Beyond Aspirin and Clopidogrel: Is There a Need for Additional Antiplatelet Therapy in ACS?

Abstract

Dual antiplatelet therapy with aspirin and clopidogrel is a well-established standard of care for patients with acute coronary syndromes. Whether there are other drug strategies or therapies that will achieve fewer ischemic events, and at the same time be associated with fewer bleeding complications, is a question recurrently asked. Finding the appropriate pharmacologic calibration of antiplatelet potency and applying such a pharmacodynamic effect to all patients has only been partially successful. The shadow of this one-size-fits-all dilemma is now being recast with the arrival of newer antiplatelet agents, which are attempting to decouple antithrombotic potency from bleeding liability. Novel antiplatelet agents that act faster and have more consistent pharmacokinetics and higher potency are steadily emerging. Additionally, newer agents that target unique sites, such as the thrombin receptor on platelets, are being studied in large-scale clinical trials. Each of these new agents has the potential to extend net clinical benefits beyond those provided by aspirin and clopidogrel.

Platelets, atherothrombosis, and atherosclerosis

“…Unhydrolysed clopidogrel is then metabolised in a 2 steps by hepatic cytochrome P450s (including CYP2C19) 106,107 . A reduced function allele of CYP2C19 is the most commonly expressed variant, found in 30% of Europeans, 40% of Africans, and more than 50% of Asians 106,107 . In a genetic sub study of the TRITON-TIMI-38 (Trial to Assess the Improvement in Therapeutic Outcomes by…”

“…In fact, the FDA has issued a boxed warning on the drug label highlighting the reduced efficacy of clopidogrel therapy in individuals with the reduced function allele of CYP2C19, the availability of CYP2C19 genotype testing, and the recommendation to consider alternative dosing regimens or other antiplatelet agents in individuals with reduced metabolism of clopidogrel 107 .…”

Platelets, atherothrombosis, and atherosclerosis

“…Clopidogrel (85-90%) is hydrolysed via intestinal esterases to a terminally inactive metabolite. Unhydrolysed clopidogrel is then metabolised in a 2 steps by hepatic cytochrome P450s (including CYP2C19) 106,107 . A reduced function allele of CYP2C19 is the most commonly expressed variant, found in 30% of Europeans, 40% of Africans, and more than 50% of Asians 106,107 .…”

“…Unhydrolysed clopidogrel is then metabolised in a 2 steps by hepatic cytochrome P450s (including CYP2C19) 106,107 . A reduced function allele of CYP2C19 is the most commonly expressed variant, found in 30% of Europeans, 40% of Africans, and more than 50% of Asians 106,107 . In a genetic sub study of the TRITON-TIMI-38 (Trial to Assess the Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction) study, this reduced function allele was found to be associated with reduced exposure to the active metabolite of clopidogrel, and an increased risk of death and acute events compared to non carriers (12.1 vs. 8%; P = 0.01) 98 .…”

“…In a genetic sub study of the TRITON-TIMI-38 (Trial to Assess the Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction) study, this reduced function allele was found to be associated with reduced exposure to the active metabolite of clopidogrel, and an increased risk of death and acute events compared to non carriers (12.1 vs. 8%; P = 0.01) 98 . In fact, the FDA has issued a boxed warning on the drug label highlighting the reduced efficacy of clopidogrel therapy in individuals with the reduced function allele of CYP2C19, the availability of CYP2C19 genotype testing, and the recommendation to consider alternative dosing regimens or other antiplatelet agents in individuals with reduced metabolism of clopidogrel 107 .…”