Atrial Fibrillation Screening According to Genetic Risk: A Secondary Analysis of the Randomized LOOP Study

BACKGROUND: Polygenic risk scores (PRS) hold promise in risk stratification and screening for cardiovascular diseases, including atrial fibrillation (AF).

OBJECTIVE: This study investigated the efficacy of AF screening for stroke prevention based on a PRS for AF.

METHODS: This prespecified post hoc analysis of the randomized LOOP (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-Risk Individuals) study included 5,656 AF-naive individuals aged ≥70 years with stroke risk factors and available genetic data. The participants were randomized 1:3 for screening with an implantable loop recorder (ILR) vs usual care. Genetic risk of AF was assessed using a PRS for AF (PRSAF). The primary outcome was a composite of stroke and systemic embolism (SE). Interaction between the randomization arm and PRSAF was assessed in cause-specific Cox regressions for the full cohort and across the observed range of polygenic risk using a continuous prediction grid. Secondary analyses included models stratified by PRS level, gene-screening interactions for major bleeding events, and associations between PRSAF and AF burden (≥1 episode lasting ≥24 hours among participants with ILR-detected AF).

RESULTS: Over a median follow-up period of 5.4 years, 969 participants (17.1%) received a diagnosis of AF, 296 (5.2%) had stroke/SE, and 206 (3.6%) had major bleeding. PRSAF was associated with higher rates of AF (HR per SD increase: 1.20; 95% CI: 1.13-1.28; P < 0.001). A significant interaction was observed between ILR screening and PRSAF for stroke/SE (Pinteraction = 0.006). ILR screening was associated with lower rates of stroke/SE in individuals with PRSAF ≥median (HR: 0.65; 95% CI: 0.43-0.97; P = 0.036) but not in those with PRSAF <median (HR: 1.06; 95% CI: 0.72-1.57; P = 0.75). ILR screening was associated with higher rates of major bleeding at lower levels of PRSAF (Pinteraction = 0.036), corresponding to a HR of 1.71 (95% CI: 1.12-2.64; P = 0.011) in those with PRSAF <median. A 1-SD increase in PRSAF was associated with an OR of 1.35 (95% CI: 1.02-1.78; P = 0.037) for having ≥1 AF episode lasting ≥24 hours.

CONCLUSIONS: ILR screening for AF was associated with a significant reduction in stroke/SE in individuals with higher genetic risk of AF but not in those with lower genetic risk. These hypothesis-generating findings indicate that genetic predisposition may aid in selecting individuals who benefit from AF screening.