PCSK9: future antithrombotic target in ACS?

Navarese EP, Kolodziejczak M, Winter MP, et al.
Int J Cardiol 2016;published online ahead of print

Background

Recurrent ischemic events after acute coronary syndrome (ACS) are due to the residual thrombotic burden caused by impaired platelet reactivity, despite the use of potent antiplatelet therapy [1,2]. There are data suggesting that PCSK9 plays a role in the activation of thrombotic pathways, a hypothesis worth investigating in the context of ACS [3].

In this study, the potential association of the PCSK9 enzyme with on-treatment platelet reactivity and ischemic CV events was evaluated in 333 ACS patients treated with prasugrel or ticagrelor.

Main results

PCSK9 concentration and platelet reactivity:

• There was a direct correlation between increased PCSK9 serum levels and platelet reactivity (r = 0.30; P = 0.004).
• There was a significant 50% increase in platelet reactivity in the upper compared to the lower PCSK9 tertile (18 [SD 10–24] U vs 12 [SD 7–18] U; P = 0.02).
• In a sensitivity analysis, patients with PCSK9 values above the median (394.80 ng/mL) had significantly higher platelet reactivity (P=0.02).
• Higher PCSK9 levels (upper tertile) was a significant predictor of higher platelet reactivity levels after prasugrel and ticagrelor in both univariate (OR: 1.58; 95% CI: 1.17–2.12; P = 0.002) and multivariate logistic regression analysis (OR: 1.56; 95% CI: 1.11–2.20; P=0.01).

Clinical outcomes:

• There was a significant association between PCSK9 tertiles (upper vs. lower) and one-year MACE.
• Patients with MACE had significantly higher concentrations of PCSK9 compared with patients without MACE (578.70 ng/mL vs 391.00 ng/mL; P = 0.008).
• 22.03% of patients in the upper PCSK9 tertile experienced MACE compared with 3.39% in the lower PCSK9 tertile.
• Comparison of upper vs. lower PCSK9 tertile in regression analysis: crude HR: 2.61; 95% CI: 1.24–5.52; P = 0.01; adjusted HR: 2.62; 95% CI: 1.18–5.83; P = 0.01.
• Receiver operating characteristic curves for PCSK9, C-reactive protein, fibrinogen, platelets and troponin T as predictors of MACE at 1 year: PCSK9 had the highest diagnostic accuracy with adequate discrimination provided by the area under the curve (AUC: 0.77; 95% CI: 0.68–0.83; P < 0.001).

Conclusion

In ACS patients treated with prasugrel or ticagrelor, PCSK9 concentrations were associated with and predictive for platelet reactivity and recurrent MACE. These data support the hypothesis of the role of PCSK9 in platelet reactivity in these patients and highlight its future potential to become an antithrombotic target in ACS.

Find this article online at Int J Cardiol

References

1. Navarese EP, et al. Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials, Br. Med. J. (Clin. Res. Ed.) 350 (2015)
2. Siller-Matula JM, et al. Distribution of clinical events across platelet aggregation values in all-comers treated with prasugrel and ticagrelor, Vasc. Pharmacol. 79 (2016) 6–10
3. Navarese EP, et al. Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies for Acute Coronary Syndrome: A Narrative Review. Annals of Internal Medicine, 2016