Prasugrel
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| Prasugrel
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| Systematic (IUPAC) name | |
| 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl acetate | |
| Identifiers | |
| CAS number | ? |
| ATC code | ? |
| PubChem | |
| Chemical data | |
| Formula | C20H20FNO3S |
| Mol. mass | 373.442 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | ? |
| Half life | ? |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
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| Legal status | |
| Routes | ? |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-525-6884
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Overview
Prasugrel is a novel platelet inhibitor developed by Daiichi Sankyo Co. and produced by Ube and currently under clinical development in cooperation with Eli Lilly and Company for acute coronary syndromes planned for percutaneous coronary intervention (PCI). Prasugrel is a member of the thienopyridine class of ADP receptor inhibitors, like ticlopidine and clopidogrel (trade name Plavix). These agents are believed to reduce the aggregation ("clumping") of platelets by irreversibly binding to P2Y12 receptors.
TRITON-TIMI 38 study
As published in the New England Journal of Medicine's online edition, the TRITON-TIMI 38 study of 13,608 patients with acute coronary syndromes compared prasugrel against clopidogrel, both in combination with aspirin, and found that, as a more potent anti-platelet agent, prasugrel reduced the combined rate of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (12.1% for clopidogrel vs. 9.9% for prasugrel). These favorable results were obtained at the expense of increasing the rate of serious bleeding (1.4%, vs. 0.9% in the clopidogrel group) and fatal bleeding (0.4% vs. 0.1%).[1] This resulted in an overall net clinical benefit in favour of prasugrel.
Antiplatelet therapy has progressively improved over time: Aspirin improved the relative risk of ischemic outcomes over placebo by 20%, clopidogrel further improved the relative risk of ischemic outcomes by another 20% relative to aspirin, and prasugrel has now further improved the relative risk of ischemic outcomes by another 20% relative to clopidogrel. Each successive improvement in efficacy has been accompanied by a modest rise in bleeding.
The addition of clopidogrel to aspirin has been associated with improved outcomes in a variety of studies, most notably the CURE study. When swallowed and absorbed into the bloodstream, clopidogrel is an inactive pro-drug, and requires conversion to the active metabolite in the liver to become an active antiplatelet agent in the bloodstream. Recent research has identified a subpopulation of patients who do not metabolize or convert inactive clopidogrel pro-drug to the active metabolite as well as the rest of the population. These 25-30% of patients who do not metabolize clopidogrel as well as other patients have been labeled “hyporesponders” or “non-responders”. These “hyporesponders” to clopidogrel have been shown to have higher ischemic event rates when compared to patients who respond well to clopidogrel. Prasugrel is also a pro-drug but it is converted more rapidly and consistently to the active metabolite as it is absorbed in the intestine and by red blood cells in the bloodstream. Because it is metabolized more effectively and more rapidly when compared to clopidogrel, prasugrel is associated with more rapid and more potent inhibition of platelets. In cross-over studies, patients who are “hyporesponders” to clopidogrel uniformly respond to prasugrel. TRITON-TIMI 38 was the first large scale trial to test whether more rapid and more potent inhibition of platelet activation by blocking the P2Y12 receptor would yield improved outcomes.
TRITON - TIMI 38, an international, double-blind, phase 3 trial enrolled 13,608 patients with moderate to high-risk ACS who were scheduled to undergo PCI. Participants were randomized at 707 sites in 30 countries. Patients were given either prasugrel (60 mg as a one-time “loading” dose follwed by a daily 10 mg maintenance dose) or the currently FDA approved dose of clopidogrel (300 mg loading dose and a daily 75 mg maintenance dose) for up to 15 months. The primary efficacy endpoint (death from cardiovascular causes, heart attack or stroke) was significantly reduced from 12.1% of patients randomized to clopidogrel to 9.9% of patients randomized to prasugrel (HR 0.81[0.73-0.90], P=0.0004) meeting the primary hypothesis of superiority. Significant reductions with prasugrel were observed in stent thrombosis (HR 0.48[0.36-0.64], (HR 0.76 [0.67-.085], P<0.0001) ,urgent target vessel revascularization (HR 0.66 [0.54-0.81], P=0.0001) and recurrent MI (HR 0.76 [0.67-.085], P<0.0001).
Major bleeding was observed in 2.4% of patients randomized to prasugrel and 1.8% of patients randomized to clopidogrel (HR 1.32 [1.03-1.68], P=0.03). The rate of life threatening bleeding was greater in the Prasugrel group (1.4% vs 0.9%, p=0.01), as was the rate of fatal bleeding (0.4% vs 0.1%, p=0.002). Non fatal bleeding trended to be higher with Prasugrel but did not reach statistical significance (1.1% vs 0.9%, HR=1.25, p=0.23).
The balance of efficacy and safety, net clinical benefit (all cause mortality, nonfatal MI, nonfatal stroke, or nonfatal major bleed), significantly favored prasugrel (HR 0.87 [0.79-0.95], P=0.004).
Disclosure: Dr. Gibson, the editor of this page, was an investigator in the TRITON-TIMI 38 trial and has received research grant support from both Eli Lilly and BMS / Sanofi Aventis.
References
External links
Prasugrel information at Prous Science.
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
