BACKGROUND It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm. METHODS We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause. RESULTS The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P = 0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P = 0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P = 0.82). CONCLUSIONS Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized.

Objective-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.Methods-We designed and implemented a multi-center trial with an adaptive, two-stage, biasadjusted, randomized, placebo-controlled, double-blind, Phase II design (n=185). The primary outcome in both stages was decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700 mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo.Results-Stage 1 selected the 2,700 mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an Kaufmann et al. Page 2Ann Neurol. Author manuscript; available in PMC 2010 August 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript accompanying pre-specified sensitivity test, and further supplementary analyses. Pre-specified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns.Interpretation-CoQ10 at 2,700 mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial.ALS is an orphan disease with an average annual incidence rate of 1 to 2 per 100,000 person-years, 1-3 and, because the disease typically leads to death within 2 to 4 years of onset, 4 a relatively low prevalence of 4-6 per 100,000 people. 5 About 10% of ALS cases are familial, and about 15 to 20% of autosomal dominant familial ALS patients have mutations the superoxide dismutase 1 (SOD1) gene. 6 The pathogenesis remains incompletely understood, but several lines of evidence suggest that oxidative stress plays an important role. SOD 1 is an enzyme that plays a role in detoxifying free radicals 7 . In a transgenic mouse model of familial ALS, there is increased oxidative stress. 8 In patients with sporadic ALS, oxidative stress indicators were found in plasma, urine, and CSF. 9-13 Mitochondrial impairment in ALS is supported by several findings in vitro, animal studies, and patients. In an ALS cell culture model, motor neuron cell lines harboring SOD1 mutations have morphologically abnormal mitochondria and impaired respiratory chain function. 14 Respiratory chain dysfunction has also been described in an ALS mouse model. 15 In spinal cord tissue of ALS patients, mutant mtDNA molecules were incre...

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.

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.

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