Current Oral Antiplatelets: Focus Update on Prasugrel
Current Oral Antiplatelets: Focus Update on Prasugrel
Antiplatelet agents play an important role in the management of ACS. Along with aspirin, many new antiplatelet agents including thienopyridines have been used clinically. All thienopyridines undergo biotransformation to active metabolites, which bind to P2Y12 receptors on platelets, resulting in inhibition of ADP-mediated platelet activation and aggregation. Prasugrel, a novel thienopyridine, has been shown to have faster and more complete antiplatelet action in vivo compared with other thienopyridines. It also has lesser inter patient variability in its antiplatelet effects when compared with clopidogrel. These desirable effects are because of better absorption and a more efficient metabolism. See Table 1 for a comparison of different antiplatelet agents.
TRITON-TIMI 38 showed that prasugrel therapy lowered the rate of ischemic events in moderate- to high-risk patients with ACS who were scheduled for PCI. This better antiplatelet effect comes, however, at the cost of an increase in major bleeding, especially among 3 high-risk groups: patients ≥75 years old, patients weighing ≤60 kg, and patients with a history of stroke or transient ischemic attack. It would be prudent to avoid the use of prasugrel in these groups of patients if possible. It has been suggested that in the former 2 groups, lowering the prasugrel dosage from the standard 10 mg/day to 5 mg/day might reduce the incidence of bleeding. Also, increased bleeding was observed in patients taking prasugrel who were undergoing coronary artery bypass graft when compared with patients taking clopidogrel.
Prasugrel is a good choice for patients with DM because they have increased platelet reactivity and higher rates of nonresponse to clopidogrel. Prasugrel has been shown to improve net outcomes among patients with DM rather than in those without DM. Although there is conflicting evidence about concurrent use of clopidogrel and PPIs, all available evidence suggests that PPIs can be safely used in patients taking prasugrel. In TRITON-TIMI 38, the incidence of stent thrombosis was lower in patients treated with prasugrel when compared with those treated with clopidogrel. It is noteworthy that results from TRITON-TIMI 38 cannot yet be applied to all ACS patients because this study looked into only patients with ACS who were scheduled for PCI. Although prasugrel seems promising, as of now its use in all patients with ACS is not advisable.
Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction of prasugrel use. Occurrence of stroke or transient ischemic attack while taking prasugrel would warrant discontinuation of the drug. Active bleeding and elective surgery are the other reasons for discontinuation of the drug. A rare but serious and potentially fatal condition, thrombotic thrombocytopenic purpura, has been reported with prasugrel. This sometimes can occur after a brief exposure (<2 weeks) and requires urgent treatment, including plasmapheresis.
Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes is a phase 3 trial, expected to be completed in April 2012, that will compare prasugrel therapy with clopidogrel therapy among patients with ACS who are medically managed and in whom no revascularization is planned. This study is expected to throw light on the efficacy and safety of prasugrel when used in a different spectrum of ACS patients.
The next antiplatelet agents in the pipeline are ticagrelor and cangrelor. Both of these are direct inhibitors of P2Y12 receptors on platelets and cause reversible inhibition of platelet function. Neither of these drugs require biotransformation before they can act and are thus different from thienopyridines in use now. Cangrelor is administered intravenously and ticagrelor is an orally active drug. Cangrelor is metabolized in the plasma and starts exerting its antiplatelet action within seconds of beginning intravenous infusion. Once the infusion is stopped, the platelet activity reverts back to normal within an hour. These characteristics would make it a major competitor to glycoprotein IIb/IIIa inhibitors and a favorite drug for interventional cardiologists once its use is approved by the FDA. CHAMPION PCI is a phase 3 trial that will investigate the proposed superiority of cangrelor over clopidogrel in reducing ischemic events when given at the start of PCI. The PLATO trial proved the superior efficacy of ticagrelor over clopidogrel in patients with ACS.
Looking back, we find that, after aspirin, new drugs with better antiplatelet activity have been added at regular intervals. This trend probably will continue and hopefully lead to the development of better antiplatelet agents.
Summary
Antiplatelet agents play an important role in the management of ACS. Along with aspirin, many new antiplatelet agents including thienopyridines have been used clinically. All thienopyridines undergo biotransformation to active metabolites, which bind to P2Y12 receptors on platelets, resulting in inhibition of ADP-mediated platelet activation and aggregation. Prasugrel, a novel thienopyridine, has been shown to have faster and more complete antiplatelet action in vivo compared with other thienopyridines. It also has lesser inter patient variability in its antiplatelet effects when compared with clopidogrel. These desirable effects are because of better absorption and a more efficient metabolism. See Table 1 for a comparison of different antiplatelet agents.
TRITON-TIMI 38 showed that prasugrel therapy lowered the rate of ischemic events in moderate- to high-risk patients with ACS who were scheduled for PCI. This better antiplatelet effect comes, however, at the cost of an increase in major bleeding, especially among 3 high-risk groups: patients ≥75 years old, patients weighing ≤60 kg, and patients with a history of stroke or transient ischemic attack. It would be prudent to avoid the use of prasugrel in these groups of patients if possible. It has been suggested that in the former 2 groups, lowering the prasugrel dosage from the standard 10 mg/day to 5 mg/day might reduce the incidence of bleeding. Also, increased bleeding was observed in patients taking prasugrel who were undergoing coronary artery bypass graft when compared with patients taking clopidogrel.
Prasugrel is a good choice for patients with DM because they have increased platelet reactivity and higher rates of nonresponse to clopidogrel. Prasugrel has been shown to improve net outcomes among patients with DM rather than in those without DM. Although there is conflicting evidence about concurrent use of clopidogrel and PPIs, all available evidence suggests that PPIs can be safely used in patients taking prasugrel. In TRITON-TIMI 38, the incidence of stent thrombosis was lower in patients treated with prasugrel when compared with those treated with clopidogrel. It is noteworthy that results from TRITON-TIMI 38 cannot yet be applied to all ACS patients because this study looked into only patients with ACS who were scheduled for PCI. Although prasugrel seems promising, as of now its use in all patients with ACS is not advisable.
Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction of prasugrel use. Occurrence of stroke or transient ischemic attack while taking prasugrel would warrant discontinuation of the drug. Active bleeding and elective surgery are the other reasons for discontinuation of the drug. A rare but serious and potentially fatal condition, thrombotic thrombocytopenic purpura, has been reported with prasugrel. This sometimes can occur after a brief exposure (<2 weeks) and requires urgent treatment, including plasmapheresis.
Future Directions
Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes is a phase 3 trial, expected to be completed in April 2012, that will compare prasugrel therapy with clopidogrel therapy among patients with ACS who are medically managed and in whom no revascularization is planned. This study is expected to throw light on the efficacy and safety of prasugrel when used in a different spectrum of ACS patients.
The next antiplatelet agents in the pipeline are ticagrelor and cangrelor. Both of these are direct inhibitors of P2Y12 receptors on platelets and cause reversible inhibition of platelet function. Neither of these drugs require biotransformation before they can act and are thus different from thienopyridines in use now. Cangrelor is administered intravenously and ticagrelor is an orally active drug. Cangrelor is metabolized in the plasma and starts exerting its antiplatelet action within seconds of beginning intravenous infusion. Once the infusion is stopped, the platelet activity reverts back to normal within an hour. These characteristics would make it a major competitor to glycoprotein IIb/IIIa inhibitors and a favorite drug for interventional cardiologists once its use is approved by the FDA. CHAMPION PCI is a phase 3 trial that will investigate the proposed superiority of cangrelor over clopidogrel in reducing ischemic events when given at the start of PCI. The PLATO trial proved the superior efficacy of ticagrelor over clopidogrel in patients with ACS.
Looking back, we find that, after aspirin, new drugs with better antiplatelet activity have been added at regular intervals. This trend probably will continue and hopefully lead to the development of better antiplatelet agents.
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