Background: 

Increased platelet P2Y₁₂ reactivity is an established predictor of atherothrombosis. However, pharmacological P2Y₁₂ inhibition failed to demonstrate clinical benefit in patients with high P2Y₁₂ reactivity. Given the lack pharmacotherapeutic strategies it remains elusive whether P2Y₁₂ inhibition constitutes a modifiable biomarker. 

Aim:

The aim of the current study was to assess the role of P2Y₁₂ reactivity in a prognostic setting and identify factors that may modulate elevated mortality risk in patients with altered P2Y₁₂ reactivity.  

Methods and results:   

P2Y₁₂ reactivity was measured by ADP-induced CD62P and CD63 expression in 1520 patients who were referred for coronary angiography between 1997 and 2000 and participated in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC).  Presence of High- and Low P2Y₁₂ reactivity was risk equivalent to the presence of coronary artery disease (log rank test: p=0.861 for CV death [p=0.164 for death] and constituted excellent predictors of cardiovascular and all-cause mortality. Multivariable adjustment did not change the significant association of P2Y₁₂ reactivity with mortality (Low P2Y₁₂: 1.4 [95%CI 1.0 – 2.0]; High P2Y₁₂ 1.4 [95%CI 1.1 – 1.9]). Additional relative weight analysis of separate cox proportional hazard models for low and high P2Y₁₂ reactivity identified glucose control (HbA1c), renal filtration (estimated Glomerular filtration rate [eGFR]), inflammation (high sensitive C-reactive protein [hsCRP]) and antiplatelet therapy by aspirin as risk modifiers for cardiovascular and all-cause mortality in patients with altered P2Y₁₂ reactivity (i.e. high or low reactivtiy). Absence of these risk modifiers in patients with altered platelet reactivity was associated with a profound risk reduction to a degree that was no longer statistical different to the reference group (i.e. patients with normal P2Y₁₂ reactivity) for cardiovascular mortality (i.e. HbA1c< 7% in patients with diabetes, Aspirin) and overall mortality (i.e. HbA1c< 7% in patients with diabetes, hsCRP < 3mg/L, eGFR > 60ml/min and Aspirin).     

Conclusions  

Here, we demonstrate that altered P2Y₁₂ reactivity is risk equivalent to coronary artery disease and an excellent predictor of cardiovascular and all-cause mortality in the LURIC study.  In patients with altered P2Y₁₂reactivity antiplatelet therapy with Aspirin, HbA1c of ≤ 7% in patients with diabetes, an eGFR ≥ 60ml/min and hsCRP < 3mg/L was associated with reduced mortality. These might constitute adjustable factors to reduce excessive mortality risk in these patients.