Association Between Decline in Slow Vital Capacity and Respiratory Insufficiency, Use of Assisted Ventilation, Tracheostomy, or Death in Patients With Amyotrophic Lateral Sclerosis.

Importance: The prognostic value of slow vital capacity (SVC) in relation to respiratory function decline and disease progression in patients with amyotrophic lateral sclerosis (ALS) is not well understood. Objective: To investigate the rate of decline in percentage predicted SVC and its association with respiratory-related clinical events and mortality in patients with ALS. Design, Setting, and Participants: This retrospective study included 893 placebo-treated patients from 2 large clinical trials (EMPOWER and BENEFIT-ALS, conducted from March 28, 2011, to November 1, 2012, and from October 23, 2012, to March 21, 2014, respectively) and an ALS trial database (PRO-ACT, containing studies completed between 1990 and 2010) to investigate the rate of decline in SVC. Data from the EMPOWER trial (which enrolled adults with possible, probable, or definite ALS; symptom onset within 24 months before screening; and upright SVC at least 65% of predicted value for age, height, and sex) were used to assess the relationship of SVC to respiratory-related clinical events; 456 patients randomized to placebo were used in this analysis. The 2 clinical trials included patients from North America, Australia, and Europe. Main Outcomes and Measures: Clinical events included the earlier of time to death or time to decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) respiratory subdomain, time to onset of respiratory insufficiency, time to tracheostomy, and all-cause mortality. Results: Among 893 placebo-treated patients with ALS, the mean (SD) patient age was 56.7 (11.2) years, and the mean (SD) SVC was 90.5% (17.1%) at baseline; 65.5% (585 of 893) were male, and 20.5% (183 of 893) had bulbar-onset ALS. In EMPOWER, average decline of SVC from baseline through 1.5-year follow-up was -2.7 percentage points per month. Steeper declines were found in patients older than 65 years (-3.6 percentage points per month [P = .005 vs <50 years and P = .007 vs 50-65 years) and in patients with an ALSFRS-R total score of 39 or less at baseline (-3.1 percentage points per month [P < .001 vs >39]). When the rate of decline of SVC was slower by 1.5 percentage points per month in the first 6 months, risk reductions for events after 6 months were 19% for decline in the ALSFRS-R respiratory subdomain or death after 6 months, 22% for first onset of respiratory insufficiency or death after 6 months, 23% for first occurrence of tracheostomy or death after 6 months, and 23% for death at any time after 6 months (P < .001 for all). Conclusions and Relevance: The rate of decline in SVC is associated with meaningful clinical events in ALS, including respiratory failure, tracheostomy, or death, suggesting that it is an important indicator of clinical progression.