Abstract 14244: SCD-HeFT Reanalyzed - A Need for Multimorbidity Risk-Stratified Trial Evaluations for Clinical Interventions

Abstract

Introduction: Patients with multiple chronic conditions (i.e., multimorbidity) are under-represented in clinical trials. This represents a challenge to the external validity of clinical trials since multimorbidity may associate with treatment effect heterogeneity (HTE). In this analysis, we sought to determine the distribution of multimorbidity scores in patients enrolled in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) and looked for an association between such scores and HTE for the outcome of all-cause mortality. Methods: A modified version of the Charlson Comorbidity Index (mCCI) was created using enrollment data. For the subgroup analysis, we fit a Cox model that included comorbidity index, randomized group, and their interaction. The interaction term allows the effect of randomized group to differ by level of comorbidity index, and is the primary effect of interest. The comorbidity index was modeled using quartiles. Following the same analysis framework as the original manuscript Amiodarone or ICD was compared to placebo in separate models. Results: The majority of patients had a mCCI score ≤ 5 (75.4%) and mortality risk was strongly associated with increased score. Interaction testing across subgroups suggested HTE for Amiodarone ( p = 0.07 ) or ICD ( p = 0.08 ) vs placebo as scores increased. For Amiodarone, the Q1 and Q4 HRs were 0.78 (0.43-1.39) and 1.50 (1.03-2.18), respectively. For ICD, the Q1 and Q4 HRs were 0.42 (0.20-0.84) and 0.99 (0.67-1.47), respectively (see Figure). Conclusions: Increasing multimorbidity may be associated with HTE for all-cause mortality when comparing Amiodarone and ICD to placebo in the SCD-HeFT trial. Our results highlight the importance of enrolling patients with advanced multimorbidity when considering interventions. As statistical power remains challenging in trial sub analysis, consideration should be given to performing separate trials for patients with more advanced multimorbidity.