Emerging antiplatelet and lipid lowering therapies

Abstract

Antiplatelet therapy is used widely with proven benefit for the primary prevention of cardiovascular disease as well as for the prevention of further ischemic cardiovascular events in patients with proven coronary artery disease (CAD) and in those with a history of acute coronary syndrome (ACS). The limitations of conventional antiplatelet therapy with aspirin, clopidogrel, or prasugrel, as well as the fact that rates of recurrent ischemic events still remain high with use of these agents, underscore the need to investigate alternative molecules that may be effective in further reducing the occurrence of events without increasing the risk of bleeding. The armamentarium of antiplatelet therapy has been further enriched by ticagrelor, cangrelor, vorapaxar, prasugrel and atopaxar. Ticagrelor was approved in 2011 by the European Medicines Agency swiftly followed by the US Food and Drug Administration. Reversible antiplatelet agents acting as P2Y12 antagonists similar to ticagrelor are cangrelor, and elinogrel. A new class of oral protease-activated receptor-1 (PAR-1) inhibitors, vorapaxar and atopaxar has also been proposed as effective antiplatelets but their clinical benefit is still under debate. The P2Y12 antagonists prasugrel and ticagrelor prevent adverse cardiac outcomes albeit their absolute benefit is very small. The beneficial effect of prasugrel and ticagrelor comes at a cost of an increased risk of bleeding. Furthermore, new adverse effects have also become evident with the new P2Y12 antagonists and these include dyspnea (for all of the reversible P2Y12 antagonists: ticagrelor, cangrelor, and elinogrel) and ventricular pauses for ticagrelor. In addition, the newer P2Y12 antagonists have a peculiar pharmacodynamic profile with a fast onset and offset. Two of these agents, cangrelor and elinogrel, are available as intravenous formulations, which may provide additional benefits in patients who undergo coronary artery bypass graft (CABG) surgery. Trials with the PAR-1 inhibitors have also shown trends toward reductions in cardiac events, but not without the possibility of increased bleeding. Physicians must carefully assess patient-specific factors such as risk of thrombosis, concomitant disease states, age, drug adherence, and aspirin dose, and plan for those patients who will be undergoing CABG when selecting antiplatelet therapy in order to optimally balance bleeding and thrombosis risk. In addition to adequate anti-platelet therapy the treatment of blood lipids is important for the primary and secondary prevention of cardiovascular disease. Elevated low-density lipoprotein cholesterol is an important risk factor for cardiovascular and cerebrovascular events. HMG-CoA reductase inhibitors, or statins, are very effective in lowering cholesterol levels, and in reducing mortality and cardiovascular events in patients with and without cardiovascular disease. The evidence cumulated with the studies conducted with statin has led to the recent recommendations that all patients with known vascular disease, or who are at high risk for vascular disease, should be considered candidates for statin therapy. Nonstatin therapies (either as monotherapy or in addition to statins) to reduce LDL cholesterol by mechanisms that do not involve inhibition of HMG-CoA reductase are likely to be useful for patients in need of LDL reduction; particularly those who either cannot take statins or respond only partially or not at all to statins alone. These therapies include cholesterol absorption inhibitors, Acyl-CoA cholesterol acyl transferase inhibitors, farnesoid X receptor antagonists, sterolregulating binding protein cleavage activating protein, and microsomal triglyceride transfer protein. Recent studies with the PCSK9 have shown that these drugs significantly reduce total and LDL cholesterol in patients with familial hypercholesterolaemia and that are effective in further reducing plasma cholesterol levels in patients receiving statins. Therefore, therapeutic options are becoming available for patients who cannot tolerate full dose statin therapy or for those few patients who are intolerant to statin therapy.