John L.P. Thompson

The ALSFRSr predicts survival time in an ALS clinic population

Objective: To determine whether the Amyotrophic Lateral Sclerosis Functional Rating Scale–revised (ALSFRSr), a predictor of survival time in ALS clinical trials, predicts survival time in an ALS clinic population. Methods: The authors prospectively evaluated 267 consecutive patients with ALS at first visit to an ALS clinic using the ALSFRSr and pulmonary function testing. The association of ALSFRSr score at baseline with death or tracheostomy in ALS was examined using Cox proportional hazards models, adjusting for age at baseline, sex, and symptom duration. Results: Of 267 patients with ALS, 103 (39%) reached the endpoint, defined as either death (79 patients) or tracheostomy (24 patients), during a mean follow-up of 1.0 ± 0.7 years. Among the 103 patients who reached the endpoint during follow-up, 77 (75%) had a baseline ALSFRSr score of less than 38 (the median baseline score of all patients), compared to 53 of 164 (32%) who remained alive without tracheostomy. Patients with a total ALSFRSr score below the median had a 4.4-fold increased risk of death or tracheostomy compared to those who scored above the median (HR: 4.38, 95% CI: 2.79 to 6.86, p < 0.001). Both the total ALSFRSr score at baseline (HR: 0.94, 95% CI: 0.91 to 0.98, p < 0.001) and forced vital capacity at baseline (HR: 0.99, 95% CI: 0.98 to 1.00, p = 0.02) were associated with death or tracheostomy when included in the same Cox model. Conclusions: In an ALS clinic population, the total Amyotrophic Lateral Sclerosis Functional Rating Scale–revised score at baseline is a strong predictor of death or tracheostomy independently of forced vital capacity and after adjustment for age at baseline, sex, and symptom duration.

Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III

Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial.

Phase IIB/III Trial of Tenecteplase in Acute Ischemic Stroke. Results of a Prematurely Terminated Randomized Clinical Trial

Background and Purpose— Intravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA. Methods— The trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a “best” dose of tenecteplase to carry forward. Once a “best” dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III. Results— The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg/kg tenecteplase group and lowest (0 of 31) in the 0.1-mg/kg tenecteplase group. Neither promise nor futility could be established. Conclusion— This prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke.

Cigarette Smoking as a Determinant of High-Grade Carotid Artery Stenosis in Hispanic, Black, and White Patients With Stroke or Transient Ischemic Attack

BACKGROUND AND PURPOSE We sought to investigate the association of cigarette smoking with high-grade carotid artery stenosis in Hispanic, black, and white patients with cerebral ischemia in two independent samples. METHODS Prospectively collected data from the Northern Manhattan Stroke Study (NOMASS) (n=431) and the Berlin Cerebral Ischemia Databank (BCID) (n=483) were used separately for a cross-sectional study estimating the association between cigarette smoking and high-grade carotid stenosis (defined as a luminal narrowing of > or =60%, diagnosed by duplex and/or Doppler ultrasound). In both studies, cerebral ischemia patients with normal sonographic findings or nonstenosing plaques of their carotid arteries served as a comparison group. Multivariate logistic regression models were used for statistical tests to determine the association between smoking and the dependent variable for high-grade carotid stenosis. Age, sex, hypertension, diabetes, hypercholesterolemia, and race/ethnicity were considered potential confounders. Further analyses of the NOMASS data estimated the effect of the amount of cigarette use and the impact of race/ethnicity. RESULTS High-grade carotid stenoses were found in 14% of the NOMASS and in 21% of the Berlin patients. In Berlin the entire sample was white, whereas in New York only 19% of the cohort were white. In both samples, smoking was independently associated with severe carotid stenosis (NOMASS: odds ratio [OR], 1.5; 95% confidence interval [CI], 1.1 to 2.0; BCID: OR, 3.9; 95% CI, 2.4 to 6.4). Patients smoking 20 pack-years or more showed a significant association (OR, 2.0; 95% CI, 1.1 to 3.9), whereas no significant effect was found for lower amounts of cigarette use. In NOMASS, white smokers displayed a significant (OR, 3.2; 95% CI, 1.1 to 8.9) association with high-grade carotid stenosis, the association for black smokers was less strong, and no association was found among Hispanics. CONCLUSIONS Smoking is an independent determinant of severe carotid artery stenosis in patients with focal cerebral ischemia. The association differs by race/ethnicity, with the greatest effect observed among whites.

A two-stage design for a phase II clinical trial of coenzyme Q10 in ALS

Background: The combination of a small pool of patients at any given time with the availability of many potential neuroprotective agents to be tested in ALS requires efficient phase II trial designs. Objective: To describe the design of the Clinical Trial of High Dose Coenzyme Q10 (CoQ10) in ALS (QALS study)—a phase II, randomized, placebo-controlled, double-blind, multicenter clinical trial. Methods: The study design features two stages. The first stage (dose selection) identifies which of two doses of CoQ10 (1800 mg or 2700 mg) is preferred using a selection procedure rather than a formal hypothesis test. The second stage (early efficacy test) compares the preferred dose of CoQ10 against placebo using a non-superiority or futility design. Data from patients assigned to the preferred dose of CoQ10 in the first stage are also used in the second stage. The primary outcome measure is the decline in Amyotrophic Lateral Sclerosis Functional Rating Scale–revised (ALSFRSr) score from baseline to 9 months. Results: The total sample size required is 185 patients, as compared to a much larger sample size estimated to be necessary using a conventional superiority design (total: 852 patients). The authors report a bias correction made necessary by the inclusion of patient data from the first stage in the second stage. Conclusions: Several features of the Clinical Trial of High Dose Coenzyme Q10 in ALS study design promote efficiency. These features may be beneficial in phase II trials in amyotrophic lateral sclerosis and other fields.

Excellent inter‐rater, intra‐rater, and telephone‐administered reliability of the ALSFRS‐R in a multicenter clinical trial

We wished to determine whether the Amyotrophic Lateral Sclerosis Functional Rating Scale‐revised (ALSFRS‐R) is reliable when used as primary outcome measure in a multicenter clinical trial. To establish inter‐rater reliability, we randomly assigned 19 primary raters and 11 back‐up raters to score nine amyotrophic lateral sclerosis (ALS) patients using the ALSFRS‐R. To assess intra‐rater reliability and reliability of telephone administration, we randomly assigned consecutive participants of the Clinical Trial of High Dose Coenzyme Q10 in ALS (QALS) to have in‐person ALSFRS‐R interviews at both screening and baseline visits (n = 41 patients) or to have the ALSFRS‐R interview by telephone at screening and in person at the baseline visit (n = 27). An intraclass correlation coefficient (ICC) of reliability was calculated using a one‐way random effects analysis of variance model. In the inter‐rater reliability assessment, the primary raters performed 54 ratings on nine patients with ICC = 0.93 (95% CI 0.84–0.98). For back‐up raters, 32 ratings on nine patients resulted in ICC = 0.93 (95% CI 0.82–0.98). The intra‐rater reliability for in‐person interviews was ICC = 0.95 (95% CI 0.92–0.98). The reliability of telephone administration compared to in‐person interviews was ICC = 0.97 (95% CI 0.93–0.98). We conclude that the ALSFRS‐R shows excellent inter‐ and intra‐rater reliability, and reliability of telephone administration when used as primary outcome measure in a multicenter ALS trial.

Comparison of Warfarin versus Aspirin for the Prevention of Recurrent Stroke or Death: Subgroup Analyses from the Warfarin-Aspirin Recurrent Stroke Study

Background and Purpose: We performed a combination of prespecified and exploratory subgroup analyses to detect any treatment differences among various baseline subgroups in the Warfarin-Aspirin Recurrent Stroke Study (WARSS) cohort. Methods: The WARSS compared the efficacy of adjusted-dose warfarin (INR 1.4–2.8) to aspirin (325 mg/day) for recurrent ischemic stroke or death within 2 years. The effect of warfarin and aspirin was compared among prespecified and exploratory subgroups with respect to sociodemographic and vascular risk factors, stroke subtype, arterial territory, and infarct topography. Hazard ratios and 95% confidence intervals comparing warfarin to aspirin were calculated using Cox proportional hazards models. Differences in hazard ratios were tested using interaction terms. Results: No treatment differences between warfarin and aspirin were found across multiple prespecified subgroups. In a multivariate model, warfarin was associated with greater hazard among patients with moderate stroke severity (HR 1.63, 95% CI 1.005–2.64, p = 0.047) and a greater benefit among those with posterior circulation location without brainstem infarction (HR 0.54, 95% CI 0.33–0.88, p = 0.013). In post-hoc analyses of the cryptogenic subgroup, warfarin was associated with worse outcomes among patients with moderate stroke severity and better outcomes among those without baseline hypertension or with posterior circulation infarcts sparing the brainstem. Conclusions: In the WARSS, the majority of subgroup analyses showed no benefit of warfarin over aspirin. Warfarin benefit was limited to brainstem-sparing posterior circulation infarcts and select cryptogenic stroke subgroups. Pending future clinical trial evidence to the contrary, antiplatelets are recommended for survivors of noncardioembolic stroke.

Gavestinel Does Not Improve Outcome After Acute Intracerebral Hemorrhage An Analysis From the GAIN International and GAIN Americas Studies

Background and Purpose— Glycine Antagonist in Neuroprotection (GAIN) International and GAIN Americas trials were prospectively designed, randomized, placebo-controlled trials of gavestinel, a glycine-site antagonist and putative neuroprotectant drug administered within 6 hours of suspected ischemic or hemorrhagic stroke. Both trials reported that gavestinel was ineffective in ischemic stroke. This analysis reports the results in those with primary intracerebral hemorrhage. Methods— The primary hypothesis was that gavestinel treatment did not alter outcome, measured at 3 months by the Barthel Index (BI), from acute intracerebral hemorrhage, based on pooled results from both trials. The BI scores were divided into 3 groups: 95 to 100 (independent), 60 to 90 (assisted independence), and 0 to 55 (dependent) or dead. Results— In total, 3450 patients were randomized in GAIN International (N=1804) and GAIN Americas (N=1646). Of these, 571 were ultimately identified to have spontaneous intracerebral hematoma on baseline head computerized tomography scan. The difference in distribution of trichotomized BI scores at 3 months between gavestinel and placebo was not statistically significant (P=0.09). Serious adverse events were reported at similar rates in the 2 treatment groups. Conclusions— These observations from the combined GAIN International and GAIN Americas trials suggest that gavestinel is not of substantial benefit or harm to patients with primary intracerebral hemorrhage. These findings are similar to results previously reported in patients with ischemic stroke.

Frequency and Determinants of Microembolic Signals on Transcranial Doppler in Unselected Patients with Acute Carotid Territory Ischemia

Background and Purpose: Few data exist regarding to the occurrence of microembolic high-intensity transient signals (HITS) on transcranial Doppler ultrasound (TCD) in unselected acute stroke patients. The aim of this study was to investigate prospectively the frequency and determinants of HITS in acute carotid territory ischemia. We hypothesized that carotid artery disease, cardiac abnormalities, and nonlacunar infarcts were independent predictors of HITS in acute stroke. Methods: We investigated 145 consecutive patients with acute internal carotid artery territory ischemia. The median time interval between stroke and TCD examination was 2 days. TCD monitoring was performed for 30 min on each middle cerebral artery. The frequency of HITS was cross-classified with carotid artery status, potential cardiac sources of embolism, and nonlacunar infarct subtype. Multivariate logistic regression models determined the independent relationship of these variables to HITS. Results: Microembolic signals were detected in 35 patients (24.1%), Ipsilateral carotid artery disease was significantly and independently associated with HITS (odds ratio 3.3, 95% confidence interval 1.4–7.8, p = 0.007), whereas potential cardiac sources (OR 1.07, 95% CI 0.48–2.4, p = 0.84) and infarct subtype (OR 0.84, 95% CI 0.29–2.4, p = 0.75) were not. Conclusions: High-intensity transient signals can be found in almost 25% of patients with acute anterior cerebral circulation ischemia and are significantly more prevalent among those with symptomatic carotid artery disease. Future clinical studies are required to determine whether HITS are a marker of increased stroke recurrence and can help to clarify stroke etiology in patients with competing stroke mechanisms.

Amino Terminal Pro–B-Type Natriuretic Peptide, Secondary Stroke Prevention, and Choice of Antithrombotic Therapy

Background and Purpose— Because of its association with atrial fibrillation and heart failure, we hypothesized that amino terminal pro–B-type natriuretic peptide (NT-proBNP) would identify a subgroup of patients from the Warfarin–Aspirin Recurrent Stroke Study, diagnosed with inferred noncardioembolic ischemic strokes, where anticoagulation would be more effective than antiplatelet agents in reducing risk of subsequent events. Methods— NT-proBNP was measured in stored serum collected at baseline from participants enrolled in Warfarin–Aspirin Recurrent Stroke Study, a previously reported randomized trial. Relative effectiveness of warfarin and aspirin in preventing recurrent ischemic stroke or death over 2 years was compared based on NT-proBNP concentrations. Results— About 95% of 1028 patients with assays had NT-proBNP below 750 pg/mL, and among them, no evidence for treatment effect modification was evident. For 49 patients with NT-proBNP >750 pg/mL, the 2-year rate of events per 100 person-years was 45.9 for the aspirin group and 16.6 for the warfarin group, whereas for 979 patients with NT-proBNP ⩽750 pg/mL, rates were similar for both treatments. For those with NT-proBNP >750 pg/mL, the hazard ratio was 0.30 (95% confidence interval: 0.12–0.84; P=0.021) significantly favoring warfarin over aspirin. A formal test for interaction of NT-proBNP with treatment was significant (P=0.01). Conclusions— For secondary stroke prevention, elevated NT-proBNP concentrations may identify a subgroup of ischemic stroke patients without known atrial fibrillation, about 5% based on the current study, who may benefit more from anticoagulants than antiplatelet agents. Clinical Trial Registration— This trial was not registered because enrollment began before 2005.