result of therapy.
Stroke 07/2009; 40(7):2433-7. · 5.73 Impact Factor
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ABSTRACT: Many clinical trials are currently evaluating the safety and efficacy of autologous bone marrow (BM) mononuclear cells (MNC) for various pathologies in younger and older non-cancer patients. Concern has been raised that autologous MNC derived from elderly patients may be less effective as a therapeutic option.
We compared the MNC yield, viability, phenotypic markers and in vitro functionality in pediatric patients compared with adult patients enrolled in clinical trials evaluating autologous BM MNC transplantation. Thirty-six patients (n=10 pediatric and n=26 adult) were included in this analysis. All patients underwent BM harvest in which 1-3 mL/kg was aspirated under local anesthesia. MNC were isolated by gradient densitometry. The average age of the older and younger patient groups was 59+/-7 years and 9+/-3 years, respectively.
The average total MNC recovered from the BM in pediatric patients was 2.1 x 10(6)/mL and in older patients was 3.2 x 10(6)/mL. There were no differences in cell viability (>97%) or phenotypic markers identifying T cells, natural killer (NK) cells and neutrophils between the two groups. Of note, the Lin(-)CD34(+) cell population was not different between the groups. Average post-processing CFU-F, CFU-GEMM and BFU-E were not statistically different but there were significantly increased levels of CFU-GM in the older population.
These results suggest that MNC from younger and older non-cancer patients are similar, but the data must be interpreted with caution given the small sample size and limited general understanding of MNC mechanisms of action on target cells. It is still possible that cells from older patients may produce fewer cytokines or be functionally impaired.
Cytotherapy 05/2009; 11(4):480-4. · 3.63 Impact Factor
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Stroke 05/2009; 40(4):1541-2. · 5.73 Impact Factor
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ABSTRACT: No effective therapy is available for treating intracerebral hemorrhage (ICH). One of several key components of brain damage after ICH is the neurotoxicity of blood products. Within hours to days after ICH, extravasated erythrocytes in the hematoma undergo lysis, releasing cytotoxic hemoglobin, heme, and iron, thereby initiating secondary processes, which negatively influence the viability of cells surrounding the hematoma. To offset this process, phagocytic cells, including the brain's microglia and hematogenous macrophages, phagocytose and then process extravasated erythrocytes before lysis and subsequent toxicity occurs. Therefore, we hypothesize that a treatment that stimulates phagocytosis will lead to faster removal of blood from the ICH-affected brain, thus limiting/preventing hemolysis from occurring. CD36 is a well-recognized integral microglia/macrophage cell membrane protein known to mediate phagocytosis of damaged, apoptotic, or senescent cells, including erythrocytes. CD36 and catalase expression are regulated by peroxisome proliferator activated receptor-gamma agonists (eg, rosiglitazone). We demonstrate that peroxisome proliferator activated receptor-gamma agonist-induced upregulation of CD36 in macrophages enhances the ability of microglia to phagocytose red blood cells (in vitro assay), helps to improve hematoma resolution, and reduces ICH-induced deficit in a mouse model of ICH. The beneficial role of peroxisome proliferator activated receptor-gamma-induced catalase expression in the context of phagocytosis is also discussed. Proxisome proliferator activated receptor-gamma agonists could represent a potential treatment strategy for treatment of ICH.
Stroke 01/2009; 40(3 Suppl):S92-4. · 5.73 Impact Factor
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ABSTRACT: Stroke incidence and outcome vary widely within and across geographical locations. We examined whether differences in index stroke severity, stroke risk factors, mortality, and stroke outcome across geographical locations remain after adjusting for case mix.
We analyzed 3284 patients from the Virtual International Stroke Trials Archive (VISTA). We used logistic regression to examine the incidence of mild index stroke, functional, and neurological outcomes after accounting for age, medical history, year of trial recruitment, and initial stroke severity in the functional and neurological outcome analyses. We examined mortality between geographical regions using a Cox proportional hazards model, accounting for age, initial stroke severity, medical history, and year of trial recruitment.
Patients enrolled in the USA and Canada had the most severe index strokes. Those recruited in Austria and Switzerland had the best functional and neurological outcomes at 90 days (P<0.05), whereas those enrolled in Germany had the worst functional outcome at 90 days (P=0.013). Patients enrolled in Austria, Switzerland, Belgium, Netherlands, Finland, Germany, Greece, Israel, Spain, and Portugal had a significantly better survival rate when compared with those enrolled in USA and Canada. Patients enrolled in trials after 1998 had more severe index strokes, with no significant difference in outcome compared with those enrolled before 1998.
We identified regional variations in index stroke severity, outcome, and mortality for patients enrolled in ischemic stroke clinical trials over the past 13 years that were not fully explained by case mix. Index stroke severity was greater in patients enrolled after 1998, with no significant improvement in outcomes compared to those enrolled before 1998.
Stroke 10/2008; 40(1):35-40. · 5.73 Impact Factor
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ABSTRACT: The free-radical-trapping agent NXY-059 showed promise as a neuroprotectant in the Stroke-Acute Ischemic NXY Treatment I (SAINT I) trial, reducing disability when given to patients who had acute ischemic stroke. We sought confirmation of efficacy in a second, larger trial.
We enrolled 3306 patients with acute ischemic stroke in a randomized, double-blind trial to receive a 72-hour infusion of intravenous NXY-059 or placebo within 6 hours after the onset of stroke symptoms. Our primary end point was the distribution of disability scores on the modified Rankin scale at 90 days. We examined scores on neurologic and activities-of-daily-living scales as secondary end points. We also tested the hypothesis that NXY-059 would reduce alteplase-related intracranial hemorrhages.
The efficacy analysis was based on 3195 patients. Prognostic factors were well balanced between the treatment groups. Mortality was equal in the two groups, and adverse-event rates were similar. The distribution of scores on the modified Rankin scale did not differ between the group treated with NXY-059 (1588 patients) and the placebo group (1607 patients; P=0.33 by the Cochran-Mantel-Haenszel test; odds ratio for limiting disability, 0.94; 95% confidence interval [CI], 0.83 to 1.06). Analysis of categorized scores on the modified Rankin scale confirmed the lack of benefit: the odds ratio for trichotomization into modified Rankin scale scores of 0 to 1 versus 2 to 3 versus 4 to 6 was 0.92 (95% CI, 0.80 to 1.06). There was no evidence of efficacy for any of the secondary end points. Among patients treated with alteplase, there was no difference between the NXY-059 group and the placebo group in the frequency of symptomatic or asymptomatic hemorrhage.
NXY-059 is ineffective for the treatment of acute ischemic stroke within 6 hours after the onset of symptoms. (ClinicalTrials.gov number, NCT00061022 [ClinicalTrials.gov].)
New England Journal of Medicine 09/2007; 357(6):562-71. · 53.30 Impact Factor
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Myzoon Ali,
Philip M W Bath,
John Curram,
Stephen M Davis,
Hans-Christoph Diener,
Geoffrey A Donnan,
Marc Fisher,
Barbara A Gregson, James Grotta,
Werner Hacke,
Michael G Hennerici,
Marc Hommel,
Markku Kaste,
John R Marler,
Ralph L Sacco,
Philip Teal,
Nils-Gunnar Wahlgren,
Steven Warach,
Christopher J Weir,
Kennedy R Lees
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ABSTRACT: Stroke has global importance and it causes an increasing amount of human suffering and economic burden, but its management is far from optimal. The unsuccessful outcome of several research programs highlights the need for reliable data on which to plan future clinical trials. The Virtual International Stroke Trials Archive aims to aid the planning of clinical trials by collating and providing access to a rich resource of patient data to perform exploratory analyses.
Data were contributed by the principal investigators of numerous trials from the past 16 years. These data have been centrally collated and are available for anonymized analysis and hypothesis testing.
Currently, the Virtual International Stroke Trials Archive contains 21 trials. There are data on >15,000 patients with both ischemic and hemorrhagic stroke. Ages range between 18 and 103 years, with a mean age of 69+/-12 years. Outcome measures include the Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials.
This resource has the potential to influence clinical trial design and implementation through data analyses that inform planning.
Stroke 06/2007; 38(6):1905-10. · 5.73 Impact Factor
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ABSTRACT: Clinical trials with rt-PA for treating AIS began 20 years ago in 1987, and the pivotal NINDS rt-PA Stroke Study was completed and published in 1995 with FDA approval in 1996, about 10 years ago. A large number of articles emanated from that study and have established the efficacy and generalizability of this treatment.
Here we summarize the background of how the NINDS trial was developed and carried out and its main findings.
The NINDS rt-PA Stroke Study resulted from preclincal and pilot studies and paralleled similar studies carried out around the world. Its positive results, compared with the other trials, probably were due to the early time window for treatment and well-organized clinical and statistical centers. Many controversies have surrounded its use since its approval. As a result of the NINDS rt-PA Stroke Study, many new approaches to thrombolytic therapy are under evaluation.
The results of the NINDS rt-PA Stroke Study have affected the management of patients with acute stroke worldwide.
Surgical Neurology 02/2007; 68 Suppl 1:S12-6. · 1.67 Impact Factor
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Kennedy R Lees,
Antonio Davalos,
Stephen M Davis,
Hans-Christoph Diener, James Grotta,
Patrick Lyden,
Ashfaq Shuaib,
Tim Ashwood,
Hans-Goran Hardemark,
Warren Wasiewski,
Ugochi Emeribe,
Justin A Zivin
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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.
Stroke 01/2007; 37(12):2970-8. · 5.73 Impact Factor
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Kennedy R Lees,
Justin A Zivin,
Tim Ashwood,
Antonio Davalos,
Stephen M Davis,
Hans-Christoph Diener, James Grotta,
Patrick Lyden,
Ashfaq Shuaib,
Hans-Göran Hårdemark,
Warren W Wasiewski
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ABSTRACT: NXY-059 is a free-radical-trapping agent that is neuroprotective in animal models of stroke. We tested whether it would reduce disability in humans after acute ischemic stroke.
We conducted a randomized, double-blind, placebo-controlled trial involving 1722 patients with acute ischemic stroke who were randomly assigned to receive a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours after the onset of the stroke. The primary outcome was disability at 90 days, as measured according to scores on the modified Rankin scale for disability (range, 0 to 5, with 0 indicating no residual symptoms and 5 indicating bedbound, requiring constant care).
Among the 1699 subjects included in the efficacy analysis, NXY-059 significantly improved the overall distribution of scores on the modified Rankin scale, as compared with placebo (P=0.038 by the Cochran-Mantel-Haenszel test). The common odds ratio for improvement across all categories of the scale was 1.20 (95 percent confidence interval, 1.01 to 1.42). Mortality and rates of serious and nonserious adverse events were each similar in the two groups. NXY-059 did not improve neurologic functioning as measured according to the National Institutes of Health Stroke Scale (NIHSS): the difference between the two groups in the change from baseline scores was 0.1 point (95 percent confidence interval, -1.4 to 1.1; P=0.86). Likewise, no improvement was observed according to the Barthel index (P=0.14). In a post hoc analysis of patients who also received alteplase, NXY-059 was associated with a lower incidence of any hemorrhagic transformation (P=0.001) and symptomatic intracranial hemorrhage (P=0.036).
The administration of NXY-059 within six hours after the onset of acute ischemic stroke significantly improved the primary outcome (reduced disability at 90 days), but it did not significantly improve other outcome measures, including neurologic functioning as measured by the NIHSS score. Additional research is needed to confirm whether NXY-059 is beneficial in ischemic stroke. (ClinicalTrials.gov number, NCT00119626.).
New England Journal of Medicine 03/2006; 354(6):588-600. · 53.30 Impact Factor
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Patrick Lyden,
Rema Raman,
Lin Liu, James Grotta,
Joseph Broderick,
Scott Olson,
Sandi Shaw,
Judith Spilker,
Brett Meyer,
Marian Emr,
Margo Warren,
John Marler
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ABSTRACT: NIH Stroke Scale certification is required for participation in modern stroke clinical trials and as part of good clinical care in stroke centers. The existing training and certification videotapes, however, are more than 10 years old and do not contain an adequate balance of patient findings.
After producing a new NIHSS training and demonstration DVD, we selected 18 patients representing all possible scores on 15 scale items for a new certification DVD. Patients were divided into 3 certification groups of 6 patients each, balanced for lesion side, distribution of scale item findings, and total score. We sought to measure interrater reliability of the certification DVD using methodology previously published for the original videotapes. Raters were recruited from 3 experienced stroke centers. Each rater watched the new training DVD and then evaluated one of the 3 certification groups.
Responses were received from 112 raters: 26.2% of all responses came from stroke nurses, 34.1% from emergency departments/other physicians, and 39.6% from neurologists. One half (50%) of raters were previously NIHSS-certified. Item responses were tabulated, scoring performed as previously published, and agreement measured with unweighted kappa coefficients for individual items and an intraclass correlation coefficient for the overall score. kappa ranged from 0.21+/-0.05 (ataxia) to 0.92+/-0.09 (LOC-C questions). Of 15 items, 2 showed poor, 11 moderate, and 2 excellent agreement based on kappa scores. The intraclass correlation coefficient for total score was 0.94 (95% confidence interval, 0.84 to 1.00). Reliability scores were similar among specialists and centers, and there were no differences between nurses and physicians. kappa scores trended higher among raters previously certified.
These certification DVDs are reliable for NIHSS certification, and scoring sheets have been posted on a web site for real-time, online certification.
Stroke 12/2005; 36(11):2446-9. · 5.73 Impact Factor
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James C Grotta
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ABSTRACT: Intracerebral hemorrhage (ICH) can be prevented by adequate treatment of hypertension. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers seem particularly effective. ICH also is associated with apolipoprotein E 4 genotype and with low cholesterol, but not statin therapy for high cholesterol. Microbleeds identified on magnetic resonance imaging scans also confer increased risk of ICH. Experimental drug regimens that target metalloproteinases and inflammation reduce damage in animal models of ICH, but none are proven effective in humans. Cerebral edema after ICH has varied mechanisms and significance, and may be another target for therapy. Cerebral blood flow is not substantially reduced in most patients with ICH. Lowering systolic blood pressure below 160 mm Hg in the first hours after ICH may prevent additional bleeding. Activated factor 7 is a promising new therapy to limit hematoma enlargement and consequently reduce morbidity and mortality after ICH. Dosages of 80 to 160 μg/kg given within the first 3 to 4 hours after symptom onset, or in patients at risk of additional bleeding such as those with coagulopathy, is logical but is unapproved. The role of activated factor 7 hopefully will be clarified by additional study. Open surgical evacuation of most spontaneous supratentorial hematomas has been shown to be ineffective in reducing mortality or disability except in certain circumstances, such as large or enlarging superficially located clots in patients who are awake. Stereotactic and endoscopic clot aspiration, often using instillation of lytic agents to liquefy the hematoma, is the most active area of surgical intervention research. Such minimally invasive approaches have been shown to safely produce more rapid removal of blood compared with standard treatment. This is particularly true for intraventricular hemorrhages. Future research will focus on the use of stem cells to restore the damaged architecture around the hematoma. The impressive scope and progress of ongoing clinical and basic research show that there is no longer a place for nihilism in the approach to ICH.
Current Treatment Options in Neurology 02/2004; 6(6):435-442. · 1.29 Impact Factor
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ABSTRACT: BACKGROUND: Previous Stroke Therapy Academic Industry Roundtable (STAIR) meetings focused on preclinical evidence of drug efficacy and enhancing acute stroke trial design and performance. A fourth (STAIR-IV) was held to discuss relevant issues related to acute stroke drug development and regulatory approval. SUMMARY OF REVIEW: The STAIR-IV meeting had 3 main focus areas. The first topic was novel approaches to statistical design of acute stroke trials and appropriate outcome measures. The second focus was the need for better cooperation among participants in stroke therapy development that may be addressed through a national consortium of stroke trial centers in the United States and elsewhere. Lastly, regulatory issues related to the approval of novel mono and multiple acute stroke therapies were discussed. CONCLUSIONS: The development of additional acute stroke therapies represents a large unmet need with many remaining challenges and also opportunities to incorporate novel approaches to clinical trial design that will lead to regulatory approval. The STAIR-IV meeting explored new concepts of trial methodology and data analysis, initiatives for implementing a US clinical trialist consortium, and pertinent regulatory issues to expedite approval of novel therapies.
Marc Fisher, MD.
