Antiplatelet therapy in cardiovascular disease: Current status and future directions

Abstract

Antiplatelet medications remain a cornerstone of therapy for atherosclerotic cardiovascular and cerebrovascular diseases. In primary prevention (patients with cardiovascular risk factors but no documented events, symptoms or angiographic disease), there is little evidence of benefit of any antiplatelet therapy, and such therapy carries the risk of excess bleeding. Where there is documented disease (secondary prevention), stable patients benefit from long-term antiplatelet monotherapy, aspirin being first choice in those with coronary heart disease and clopidogrel in those with cerebrovascular disease; moreover, recent evidence shows that low-dose rivaroxaban in combination with aspirin confers added benefit, in patients with stable cardiovascular and peripheral arterial disease. In patients with acute cerebrovascular disease, aspirin combined with clopidogrel reduces subsequent risk, while in acute coronary syndrome, dual antiplatelet therapy comprising aspirin and a P2Y₁₂ inhibitor (clopidogrel, prasugrel or ticagrelor) confers greater protection than aspirin monotherapy, with prasugrel and ticagrelor offering greater antiplatelet efficacy with faster onset of action than clopidogrel. Although greater antiplatelet efficacy is advantageous in preventing thrombotic events, this must be tempered by increased risk of bleeding, which may be a particular issue in certain patient groups, as will be discussed. We will also discuss possible future approaches to personalisation of antiplatelet therapy.

Keywords: antiplatelet agents; cardiovascular disease; thrombosis.

FIGURE 1

Antiplatelet drug mechanisms of action. The thienopyridines clopidogrel and prasugrel prevent ADP from binding its specific P2Y₁₂ receptor and cause its irreversible inhibition; ticagrelor exerts reversible P2Y₁₂ receptor antagonism. While clopidogrel and prasugrel require hepatic metabolism to produce the active drug metabolite, ticagrelor is not a prodrug and has a direct inhibitory action, although additionally undergoing a cytochrome‐dependent oxidation that also produces an active metabolite contributing to the pharmacological effect. Aspirin irreversibly blocks the enzymatic activity of cyclooxygenase‐1 (COX‐1), which is a key enzyme in the metabolism of arachidonic acid to produce prostanoids. COX‐1 converts arachidonic acid to the unstable intermediate prostaglandin G2 (PGG2). Further metabolism of PGG2 by hydroperoxidases (HOX) leads to prostaglandin H2 synthesis that is finally converted into prostanoids by tissue‐specific isomerases (platelets mainly contain thromboxane A2 [TxA2] synthase resulting in production and release of TxA2). By acting on COX‐1, aspirin reduces TxA2‐dependent platelet activation. CYP: cytochrome P450. hCE: human carboxylesterase