Defining Survival as an Outcome Measure in Amyotrophic Lateral Sclerosis

Abstract

To examine how respiratory interventions affect survival as an outcome measure and to define survival rate for trials in amyotrophic lateral sclerosis. Design and Setting: We reviewed the data of 3 phase 3 clinical trials and examined differences in times to death, tracheostomy, and permanent assisted ventilation. We assessed the outcomes with 2 and Fisher exact tests for categorical variables and unpaired, 2-tailed t tests for continuous variables. We used Kaplan-Meier methods to estimate the differences in survival times between interventions. A power analysis generated sample size estimates for different end points. Patients: In all, 2077 patients in 2 phase 3 trials of xaliproden and 400 patients in a phase 3 trial of pentoxifylline. Main Outcome Measures: Death or combined death, tracheostomy, or permanent assisted ventilation. Results: Of 745 deaths, 611 (82.0%) were owing to respiratory failure and 134 (18.0%) to other causes. The use of respiratory interventions across centers ranged from 0% to 6.6% (P=.001) of patients for tracheostomy and 11.1% to 23.1% (P=.05) of patients for noninvasive ventilation. Twelve of 55 patients (21.8%) undergoing tracheostomy had a vital capacity of 50% or more. Mean (SD) survival time was 457.9 (3.1) days using a combined end point and 467.2 (2.9) days with death alone as the outcome (P =.02). An estimated sample size to detect a 10% difference at 18 months between groups was 490 patients per arm for the combined end point and 410 patients for death alone. Conclusions: Tracheostomy and permanent assisted ventilation are not equivalent to death in amyotrophic lateral sclerosis. The use of respiratory interventions differs between centers, leading to variability in combined outcome assessments. The time to the end point can differ significantly depending on its definition, and combining outcomes does not reduce the estimated sample size of a trial. The death rate alone is the least variable and most easily identifiable measure of survival rate in amyotrophic lateral sclerosis.

Noninvasive Ventilation Improves Sleep in Amyotrophic Lateral Sclerosis: A Prospective Polysomnographic Study

“…In addition to weakness of peripheral muscles, respiratory muscle weakness develops during the course of the disease, leading to reduced alveolar ventilation and respiratory failure, which is the main cause of death in ALS. 1,2 A randomized controlled trial showed improvement in survival and quality of life (QoL) in ALS patients treated with noninvasive ventilation (NIV). 3 Although survival in the subgroup of patients with severe bulbar impairment did not improve, small improvements in QoL were observed.…”

Respiratory Muscle Strength as a Predictive Biomarker for Survival in Amyotrophic Lateral Sclerosis

“…This is in line with findings from a pooled analysis (in 2,477 patients with ALS) reporting that relatively high VC values may be observed close to a clinical meaningful event (e.g., tracheostomy) Table E2. (25). In that study, VC measurements were available for 50 patients with ALS requiring tracheostomy within 30 days of the need for tracheostomy, and were 50% or more of the predicted value in 11 patients, 60% or more of the predicted value in seven patients, and 70% or more of the predicted value in five patients.…”

Can Non-invasive Ventilation Settings Predicts Functional and Survival Outcome in ALS Patients?

“…Non-invasive ventilation unfortunately will not prevent a fatal event at final stages of disease as death by respiratory failure [33]. However, respect the limits of tolerance of patients as well as validate their complaints, recognize symptoms of discomfort related to mask-such as face/nose pain, nasal congestion, aerophagia and sleep disruption can influence a proper compliance [34].…”