Comparative effectiveness using a matching-adjusted indirect comparison between delayed-release dimethyl fumarate and fingolimod for the treatment of multiple sclerosis.

OBJECTIVE: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) and fingolimod are approved oral disease-modifying treatments for relapsing-remitting multiple sclerosis. In phase 3 trials, DMF (DEFINE/CONFIRM) and fingolimod (FREEDOMS/FREEDOMS II) resulted in significant reductions in clinical and magnetic resonance imaging activity, with acceptable safety profiles. Direct comparisons of these treatments are not possible due to a lack of head-to-head trials. We compared 2 year efficacy of DMF versus fingolimod at the approved dosage using a matching-adjusted indirect approach. RESEARCH DESIGN AND METHODS: Individual patient data from DEFINE and CONFIRM, and aggregate data from FREEDOMS and FREEDOMS II, were pooled and compared using the matching-adjusted in-direct method. To account for cross-trial differences, data from trials with available individual patient data were adjusted to match aggregate data (i.e. average patient characteristics) from trials without patient-level data. Data from DMF-treated patients were weighted such that average baseline characteristics matched those of fingolimod-treated patients. After matching, weighted treatment outcomes for DMF-treated patients (240 mg twice daily) were compared with summary outcomes for fingolimod-treated patients (0.5 mg once daily). All comparison results of DMF versus fingolimod used fingolimod as the reference. RESULTS: After matching, baseline characteristics were balanced between DMF and fingolimod. At year 2, the efficacy of DMF was similar to that of fingolimod for annualized relapse rate (rate ratio [95% confidence interval (CI)]: 1.11 [0.88, 1.40]), 12 week confirmed disability progression (hazard ratio [95% CI]: 0.90 [0.63, 1.29]), and Multiple Sclerosis Functional Composite (mean difference [95% CI]: 0.04 [-0.05, 0.13]). For patient-reported outcomes (EuroQoL 5-Dimensions questionnaire), the mean differences (95% CI) were 0.05 (0.01, 0.08) for utility score and 3.22 (0.58, 5.86) for visual analog scale score, significantly favoring DMF. There was no significant difference in the percentage of patients with no evidence of disease activity (NEDA) for DMF versus fingolimod among matching-adjusted patients with complete NEDA data: rate ratio (95% CI): 0.92 (0.51, 1.64). CONCLUSIONS: Using the matching-adjusted indirect comparison approach, the efficacy of DMF and fingolimod were similar on all clinical outcomes, while patient-reported outcomes showed greater benefit with DMF. Study limitations include possible confounding from unobserved/unknown differences between trials, and trial length may have been insufficient to detect significant differences on disability progression. CLINICAL TRIAL REGISTRATION: NCT00420212 (DEFINE); NCT00451451 (CONFIRM); NCT00289978 (FREEDOMS); NCT00355134 (FREEDOMS II).

Systematic review of the impact of endoscopic ultrasound on the management of patients with esophageal cancer.

OBJECTIVES: Although endoscopic ultrasound (EUS) staging of esophageal cancer is established in clinical practice, high-quality evidence about its impact on patient outcomes is not available. This study aims to determine the impact of EUS for esophageal cancer staging on patient management and survival. METHODS: A systematic review was conducted using Medline, PreMedline, Embase, and The Cochrane Library. Included studies were (i) comparative studies reporting survival following EUS esophageal cancer staging, (ii) therapeutic impact studies reporting change in patient management following EUS. The quality of included studies was critically appraised. RESULTS: One systematic review, five studies reporting therapeutic impact, and two studies reporting patient survival were identified. The design and quality of the therapeutic impact studies varied widely. Management changed in 24-29 percent of patients following EUS staging of esophageal cancer (two studies). No studies provided data on the avoidance of surgery for this indication. One retrospective cohort study with historical control found EUS staging of esophageal cancer improved patient survival; a second study with similar design limitations did not find a survival benefit for EUS staging in patients undergoing resection. These studies had a high potential for bias, limiting the value of these findings. CONCLUSIONS: Two studies provided evidence of a change in patient management following EUS for staging esophageal cancer, a higher level of evidence for a clinical benefit than can be obtained from accuracy studies alone. This evidence contributed to a recommendation for public funding of EUS in staging esophageal cancer in Australia.

A dose-specific meta-analysis of lipid changes in randomized controlled trials of atorvastatin and simvastatin.

BACKGROUND: The available statins exhibit differences in the potency with which they alter serum lipid levels. OBJECTIVE: Meta-analyses were conducted to assess the relative potency of atorvastatin and simvastatin (the 2 most commonly prescribed statins) across all possible dose combinations in terms of changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C). METHODS: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, National Health Service (NHS) Centre for Reviews and Dissemination database, NHS Economic Evaluation Database, and Database of Abstracts of Reviews of Effects were searched for randomized, head-to-head trials of atorvastatin and simvastatin in patients aged >or=18 years with elevated levels of serum TC and LDL-C. Reference lists of the identified articles, letters, and editorials also were reviewed. The manufacturers of atorvastatin and simvastatin products were contacted for relevant unpublished data. All studies were reviewed and rated for quality by 2 independent reviewers. The maximum quality score was 4 points; trials with a score of <2 points were considered to be of poor quality and were excluded from analysis. Dose comparisons were abstracted in pairs from each trial. Meta-analyses were conducted on the fixed-dose pairs for each lipid parameter. Weighted mean differences in the change in TC, LDL-C, TG, and HDL-C were estimated using the Der Simonian and Laird random-effects model. RESULTS: Seventeen published trials and 1 unpublished study were included in the meta-analyses. Atorvastatin treatment was associated with significantly greater reductions in TC, LDL-C, and TG in the majority of dose comparisons with simvastatin. The potency of atorvastatin and simvastatin was comparable at dose ratios between 1:2 and 1:4. Higher doses of simvastatin were more effective in increasing HDL-C levels than atorvastatin, with no apparent dose-equivalence point. The HDL-C advantage of simvastatin was greatest when simvastatin 80 mg was compared with atorvastatin 80 mg (weighted mean difference, -4.35%; 95% CI, -5.64 to -3.08, P < 0.001). CONCLUSIONS: In these meta-analyses, atorvastatin was 2 to 4 times as potent as simvastatin in reducing TC, LDL-C, and TG, indicating that the dose equivalence of atorvastatin and simvastatin lay between 1:2 and 1:4. In contrast, simvastatin was more effective than atorvastatin in increasing HDL-C, but without any indication of a point of dose equivalence.

NT-3 expression from engineered olfactory ensheathing glia promotes spinal sparing and regeneration.

Adenoviral (AdV) vectors encoding neurotrophin-3 (AdV-NT-3) or the bacterial marker enzyme beta-galactosidase (LacZ gene) were used to transduce olfactory ensheathing glia (OEG) cultures. AdV vector-transduced OEG expressed high levels of recombinant neurotrophin as shown by in situ hybridization and enzyme-linked immunosorbent assay techniques. The biological activity of vector-derived NT-3 was determined in a dorsal root ganglia neurite outgrowth assay. Engineered cell suspensions were then injected into adult Fischer 344 rat spinal cord immediately after unilateral cervical (C4) corticospinal tract (CST) transection. Transplanted animals received a total of 200,000 cells; either non-transduced OEG or OEG transduced with AdV vectors encoding NT-3 or LacZ, respectively. At 3 months after injury, lesion volumes were significantly smaller in all OEG-transplanted rats when compared with control (medium-injected) rats. Anterograde tracing of the lesioned CST projection, originating from the contralateral sensorimotor cortex, showed a significantly greater number of distal CST axons only in OEG-NT-3-transplanted rats. Behavioural analysis was performed on all rats using open field locomotion scoring, and a forelimb reaching task with Eshkol-Wachman movement notation. Analysis of behavioural tests revealed no significant differences in recovery between experimental groups, although movement analysis indicated that possible compensatory mechanisms were occurring after OEG implantation. The results demonstrate that OEG transplantation per se can promote tissue sparing after injury, but, after appropriate genetic modification, these olfactory-derived cells become far more effective in promoting long-distance maintenance/regeneration of lesioned adult CST axons.

Peripheral nerve injury evokes disabilities and sensory dysfunction in a subpopulation of rats: a closer model to human chronic neuropathic pain?

Chronic pain conditions for which treatment is sought are characterized usually by complex behavioural disturbances as well as pain. We review here evidence that although chronic constriction injury (CCI) of the sciatic nerve evokes allodynia and hyperalgesia in all rats, persistent social behavioural and sleep disruption occurs only in a subpopulation of animals. The finding that the 'degree of pain', as defined by allodynia and hyperalgesia, is the same in all animals suggests that the complex behavioural disabilities are independent of the level of sensory dysfunction. An absence of correlation between disability and sensory dysfunction is characteristic also of human neuropathic pain. These findings indicate that: (i). in a subpopulation of rats sciatic injury evokes disabilities characteristic of human neuropathic pain conditions; and (ii). testing for sensory dysfunction alone cannot detect this subpopulation.