Risk modifiers and mortality in patients with high platelet reactivity to Adenosine-diphosphate (ADP) in the LURIC study
Authors: Berger M , Kleber M , Winfried Maerz W , Hellstern P , Marx N , Schuett K.A 
Published: November 2020

Abstract

Background
Increased platelet reactivity (PR) is an established predictor of cardiovascular (CV) and all-cause mortality. However, therapeutic targeting of PR by tailored antiplatelet therapy (APT) failed to show significant clinical benefit. It remains unclear whether increased PR constitutes a risk-modifier that identifies patients that benefit from risk-factor adjustment.

Purpose
To identify risk factors that allow modification and/or elimination of increased CV and all-cause mortality in patients with altered PR.

Methods
ADP- and TRAP-induced PR was measured by CD62P and CD63 expression in 1780 patients who were referred for coronary angiography between 1997 and 2000 and participated in the LURIC study. Statistical analysis was performed by SPSS v25.0 and R v3.6.1

Results
ADP-induced PR was an excellent predictor of CV-mortality and risk-equivalent to the presence of coronary artery disease (Figure 1A). Stratification of platelet ADP-response into tertiles demonstrated that patients with high-PR (HPR) and low-PR (LPR) were at increased risk for CV-mortality when compared to the reference group (HPR: HR 1.7 [95% CI: 1.3–2.3]; LPR: HR 1.4 [95% CI: 1.0–1.8]) (Figure 1B). Multivariable-adjustment did not change the association of PR with CV-mortality. Using a relative weight analysis, we identified HbA1c and estimated glomerular filtration rate (eGFR) as potential risk-modifiers. In addition, presence of APT appeared to be an exclusive risk-modifier in the HPR-group. In an multivariable-adjusted risk assessment, we verified that in the HPR group (i) treatment of PR by APT reduced CV-mortality with a HR of 0.5 (95% CI: 0.3–0.7) p=0.0004), (ii) HbA1c of &gt;7.0% in patients with diabetes increased CV-mortality with a HR of 2.0 (95% CI: 1.2–3.2 p=0.004) and (iii) eGFR &lt;60ml/min increased CV-mortality with a HR 1.7 (95% CI: 1.1–2.6 p=0.013). Other risk-factors including blood pressure (&lt;140mmHg), LDL-C (&lt;100mg/dL) and hs-CRP (&lt;2mg/dL) did not alter the mortality risk. None of the risk-modifiers tested affected CV-mortality risk of patients in the LPR group.
In the HPR group, risk modification by APT and HbA1c &lt;7.0% in patients with diabetes independently reduced CV-mortality risk to a level that was no longer statistically different to the reference group (p&gt;0.05). Risk modification by an eGFR &gt;60ml/min led to a profound risk reduction in the HPR group but remained statistically different from the reference group (Figure 1C).

Conclusion
Here, we demonstrate that HPR and LPR are predictors for CV mortality in the LURIC study. Treatment of platelet hyperreactivity by APT, HbA1c of ≤7% in patients with diabetes and an eGFR ≥60ml/min were associated with a reduced CV-mortality in HPR patients and might constitute adjustable risk factors in this group. In addition, we were unable to identify any significant risk factors for patients with LPR underlining a high-risk patient group with insufficient therapeutic options.
Figure 1

Funding Acknowledgement
Type of funding source: None