Current and Novel Antiplatelet Therapies for the Treatment of Cardiovascular Diseases

Abstract

Over the last decades, antiplatelet agents, mainly aspirin and P2Y₁₂ receptor antagonists, have significantly reduced morbidity and mortality associated with arterial thrombosis. Their pharmacological characteristics, including pharmacokinetic/pharmacodynamics profiles, have been extensively studied, and a significant number of clinical trials assessing their efficacy and safety in various clinical settings have established antithrombotic efficacy. Notwithstanding, antiplatelet agents carry an inherent risk of bleeding. Given that bleeding is associated with adverse cardiovascular outcomes and mortality, there is an unmet clinical need to develop novel antiplatelet therapies that inhibit thrombosis while maintaining hemostasis. In this review, we present the currently available antiplatelet agents, with a particular focus on their targets, pharmacological characteristics, and patterns of use. We will further discuss the novel antiplatelet therapies in the pipeline, with the goal of improved clinical outcomes among patients with atherothrombotic diseases.

Keywords: P2Y12 receptor antagonists; acute coronary syndrome; aspirin; atherothrombosis; bleeding; cardiovascular disease; dual antiplatelet therapy; platelets.

Figure 1

Major signaling events and responses in resting and activated platelets. Under physiological conditions, endothelial cells release nucleotidases that degrade adenosine di- and tri-phosphate (ADP and ATP, respectively) to adenosine. They also secrete prostacyclin (also known as prostaglandin I2; PGI2) and nitric oxide (NO). NO and PGI2 as well as adenosine activate within platelets guanylyl (GC) and adenylyl cyclases (AC) respectively, increasing intra-platelet cyclic guanosine and adenosine 3′,5′-monophosphate (cGMP and cAMP, respectively) which are powerful platelet inhibitors maintaining the glycoprotein (GP) IIbIIIa, also called integrin αIIbβ3, in its inactive form. cAMP and cGMP are subsequently hydrolyzed by phosphodiesterases (PDE) limiting their intracellular levels. Following platelet activation, arachidonic acid (AA) produced from membrane phospholipids upon the action of phospholipase A2 is metabolized in thromboxane A2 (TXA2) that activates the Thromboxane Prostanoid (TP) receptor. ADP, by activating P2Y12 receptor, induces an inhibition of the AC that decreases cAMP synthesis. Following coagulation activation, generated thrombin cleaves its receptors on platelet surface, i.e., the protease-activated receptors (PAR1 and PAR4), resulting in their activation. TP, P2Y12, and PAR activation increases the cytosolic Ca2+ level and induces a conformational change of αIIbβ3 on the platelet surface that links its substrates, mainly fibrinogen and the von Willebrand factor (VWF), resulting in platelet aggregation.

Figure 2

P2Y12 receptor signaling pathways in platelets. ADP acts as a soluble agonist of P2Y12 receptor. It is a Gi-protein-coupled receptor consisting of a single polypeptide chain of seven transmembrane α helices. Its activation inhibits via the Gαi subunit, the adenylate cyclase-mediated signaling, which decreases the cyclic adenosine 3′,5′-monophosphate (cAMP) levels and results in the dephosphorylation of some cytoskeletal proteins, including vasodilator-stimulated phosphoprotein (VASP). P2Y12 receptor activation also stimulates the phosphoinositide 3-kinase (PI3K) via Gβγ protein complex resulting in Akt stimulation, which activates a number of downstream substrate proteins thereby increasing the cytosolic Ca²⁺ levels and inducing granule secretion. Both pathways ultimately lead to a conformational change in the glycoprotein (GP) IIbIIIa (also known as integrin αIIbβ3) on the platelet surface, which links fibrinogen, resulting in platelet aggregation.

Figure 3

Targets of current and emerging antiplatelet therapies. The currently available antiplatelet drugs (in grey) essentially act by preventing the formation of secondary messengers (cyclooxygenase-1 [COX1] inhibitors), by interacting with intracellular signaling pathways (phosphodiesterases [PDE] inhibitors and the prostacyclin [PGI₂] analogue), by blocking membrane receptors (P2Y₁₂ receptor antagonists and the protease-activated receptor PAR1 antagonist), or by inhibiting platelet aggregation (glycoprotein [GP] IIbIIIa inhibitors). Novel antiplatelet drugs in development (in purple) are mainly directed against platelet glycoproteins such as GPVI, GPIbα, and GPIIbIIIa or block membrane receptors such as the 2 purinergic receptors P2Y₁₂ and P2Y₁ as well as the receptors PAR1 and PAR4. Other drugs directed against different platelet-activation processes, such as adhesion, signaling and pro-coagulant activity, are also under development.

Figure 4

Clopidogrel metabolism pathways. Clopidogrel is extensively metabolized (85%) to a pharmacologically inactive metabolite via intestinal carboxylesterase 1 (CES1) and is eliminated in the urine and feces. The remaining 15% is metabolized by mixed-function oxidase enzymes from the CYP superfamily, first to 2-oxo-clopidogrel via CYP2C19, 1A2, and 2B6, and then to the active metabolite via CYP2C19 and, to a lesser extent, 2C9, 3A4, 3A5, and 2B6.