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Aspirin protects against atherothrombosis while increasing the risk of major bleeding. Although it is widely used to prevent cardiovascular disease (CVD), its benefit does not outweigh its risk for primary CVD prevention in large population settings. The recent United States Preventive Services Task Force guidelines on aspirin use to prevent CVD reflect this clinical tradeoff as well as the persistent struggle to define a population that would benefit from prophylactic aspirin therapy. Past clinical trials of primary CVD prevention with aspirin have not included consideration of a biomarker relevant to aspirin’s mechanism of action, platelet inhibition. This approach is at odds with the paradigm used in other key areas of pharmacological CVD prevention, including antihypertensive and statin therapy, which combine cardiovascular risk assessment with the measurement of mechanistic biomarkers (eg, blood pressure and LDL [low-density lipoprotein]-cholesterol). Reliable methods for quantifying platelet activity, including light transmission aggregometry and platelet transcriptomics, exist and should be considered to identify individuals at elevated cardiovascular risk due to a hyperreactive platelet phenotype. Therefore, we propose a new, platelet-guided approach to the study of prophylactic aspirin therapy. We think that this new approach will reveal a population with hyperreactive platelets who will benefit most from primary CVD prevention with aspirin and usher in a new era of precision-guided antiplatelet therapy.

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Background: End-stage kidney disease (ESKD) and peripheral artery disease (PAD) are frequently co-prevalent and each associated with increased cardiovascular (CV) risk. Platelets drive PAD pathogenesis and mediate atherothrombosis. Their function and influence on CV risk in ESKD remain unclear. We hypothesized that ESKD is associated with heightened platelet activity and incident cardiac and limb events in patients with PAD. Methods: The Platelet Activity and Cardiovascular Events study enrolled 289 patients with PAD undergoing lower extremity revascularization (LER). We measured platelet activity prior to LER via light transmission aggregometry in response to submaximal ADP, collagen, serotonin, epinephrine, and arachidonic acid. We followed patients for a median of 18 months for a primary endpoint of major adverse CV event (MACE; MI, stroke, death) and a secondary composite of major adverse CV or limb event (MACLE; MACE or acute limb ischemia). Results: Among enrolled subjects, 25 (9%) had ESKD. They were younger and more likely to have a history of coronary artery disease (CAD), heart failure, and critical limb ischemia (CLI) than those without ESKD (P<0.05 for each). Aggregation in response to epinephrine 2.0 uM after 5 minutes and at maximum was greater in those with compared to without ESKD (61% vs. 48%; P=0.004 and 77% vs. 60%; P=0.001, respectively). After multivariable adjustment, patients with vs. without ESKD were at greater risk for CV events ( Figure ). Platelet aggregation in response to submaximal epinephrine stimulation had a 32% and 45% mediating effect on the excess risk for MACE and MACLE, respectively, associated with ESKD ( Figure ). Conclusions: In patients with PAD, ESKD was associated with increased platelet aggregation in response to submaximal epinephrine that partially mediated increased risk for incident cardiac and limb events. Platelet activity appears to be an important mechanism underlying CV risk in ESKD.