Prasugrel was approved for use in the European Union in February 2009,[2] and in the US in July 2009, for the reduction of thrombotic cardiovascular events (includingstent thrombosis) in people withacute coronary syndrome (ACS) who are to be managed withpercutaneous coronary intervention (PCI).[3]
Prasugrel is used in combination withlow-dose aspirin to prevent thrombosis in patients with acute coronary syndrome, includingunstable angina pectoris, non-ST elevationmyocardial infarction (NSTEMI), and ST elevation myocardial infarction (STEMI), who are planned for treatment with PCI. Prasugrel is associated with a higher bleeding risk compared to clopidogrel but has demonstrated superiority in reducing the composite endpoint of death, recurrent myocardial infarctions and stroke.[4]
Prasugrel does not change the risk of death when given to people who have had a STEMI[citation needed] or NSTEMI.
Given the risk of bleeding, prasugrel should not be used in people who are older than 75 years, who have low body weight or a history of transient ischemic attacks or strokes.[4][5] The initiation of prasugrel before coronary angiography outside the context of primary PCI is not recommended.[6][7][5]
The drug was introduced to clinical practice in Canada in 2010[8] but was subsequently withdrawn by the manufacturer in 2020 as a "business decision". This has left a gap in the management of high-risk patients in certain situations in Canada where Effient was the drug of choice.[9]
Prasugrel should not be given to people with active pathological bleeding, such as peptic ulcer or a history of transient ischemic attack or stroke, because of higher risk of stroke (thrombotic stroke and intracranial hemorrhage).[10]
Prasugrel has a low potential for interactions. It may, for example, be used withproton pump inhibitors to reduce the risk of gastrointestinal bleeding without loss of its antiplatelet effect.[12][13][14][15]
Prasugrel is a member of thethienopyridine class ofADP receptor inhibitors, liketiclopidine (trade name Ticlid) andclopidogrel (trade name Plavix). These agents reduce the aggregation ("clumping") ofplatelets by irreversibly binding toP2Y12 receptors. Prasugrel inhibits platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel.[16][17] The TRITON-TIMI 38 study compared prasugrel with clopidogrel, and showed that prasugrel reduced rates of ischaemic events, but increased bleeding risk. Overall mortality rates were similar for each drug.[4]
Clopidogrel, unlike prasugrel, was issued ablack box warning from the FDA on 12 March 2010, as the estimated 2–14% of the US population who have low levels of theCYP2C19 liver enzyme needed to activate clopidogrel may not get the full effect. Tests are available to predict if a patient would be susceptible to this problem or not.[18][19]Unlike clopidogrel, prasugrel is effective in most individual with the exception in patients over the age of 75, weight under 60 kg, and patients with a history of stroke or TIA due to increased risk of bleeding,[20][4] although several cases have been reported of decreased responsiveness to prasugrel.[21] It has been suggested that the decreased responsiveness observed in prasugrel is likely due to its low but significant frequency of High Platelet Reactivity (HPR).[22]
Prasugrel produces inhibition ofplatelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry.[23] Following a 60-mg loading dose of the drug, about 90% of patients had at least 50% inhibition of platelet aggregation by one hour. Maximum platelet inhibition was about 80%. Mean steady-state inhibition of platelet aggregation was about 70% following three to five days of dosing at 10 mg daily after a 60-mg loading dose.Platelet aggregation gradually returns to baseline values over five to 9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75 mg and initiating prasugrel 10 mg with the next dose resulted in increased inhibition of platelet aggregation, but not greater than that typically produced by a 10-mg maintenance dose of prasugrel alone. Increasing platelet inhibition could increase bleeding risk. The relationship between inhibition of platelet aggregation and clinical activity has not been established.[11]
The reaction of prasugrel (top left) to its active metabolite (R-138727, top right). The two structures at the bottom represent the inactivethiolactone; they aretautomers of each other.
Prasugrel is aprodrug and is rapidly metabolized bycarboxylesterase 2 in the intestine andcarboxylesterase 1 in the liver to a likewise inactivethiolactone, which is then converted by CYP3A4 and CYP2B6, and to a minor extent by CYP2C9 and CYP2C19, to a pharmacologicallyactive metabolite (R-138727).[24][25] R-138727 has anelimination half-life of about 7 hours (range 2 h to 15 h). Healthy subjects, patients with stableatherosclerosis, and patients undergoing PCI show similar pharmacokinetics.
^Baker WL, White CM (2009). "Role of prasugrel, a novel P2Y(12) receptor antagonist, in the management of acute coronary syndromes".American Journal of Cardiovascular Drugs.9 (4):213–229.doi:10.2165/1131209-000000000-00000.PMID19655817.S2CID37160513.
^abChew DP, Scott IA, Cullen L, French JK, Briffa TG, Tideman PA, et al. (August 2016). "National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Australian clinical guidelines for the management of acute coronary syndromes 2016".The Medical Journal of Australia.205 (3):128–133.doi:10.5694/mja16.00368.PMID27465769.S2CID13014429.{{cite journal}}: CS1 maint: overridden setting (link)
^O'Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, et al. (September 2009). "Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials".Lancet.374 (9694):989–997.doi:10.1016/S0140-6736(09)61525-7.PMID19726078.S2CID205956050.{{cite journal}}: CS1 maint: overridden setting (link)
^Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, et al. (January 2007). "A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation".American Heart Journal.153 (1): 66.e9–66.16.doi:10.1016/j.ahj.2006.10.010.PMID17174640.{{cite journal}}: CS1 maint: overridden setting (link)
^Wiviott SD, Trenk D, Frelinger AL, O'Donoghue M, Neumann FJ, Michelson AD, et al. (December 2007). "Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial".Circulation.116 (25):2923–2932.doi:10.1161/CIRCULATIONAHA.107.740324.PMID18056526.S2CID8226182.{{cite journal}}: CS1 maint: overridden setting (link)
^Ruff CT, Giugliano RP, Antman EM, Murphy SA, Lotan C, Heuer H, et al. (March 2012). "Safety and efficacy of prasugrel compared with clopidogrel in different regions of the world".International Journal of Cardiology.155 (3):424–429.doi:10.1016/j.ijcard.2010.10.040.PMID21093072.{{cite journal}}: CS1 maint: overridden setting (link)
^Silvano M, Zambon CF, De Rosa G, Plebani M, Pengo V, Napodano M, et al. (February 2011). "A case of resistance to clopidogrel and prasugrel after percutaneous coronary angioplasty".Journal of Thrombosis and Thrombolysis.31 (2):233–234.doi:10.1007/s11239-010-0533-x.PMID21088983.S2CID20617890.
^Rehmel JL, Eckstein JA, Farid NA, Heim JB, Kasper SC, Kurihara A, et al. (April 2006). "Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450".Drug Metabolism and Disposition.34 (4):600–607.doi:10.1124/dmd.105.007989.PMID16415119.S2CID1698598.{{cite journal}}: CS1 maint: overridden setting (link)
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