Abstract Body (Do not enter title and authors here): Background: Identifying platelet hyperreactivity is critical for selecting patients who may benefit from antiplatelet therapy in cardiovascular (CV) prevention. We previously developed and validated the Platelet Reactivity ExpreSsion Score (PRESS) as a transcriptomic signature to discriminate platelet hyperreactivity and associated CV risk. Whether PRESS is modifiable with antiplatelet therapy is unknown.

Methods: In an open-label, randomized crossover study, participants without established CV disease received aspirin (81 mg vs. 325 mg daily) and ticagrelor (90 mg twice daily) for 4 weeks each. Blood was serially collected before and after each treatment phase. Platelet aggregation was measured in response to submaximal agonist stimulation, platelet RNA was collected, sequenced and PRESS was calculated. Self-reported bleeding events were recorded. The primary endpoint was PRESS, with a key secondary endpoint of a composite of platelet aggregation measures termed platelet function score (PFS).

Results: Among 63 participants (mean age 44 years; 67% female; 54% non-white) with platelet RNA sequencing data, 25 (39.7%) exhibited high PRESS (>0.37), suggestive of a platelet hyperreactive phenotype. Consistently, high PRESS participants demonstrated significantly greater platelet aggregation in response to submaximal epinephrine (p=0.003), collagen (p=0.036), and higher composite PFS (p=0.028). Aspirin (both 81mg and 325mg) and ticagrelor each significantly reduced PFS (p<0.001 for each comparison). Aspirin had no significant effect on PRESS, whereas ticagrelor induced a significant reduction in PRESS (p<0.01). Stratified analyses showed ticagrelor significantly decreased PRESS in participants with high baseline platelet reactivity score (p<0.0001), but not in those with normal baseline scores (p=0.69). Minor bleeding was reported in five participants following ticagrelor administration; these individuals showed a non-significant trend toward lower PRESS both pre- (p=0.108) and post-ticagrelor (p=0.088).

Conclusions: PRESS is a modifiable biomarker responsive to ticagrelor therapy and may serve as a useful tool to identify individuals who derive optimal risk-benefit balance from primary prevention with antiplatelet agents.