Acute Coronary Syndromes
Patients Undergoing Percutaneous Coronary Intervention
Prasugrel hydrochloride is used in combination with aspirin for the reduction of thrombotic cardiovascular events (e.g., stent thrombosis, myocardial infarction [MI]) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Prasugrel is used in patients with unstable angina or non-ST-segment-elevation MI (NSTEMI) undergoing PCI and in patients with ST-segment-elevation MI (STEMI) managed with primary or nonprimary/delayed (i.e., after medical treatment for STEMI) PCI.
Dual-drug antiplatelet therapy with a P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) and aspirin is part of the current standard of care in patients with ACS. The American Heart Association (AHA), the American College of Cardiology Foundation (ACCF), the Society for Cardiovascular Angiography and Interventions (SCAI), and the American College of Chest Physicians (ACCP) recommend antiplatelet therapy with a P2Y12-receptor antagonist (clopidogrel, prasugrel, or ticagrelor) in conjunction with aspirin for treatment and secondary prevention in patients with ACS. These experts generally recommend ticagrelor or clopidogrel as the P2Y12-receptor antagonist in patients with ACS who are treated medically without stent placement; because prasugrel has been studied principally in patients undergoing planned PCI, recommendations for the use of this drug are restricted to that population. In patients undergoing PCI with stent placement (bare-metal or drug-eluting), a loading dose of ticagrelor, clopidogrel, or prasugrel is recommended, followed by maintenance therapy with one of these agents for at least 12 months (unless the risk of bleeding outweighs the anticipated net benefit of therapy); aspirin should be continued indefinitely in such patients. There is some evidence suggesting that a longer duration of dual antiplatelet therapy (for more than 12 months) may be beneficial in some patients with drug-eluting stents to reduce the risk of late stent thrombosis and other cardiovascular events, but such prolonged therapy may be associated with an increased risk of bleeding and other adverse effects.
(See Discontinuance of Therapy under Warnings/Precautions: Warnings, in Cautions.)
Current ACCF/AHA guidelines make no recommendations regarding the P2Y12-receptor antagonist of choice in patients with ACS. Unlike clopidogrel, genetic polymorphism of the cytochrome P-450 (CYP) 2C19 isoenzyme does not appear to affect the pharmacodynamic or clinical response to prasugrel; therefore, some experts recommend the use of prasugrel as an alternative to clopidogrel in patients who are identified as potential poor metabolizers of clopidogrel. In preclinical and early clinical studies, prasugrel inhibited platelet aggregation more potently and rapidly than standard or higher dosages of clopidogrel and was associated with less interpatient variability in antiplatelet effects. Such improved inhibition of platelet aggregation was associated with reduced ischemic events (e.g., reductions in stent thrombosis and MI) in a large prospective randomized study of patients with ACS undergoing PCI; however, these benefits were accompanied by an increased risk of bleeding. When considering the use of prasugrel over other P2Y12-receptor antagonists, clinicians should balance the anticipated greater benefits with prasugrel against the increased risk of bleeding, and also consider the patient populations in whom the drugs have been used. Some evidence suggests that certain patient populations (e.g., those with diabetes or previous MI) are more likely to benefit from prasugrel's greater inhibition of platelet aggregation, while others (e.g., geriatric patients, those with low body weight or history of stroke/transient ischemic attack [TIA]) may experience harm.
Because of the substantial risk of serious bleeding, prasugrel should not be initiated in patients who are likely to undergo urgent coronary artery bypass grafting (CABG); when possible, therapy with the drug should be discontinued at least 7 days prior to any surgery.
(See Bleeding, under Warnings/Precautions: Warnings, in Cautions.)In addition, prasugrel should not be used in patients with a history of TIA or stroke. (See Cautions: Contraindications.)
The current indication for prasugrel is based principally on results of a multicenter, randomized, double-blind parallel group study (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction [TRITON-TIMI 38]) comparing efficacy and safety of prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk ACS undergoing planned PCI. Patients with unstable angina or NSTEMI were eligible if they had ischemic manifestations lasting 10 minutes or more within 72 hours prior to randomization, a TIMI risk score of at least 3, and either ST-segment deviation of at least 1 mm or elevated levels of a cardiac biomarker of necrosis; patients with STEMI were enrolled within 12 hours of symptom onset if primary PCI was planned or within 14 days after receiving medical treatment for STEMI (nonprimary/delayed PCI). Patients received either clopidogrel (300-mg loading dose followed by 75 mg daily) or prasugrel (60-mg loading dose followed by 10 mg daily) for 6-15 months. The loading dose of the study drug was administered anytime between randomization and 1 hour after the patient was transferred from the cardiac catheterization laboratory; most patients (approximately 75%) received the study drug after the first coronary guidewire was placed or within 1 hour of PCI. Patients were required to receive concomitant treatment with aspirin 75-325 mg daily; other standard therapies (e.g., heparin, platelet glycoprotein [GP] IIb/IIIa-receptor inhibitors) were given at the discretion of the treating clinician. Most patients (94%) received at least one intracoronary stent.
Treatment with prasugrel resulted in a 19% relative reduction in the composite primary end point of cardiovascular death, nonfatal MI, or nonfatal stroke compared with clopidogrel; such benefits were apparent within 3 days and persisted throughout the duration of the study (median 14.5 months). The reduction in the primary end point was largely driven by a substantial reduction in MI (new or recurrent) with little or no difference in the incidence of stroke or cardiovascular death (other than from MI) between groups. Reductions in the rate of stent thrombosis and urgent target-vessel revascularization also favored prasugrel. Stent thrombosis was substantially reduced with prasugrel in patients who received at least one intracoronary stent irrespective of the stent type (bare-metal or drug-eluting).
The benefit of prasugrel in reducing ischemic events in the TRITON-TIMI 38 study was accompanied by an increased risk of bleeding. Major and minor bleeding complications, including life-threatening and fatal bleeding, occurred more frequently in patients receiving prasugrel compared with clopidogrel.
(See Bleeding under Warnings/Precautions: Warnings, in Cautions.)When efficacy and bleeding end points were combined, the net clinical benefit (defined as death from any cause, nonfatal MI, nonfatal stroke, or non-CABG-related nonfatal TIMI major hemorrhage) favored prasugrel over clopidogrel in the overall study population, but not in all subgroups. In post hoc analyses, patients 75 years of age or older, those weighing less than 60 kg, and those with previous stroke or TIA were identified as subgroups experiencing no net clinical benefit and possibly harm with such therapy. In patients with diabetes mellitus, however, a trend towards greater efficacy of prasugrel compared with nondiabetics was noted without a relative increase in major bleeding. Results of such subgroup analyses should be considered exploratory and should be interpreted with caution.
The prasugrel dosage regimen used in the TRITON-TIMI 38 study (60-mg loading dose, 10 mg daily maintenance dosage) has been shown to produce substantially greater and more consistent inhibition of platelet aggregation than that produced by a clopidogrel loading dose of 600 mg and maintenance dosage of 150 mg daily, dosages higher than current FDA-labeled loading and maintenance dosages. In addition, while it is generally recommended that antiplatelet agents be administered promptly upon presentation or diagnosis in patients with ACS, administration of prasugrel and clopidogrel in the TRITON-TIMI 38 study was delayed until after coronary anatomy was determined to be appropriate for PCI. Therefore, this study does not provide information on the comparative efficacy and safety of clopidogrel and prasugrel in dosages that provide equivalent inhibition of platelet aggregation, nor does it directly address the potential effects on efficacy of routine pretreatment with clopidogrel or prasugrel before diagnostic cardiac catheterization.
Increased risk of bleeding is a concern in patients receiving antiplatelet agents who require urgent CABG. Because most patients with ACS are managed without CABG, pretreatment with prasugrel may be considered prior to performing diagnostic coronary angiography in patients who are not likely to undergo CABG. The potential benefits of pretreatment should be balanced against the risk of surgical bleeding in patients who may subsequently require CABG.