Differences of women and men in smartphone-based screening for atrial fibrillation: a pre-specified subgroup analysis of the eBRAVE-AF trial

Abstract

Abstract Background eBRAVE-AF, a siteless, randomized, controlled trial, showed that digital smart-device based screening for atrial fibrillation (AF) significantly increased the detection rate of treatment-relevant AF when compared to usual care. Purpose In this pre-specified subgroup analysis, we aimed to investigate the effect of sex on compliance, efficacy of digital screening, as well as the interaction between sex and AF-triggered major adverse cardiovascular complications (MACCE). Methods 5.551 individuals, free of AF at baseline were randomized to digital screening (n=2.860) or usual care (n=2.691). For digital screening, participants used a certified app to screen for irregularities in their pulse waves by means of photoplethysmography (PPG). Abnormal findings were confirmed by a 14-day Holter-ECG. The primary endpoint was newly diagnosed AF treated with oral anticoagulation (OAC) within 6 months. After 6 months, participants were invited to cross-over for a second study phase with reverse assignment. For this analysis we combined the two phases of the study using multilevel clustered Cox-regression analysis. Results The median age was 65 ± 11 years, the median CHA2DS2-VASc score was 3 ± 1 and 1.725 participants (31%) were females. Female sex was associated with better compliance in terms of more frequent PPG-measurements (57 ± 57) compared to male sex (50 ± 62; p<0.001). During a median follow-up time of 12 months 102 subjects reached the primary endpoint (including 2 endpoints in the cross-over window). Male sex (81 events) compared to female sex (21 events) was a significant predictor for reaching the primary endpoint (HR 1.74; 95% CI 1.08-2.82, p=0.023). While digital screening significantly increased the detection rate of AF requiring OAC in men (HR 2.48; 95% CI 1.52-4.05, p <0.001; Fig 1A), this effect did not reach the level of statistical significance in women (HR 1.83; 95% CI 0.74-4.54, p=0.193; Fig 1B), most probably due to the lower event-rate. The interaction between sex and the efficacy of digital screening was not statistically significant (p=0.563). Next to a higher incidence of AF in men (3.0% per year; 95% CI 2.4-4.5%) compared to women (1.8% per year; 95% CI 1.1%-2.4%; p=0.013), male participants were also at a higher risk for developing MACCE (106 vs. 20 events) (HR 2.57; 95% CI 1.57-4.20, p <0.001). AF was a significant predictor for developing MACCE in men (HR 6.52; 95% CI 3.42-12.43, p<0.001). Only one female participant with AF developed MACCE. Therefore, this analysis cannot be applied in females. Conclusion In a large-scale clinical trial, comparing digital screening to usual care for detecting AF requiring OAC, female sex was associated with better compliance to the study protocol and lower risk for developing AF requiring OAC. There was no significant interaction between sex and the efficacy of digital screening for detecting AF requiring OAC. In men, newly-diagnosed AF was associated with increased risk for MACCE.