Relative effects of forced vital capacity and ALSFRS‐R on survival in ALS

Abstract Introduction/Aim Amyotrophic lateral sclerosis (ALS) is a degenerative neuromuscular disease with marked clinical heterogeneity. This heterogeneity can be partly captured by clinical measures, such as the forced vital capacity (FVC) and ALS Functional Rating Scale‐Revised (ALSFRS‐R). We aimed to further characterize the performance of these clinical measures, including their independence and additivity, in predicting mortality. Methods We leveraged the Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT ALS) database, which includes data from 23 clinical trials ( n = 2050). The primary exposures were baseline FVC and ALSFRS‐R. The primary outcome was 1‐y mortality. We performed correlation analyses, survival analyses and assessed classification performance using receiver operator characteristic (ROC) curves. Results FVC and ALSFRS‐R were weakly correlated (r = 0.31, p < .001). A 1‐SD increase in FVC (hazard ratio [HR]: 0.66; 95% confidence interval [CI]: 0.59–0.74) and ALSFRS‐R (HR: 0.75; 95% CI: 0.68–0.82) were associated with reduced risk of 1‐y mortality. ROC analyses showed optimal predictive cutoffs at 80% for FVC (area under the curve [AUC]: 0.69) and 38 for ALSFRS‐R (AUC: 0.67). After stratifying patients based on these cutoffs, we found a marked reduction (HR: 0.25; 95% CI: 0.19–0.33) in incident mortality for patients in the high FVC and high ALSFRS‐R group relative to the low FVC and low ALSFRS‐R group. Discussion ALSFRS‐R and FVC are comparable predictors of survival that are only weakly correlated. When considered together, they synergistically predict survival. As such, consideration of both measures should be a routine part of prognostication in care of patients with ALS.