Meta-research metrics matter: letter regarding article “indirect tolerability comparison of Deutetrabenazine and Tetrabenazine for Huntington disease”

Here we discuss the report by Claassen and colleagues describing an indirect treatment comparison between tetrabenazine and deutetrabenazine for chorea in Huntington’s disease using individual patient data. We note the potential for discrepancies in apparently statistically significant findings, due to the rank reversal phenomenon. We provide some cautionary observations and suggestions concerning the limitations of indirect comparisons and the low likelihood that good quality evidence will become available to guide clinical decision comparing these two agents

Tetrabenazine versus deutetrabenazine for Huntington's disease: twins or distant cousins?

BACKGROUND: Tetrabenazine is the only US Food and Drug Administration-approved drug for Huntington's disease, and deutetrabenazine was recently tested against placebo. A switching-trial from tetrabenazine to deutetrabenazine is underway, but no head-to-head, blinded, randomized controlled trial is planned. Using meta-analytical methodology, the authors compared these molecules. METHODS: RCTs comparing tetrabenazine or deutetrabenazine with placebo in Huntington's disease were searched. The authors assessed the Cochrane risk-of-bias tool, calculated indirect treatment comparisons, and applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. RESULTS: The evidence network for this report comprised 1 tetrabenazine trial and 1 deutetrabenazine trial, both against placebo. Risk of bias was moderate in both. Participants in the tetrabenazine and deutetrabenazine trials did not differ significantly on motor scores or adverse events. Depression and somnolence scales significantly favored deutetrabenazine. CONCLUSION: There is low-quality evidence that tetrabenazine and deutetrabenazine do not differ in efficacy or safety. It is important to note that these results are likely to remain the only head-to-head comparison between these 2 compounds in Huntington's disease

Endovascular treatment versus medical care alone for ischaemic stroke: systematic review and meta-analysis

Objectives: To evaluate the efficacy and safety of endovascular treatment, particularly adjunctive intra-arterial mechanical thrombectomy, in patients with ischaemic stroke. / Design: Systematic review and meta-analysis. / Data sources: Medline, Embase, Cochrane Central Register of Controlled Trials, Web of Science, SciELO, LILACS, and clinical trial registries from inception to December 2015. Reference lists were crosschecked. / Eligibility criteria for selecting studies: Randomised controlled trials in adults aged 18 or more with ischaemic stroke comparing endovascular treatment, including thrombectomy, with medical care alone, including intravenous recombinant tissue plasminogen activator (rt-PA). Trial endpoints were functional outcome (modified Rankin scale scores of ≤2) and mortality at 90 days after onset of symptoms. No language or time restrictions applied. / Results: 10 randomised controlled trials (n=2925) were included. In pooled analysis endovascular treatment, including thrombectomy, was associated with a higher proportion of patients experiencing good (modified Rankin scale scores ≤2) and excellent (scores ≤1) outcomes 90 days after stroke, without differences in mortality or rates for symptomatic intracranial haemorrhage, compared with patients randomised to medical care alone, including intravenous rt-PA. Heterogeneity was high among studies. The more recent studies (seven randomised controlled trials, published or presented in 2015) proved better suited to evaluate the effect of adjunctive intra-arterial mechanical thrombectomy on its index disease owing to more accurate patient selection, intravenous rt-PA being administered at a higher rate and earlier, and the use of more efficient thrombectomy devices. In most of these studies, more than 86% of the patients were treated with stent retrievers, and rates of recanalisation were higher (>58%) than previously reported. Subgroup analysis of these seven studies yielded a risk ratio of 1.56 (95% confidence interval 1.38 to 1.75) for good functional outcomes and 0.86 (0.69 to 1.06) for mortality, without heterogeneity among the results of the studies. All trials were open label. Risk of bias was moderate across studies. The full results of two trials are yet to be published. / Conclusions: Moderate to high quality evidence suggests that compared with medical care alone in a selected group of patients endovascular thrombectomy as add-on to intravenous thrombolysis performed within six to eight hours after large vessel ischaemic stroke in the anterior circulation provides beneficial functional outcomes, without increased detrimental effects. / Systematic review registration: PROSPERO CRD42015019340

Does undiagnosed diabetes mitigate the association between diabetes and cognitive impairment? Findings from the ELSI‐Brazil study

Background: Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment. However, most of the evidence has been based on self‐reported T2DM, and undiagnosed diabetes has not been considered as a separate category. We aimed to examine the extent to which undiagnosed diabetes modifies the association between diabetes and cognitive impairment in a representative sample of Brazilian adults aged 50 years and older. / Methods: We analyzed baseline data from 1944 participants of the Brazilian Longitudinal Study of Aging (ELSI‐Brazil) conducted from 2015 to 2016. Diabetes was evaluated based on self‐reported doctor diagnosis and glycosylated hemoglobin levels. Participants were classified as diabetics (D), undiagnosed diabetics (UDD), or nondiabetics (ND). Cognitive function was assessed by word list learning and verbal fluency tests. Three multiple logistic regression models were used to evaluate the changes in the strength of the associations. / Results: Participants with diabetes had 49% greater odds of exhibiting impaired memory than nondiabetics (odds ratio [OR] = 1.49; 95% CI: 1.01‐2.20). By combining UDD and ND, the association between diabetes and impaired memory was attenuated by 2.0%, losing its statistical significance (OR = 1.46; 95% CI: 0.98‐2.17). By combining UDD and D, the association was attenuated by 7.4% (OR = 1.38; 95% CI: 1.01‐1.90). No significant association was found between T2DM and impaired verbal fluency. / Conclusion: This study found an association between T2DM and impaired memory but not with impaired verbal fluency. When UDD individuals are considered diabetics, this association is attenuated; when UDD individuals are considered as ND, this association is attenuated to the extent that it loses its statistical significance, affecting thus the clinical interpretation

Differences in the prevalence of prediabetes, undiagnosed diabetes and diagnosed diabetes and associated factors in cohorts of Brazilian and English older adults

OBJECTIVE: To analyse differences in the prevalence of prediabetes (PD), undiagnosed diabetes (UDD) and diagnosed diabetes (DD) and associated factors between Brazilian and English older adults. DESIGN: Cross-sectional study. SETTING: England and Brazil. PARTICIPANTS: 5301 participants of the English Longitudinal Study of Ageing study and 1947 participants of the Brazilian Longitudinal Study of Aging study classified as non-diabetics, PD, UDD and DD. RESULTS: The prevalence of PD, UDD and DD was 48·6, 3 and 9·6 % in England and 33, 6 and 20 % in Brazil. In England, the increase in age, non-white skin colour, smoking, general obesity and abdominal obesity were associated with PD, UDD and DD, whereas hypertriglyceridaemia, low HDL levels, hypertension and stroke were associated with UDD and DD. In Brazil, the increase in age was associated with DD and UDD, non-white skin colour and smoking were associated with UDD and abdominal obesity and hypertriglyceridaemia were associated with all three conditions. CVD in England and schooling in Brazil were associated with PD and DD. A sedentary lifestyle was associated with DD in both samples. CONCLUSIONS: The prevalence of diabetes was higher in the Brazilian sample. Different associated factors were found in the two samples, which may be related to differences in nutritional transition, access to healthcare services and the use of such services