The Vitamin E in Neuroprotection Study (VENUS) Investigators IMPORTANCE Management of painful diabetic peripheral neuropathy remains challenging. Most therapies provide symptomatic relief with varying degrees of efficacy. Tocotrienols have modulatory effects on the neuropathy pathway and may reduce neuropathic symptoms with their antioxidative and anti-inflammatory activities.OBJECTIVE To evaluate the efficacy of oral mixed tocotrienols for patients with diabetic peripheral neuropathy. DESIGN, SETTING, AND PARTICIPANTSThe Vitamin E in Neuroprotection Study (VENUS) was a parallel, double-blind, placebo-controlled trial that recruited participants from January 30, 2011, to December 7, 2014, with 12 months of follow-up. This trial screened 14 289 patients with diabetes from 6 health clinics and ambulatory care units from 5 public hospitals in Malaysia. A total of 391 patients who reported neuropathic symptoms were further assessed with Total Symptom Score (TSS) and Neuropathy Impairment Score (NIS). Patients 20 years or older with a TSS of 3 or higher and an NIS of 2 or higher were recruited.INTERVENTIONS Patients were randomized to receive 200 mg of mixed tocotrienols twice daily or matching placebo for 12 months. Patients with hyperhomocysteinemia (homocysteine level Ն2.03 mg/L) received oral folic acid, 5 mg once daily, and methylcobalamin, 500 μg thrice daily, in both groups. MAIN OUTCOMES AND MEASURESThe primary outcome was patient-reported neuropathy TSS (lancinating pain, burning pain, paresthesia, and asleep numbness) changes at 12 months. The secondary outcomes were NIS and sensory nerve conduction test result. RESULTSOf 391 eligible patients, 300 were recruited (130 [43.3%] male; mean [SD] age, 57.6 [8.9] years; mean [SD] duration of diabetes, 11.4 [7.8] years) and 229 (76.3%) completed the trial. The TSS changes between the tocotrienols and placebo groups at 12 months (−0.30; 95% CI, −1.16 to 0.56; P = .49) were similar. No significant differences in NIS (0.60; 95% CI, −1.37 to 2.65; P = .53) and sensory nerve conduction test assessments were found between both groups. In post hoc subgroup analyses, tocotrienols reduced lancinating pain among patients with hemoglobin A 1C levels greater than 8% (P = .03) and normohomocysteinemia (homocysteine level <2.03 mg/L; P = .008) at 1 year. Serious adverse events in both groups were similar, except more infections were observed in the tocotrienols group (6.7% vs 0.7%, P = .04). Results reported were of modified intention-to-treat analyses.CONCLUSIONS AND RELEVANCE Supplementation of oral mixed tocotrienols, 400 mg/d for 1 year, did not improve overall neuropathic symptoms. The preliminary observations on lancinating pain among subsets of patients require further exploration.

AimMany patients, especially the elderly, who require renal replacement therapies (RRT) have delayed or rejected dialysis for various reasons. Current dialysis guidelines may not be relevant for the elderly or frail patients. We aim to determine survival advantage of initiating dialysis in patients deemed to require RRT.MethodsThis was an observational cohort on incident end‐stage kidney disease (ESKD) patients from January 1, 2007 to December 31, 2008. The primary outcome was all‐cause mortality. Patients contributed person‐time from the date of ESKD diagnosis until death, transplant or end of study on December 31, 2014, whichever occurred first. An extended Cox regression model with time‐varying exposure to dialysis was used to account for immortal time bias.ResultsOf 3990 incident ESKD patients included, 70.2% patients initiated dialysis; 78.8% with haemodialysis (HD) while the remaining 21.2% with peritoneal dialysis (PD). Dialysis reduced hazard of death in both elderly and non‐elderly patients even after controlling for comorbidities (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.50, 0.68 and HR 0.76, 95% CI 0.69, 0.85, respectively). HD was protective in both the elderly and non‐elderly (HR 0.53, 95% CI 0.45, 0.63 and HR 0.71, 95% CI 0.64, 0.80, respectively). PD significantly reduced risk of death compared to no dialysis in the elderly but not in the non‐elderly.ConclusionDialysis improved survival in all incident ESKD patients. The findings suggested a larger protection offered by HD. Although improvement in survival from initiating dialysis was large, its true benefit should take overall quality of life into account.SUMMARY AT A GLANCEThis observational study showed that initiation of dialysis improves the survival of end‐stage kidney disease (ESKD) patients of all age groups, but the quality of life is an important aspect that has not been explored.