Combination of cyclic nucleotide modulators with P2Y12 receptor antagonists as anti‐platelet therapy

Paul C Armstrong,Plinio M Ferreira,Melissa V Chan,Martina H Lundberg Slingsby,Marilena Crescente,Chih‐Chin Shih,Nicholas S Kirkby,Adrian J Hobbs,Timothy D Warner

doi:10.1111/jth.14826

Abstract

BackgroundEndothelium‐derived prostacyclin and nitric oxide elevate platelet cyclic nucleotide levels and maintain quiescence. We previously demonstrated that a synergistic relationship exists between cyclic nucleotides and P2Y12 receptor inhibition. A number of clinically approved drug classes can modulate cyclic nucleotide tone in platelets including activators of NO‐sensitive guanylyl cyclase (GC) and phosphodiesterase (PDE) inhibitors. However, the doses required to inhibit platelets produce numerous side effects including headache. ObjectiveWe investigated using GC‐activators in combination with P2Y12 receptor antagonists as a way to selectively amplify the anti‐thrombotic effect of both drugs. MethodsIn vitro light transmission aggregation and platelet adhesion under flow were performed on washed platelets and platelet rich plasma. Aggregation in whole blood and a ferric chloride‐induced arterial thrombosis model were also performed. ResultsThe GC‐activator BAY‐70 potentiated the action of the P2Y12 receptor inhibitor prasugrel active metabolite in aggregation and adhesion studies and was associated with raised intra‐platelet cyclic nucleotide levels. Furthermore, mice administered sub‐maximal doses of the GC activator cinaciguat together with the PDE inhibitor dipyridamole and prasugrel, showed significant inhibition of ex vivo platelet aggregation and significantly reduced in vivo arterial thrombosis in response to injury without alteration in basal carotid artery blood flow. ConclusionsUsing in vitro, ex vivo, and in vivo functional studies, we show that low dose GC activators synergize with P2Y12 inhibition to produce powerful anti‐platelet effects without altering blood flow. Therefore, modulation of intra‐platelet cyclic nucleotide levels alongside P2Y12 inhibition can provide a strong, focused anti‐thrombotic regimen while minimizing vasodilator side effects.

Highlights

Platelets play a central role in cardiovascular disease, as they are integral to the development of acute thrombotic events
We have recently demonstrated that blockade of platelet P2Y12 receptor further synergizes with PGI2 and NO17,18 to produce profound platelet inhibition
Aggregation (Figure 1D) conducted in the presence of 10 μmol/L BAY 60-2770 (BAY-70) plus prasugrel active metabolite (PAM) were inhibited by 55 ± 10% and 76 ± 11% when induced by TRAP-6 and collagen, respectively, compared to 15 ± 3% and 28 ± 5%, respectively, when PAM was not present (P < .05 versus BAY-70 plus PAM)

Summary

| INTRODUCTION

Platelets play a central role in cardiovascular disease, as they are integral to the development of acute thrombotic events. For this reason, anti-platelet therapy is prescribed for the secondary prevention of atherothrombotic events in patients with acute coronary syndromes or following percutaneous coronary intervention.[1,2] Aspirin, which irreversibly inhibits the cyclooxygenase enzyme and downstream thromboxane (Tx)A2 production,[3,4] is often coadministered with a P2Y12 receptor antagonist, such as clopidogrel or prasugrel, to produce dual anti-platelet therapy (DAPT). We hypothesized that the actions of pharmacological agents acting upon cyclic nucleotides could be selectively amplified in platelets by combination with P2Y12 receptor antagonists, thereby producing an enhanced anti-platelet effect of both drugs at doses which do not produce systemic vasodilator side effects.

| METHODS

60 Vehicle

A Vehicle PAM

Findings

| DISCUSSION