Atrial fibrillation screening effects 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). Purpose This study aimed to investigate screening efficacy based on a PRS for AF, with respects to stroke prevention. Methods The LOOP study (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-Risk Individuals) included 6,004 AF-naive individuals aged 70 years or older with additional risk factors for stroke. Participants were randomized 1:3 to receive continuous screening with implantable loop recorder (ILR) and initiation of anticoagulation upon AF detection vs usual care. For this post-hoc analysis, we included only participants with available genetic data. Genetic risk of AF was assessed using a previously validated PRS for AF. Efficacy of ILR screening was evaluated using Cox regressions models adjusted for cardiovascular risk factors. Analyses were stratified by PRS category (above vs. below median). The primary outcome was a composite of stroke and systemic arterial embolism (SAE), with major bleeding as a secondary outcome. Cumulative incidences were calculated using the Aalen-Johansen estimator, considering all-cause mortality as a competing risk. ILR screening was also evaluated across the range of the PRS as a continuous variable for stroke/SAE, major bleeding, and all-cause mortality. Results A total of 5,656 individuals were included (94.2% of the trial population). Median age was 73.2 years and 47.2% were female. Over a median follow-up of 5.4 years (1st-3rd quartile: 4.9-5.2), 969 (17.1%) were diagnosed with AF, 296 (5.2%) suffered a stroke or SAE, and 206 (3.6%) suffered a major bleeding. An AF PRS ≥median was associated with higher rates of AF (HR: 1.34, 95% confidence intervals [CI] 1.18-1.52, P<0.001), and stroke/SAE (HR: 1.30, 95% CI: 1.03-1.64, P=0.026). ILR screening was associated with lower rates of stroke/SAE in individuals with PRS ≥median (HR: 0.65, 95% CI: 0.43-0.97, P=0.032), but not in those with PRS below median (HR: 1.07, 95% CI: 0.72-1.58, P=0.75). In contrast, ILR-screening was associated with higher rates of major bleeding in those with PRS below median (HR: 1.71, 95% CI: 1.12-2.61, P=0.0126), but not among those with PRS ≥median (HR: 1.00, 95% CI: 0.65-1.55, P=0.98). Analyses with the PRS as a continuous variable showed similar findings. We observed a significant interaction between PRS and ILR screening on rates of stroke/SAE (P=0.007) and rates of major bleeding (P=0.048). Conclusions ILR screening for AF was associated with a significant reduction in stroke risk among individuals with clinical risk factors for stroke and genetic predisposition for AF. Individuals with lower genetic risk did not benefit from ILR-screening and had higher rates of major bleeding. These exploratory findings indicate that genetic data may be useful to select individuals for AF screening.