Prasugrel Tablets (Effient™)
Pharmacology Update
Prasugrel Tablets (Effient™)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
A new antiplatelet drug has been approved by the FDA for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention. Prasugrel is a thienopyridine platelet P2Y12 adenosine-diphosphate receptor blocker similar to clopidogrel and ticlopidine. The drug is a potent and irreversible inhibitor of platelet aggregation and is positioned to challenge clopidogrel in this billion dollar plus market. It is marketed by Daiichi Sankyo, Inc., and Eli Lilly and Company as Effient™.
Indications
Prasugrel is indicated for the reduction of thrombotic cardiovascular events in patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention (PCI). These include patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI) and patients with ST-elevation myocardial infarction (STEMI) when managed with either primary or delayed PCI.1
Dosage
The initial loading dose is 60 mg followed by 10 mg once daily. A lower dose (5 mg) should be considered for patients weighing less than 60 kg. Prasugrel may be taken without regard to meals. No dosage adjustment is required for patients with renal impairment or mild-to-moderate hepatic impairment.1
Prasugrel is available as 5 mg and 10 mg tablets.
Potential Advantages
Prasugrel is a more potent inhibitor of platelet aggregation than clopidogrel and appears more effective in reducing primary cardiovascular events and recurrent cardiovascular events in patients with ACS.1-3
Potential Disadvantages
Compared to clopidogrel, prasugrel is associated with a higher risk of major bleeding and life-threatening bleeding.1,3 Subjects with a history of cerebrovascular events did not benefit and showed a strong trend for a higher rate of TIMI major bleed.3
Comment
Prasugrel is a prodrug that is converted to a potent irreversible platelet P2Y12 adenosine-diphosphate receptor blocker in a two-step process (intestinal carboxy-esterases and CYP 3A4 and 2B6). It is a more potent platelet inhibitor than clopidogrel.4,5 Efficacy comparable to clopidogrel was shown in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) and various subanalyses.3,4,6,7 TRITON-TIMI was a double-blind, randomized superiority study involving 13,608 subjects with moderate-to-high risk ACS with scheduled PCI. The majority (74%) had unstable angina or NSTEMI and the remainder had STEMI. Subjects were randomized to prasugrel (60 mg loading and 10 mg daily) or clopidogrel (300 mg loading and 75 mg daily). All subjects received aspirin. The median treatment period was 14.5 months. The primary efficacy endpoint was death from cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke. The primary safety endpoint was major bleeding. Occurrence of the primary endpoint was reduced in the prasugrel group (9.9% vs 12.1%; hazard ratio [HR], 0.81; 95% confidence interval, 0.73-0.90; P < 0.001). The greatest benefit was reduction in nonfatal MIs. Benefits of prasugrel over clopidogrel were similar between UA/NSTEMI and STEMI subjects. Rates of MI, urgent target-vessel revascularization, and stent thrombosis were significantly lower in the prasugel group. Prasugrel was also more effective in reducing subsequent cardiovascular events than clopidogrel.2 Diabetic subjects showed greater benefit with prasugrel than nondiabetic subjects and males more than females.3,7 Clinical outcomes were less favorable in subjects with a history of stroke or transient ischemic attacks, age 75 years or older, and those with body weight less than 60 kg.3 Non-CABG-related TIMI major bleeding was significantly higher with prasugrel (2.4% vs 1.8%; P = 0.03). Prasugrel resulted in a higher risk for life-threatening bleeding (1.4% vs 0.9%; P = 0.01) and fatal major bleeding (0.4% vs 0.1%; P = 0.002.). CABG-related major bleeding events were 13.4% for the prasugrel groups vs 3.2% (P < 0.001). Overall mortality was not significantly different (3.0% vs 3.2%). When the primary efficacy and safety endpoints (major bleed) were combined, diabetic subjects showed a statistically significant benefit with prasugrel vs clopidogrel (14.6% vs 19.2%; HR, 0.74 [0.62-0.89]; P = 0.001) compared to nondiabetics (11.5% vs 12.3%; P = 0.16).7 In addition, diabetics on insulin gained more benefit than those not on insulin. The rate of newly diagnosed malignancies was 1.82% for prasugrel and 1.54% with clopidogrel (P = 0.28).9
Clinical Implications
Prasugrel appears to be more effective than clopidogrel in patients with unstable angina/NSTEMI and STEMI scheduled for PCI as administered in TRITON-TIMI 38. However, the greater benefit comes with greater risk. It is estimated that with 1000 patients treated, 24 events are avoided, but at the cost of 10 excess major or minor bleeding events.8 In terms of death, there were 3 CV deaths averted but 2 additional deaths due to fatal hemorrhage. It appears the diabetic patients show the best benefit:risk ratio. Critics of the study point out the drugs were not given at the same potency and the faster onset of prasugrel favor it in the trial.
References
1. Prasugrel Product Information. Indianapolis, IN: Daiichi Sankyo, Inc., and Eli Lilly and Company; July 2009.
2. Murphy SA, et al. Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON-TIMI 38 trial. Eur Heart J 2008;29:2473-2479.
3. Wiviott SD, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357;2001-2015.
4. Wiviott SD, et al. 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 2007;116:2923-2932.
5. Bhatt DL. Prasugrel in clinical practice. N Engl J Med 2009 Jul 15; Epub ahead of print.
6. Montalescot G, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): Double-blind, randomised controlled trial. Lancet 2009;373:723-731.
7. Wiviott SD, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrelThrombolysis in Myocardial Infarction 38. Circulation 2008;118:1626-1636.
8. Center for Drug Evaluation and Research. Application # 22-307. Available at: www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000_SumR.pdf. Accessed Aug. 6, 2009.
9. Letter to FDA About Safety Concerns with Prasugrel Hydrochloride and Removal of Dr. Sanjay Kaul from Cardiovascular and Renal Drugs Advisory Committee Meeting (HRG Publication #1857). Available at: www.citizen.org/documents/Prasugrel_letter_to_FDA_1.pdf. Accessed Aug. 5, 2009.
A new antiplatelet drug has been approved by the FDA for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention.Subscribe Now for Access
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