Prasugrel
2010; Lippincott Williams & Wilkins; Volume: 122; Issue: 4 Linguagem: Estoniano
10.1161/circulationaha.109.921502
ISSN1524-4539
AutoresStephen D. Wiviott, Elliott M. Antman, Eugene Braunwald,
Tópico(s)Acute Myocardial Infarction Research
ResumoHomeCirculationVol. 122, No. 4Prasugrel Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessReview ArticlePDF/EPUBPrasugrel Stephen D. Wiviott, MD, Elliott M. Antman, MD and Eugene Braunwald, MD Stephen D. WiviottStephen D. Wiviott From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. , Elliott M. AntmanElliott M. Antman From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. and Eugene BraunwaldEugene Braunwald From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. Originally published27 Jul 2010https://doi.org/10.1161/CIRCULATIONAHA.109.921502Circulation. 2010;122:394–403Platelet adhesion, activation, and aggregation play key roles in both normal hemostasis and pathological thrombosis. In the latter, these factors are paramount in the initiation of the intracoronary thromboses that cause acute coronary syndromes (ACS) and the ischemic complications following coronary artery interventions, including recurrent myocardial infarction (MI) and stent thrombosis.1 The interaction of ADP with purenergic P2Y1 and P2Y12 receptors serves to amplify and sustain platelet activation.2 Activated platelets expose glycoprotein IIb/IIIa receptors, which crosslink with fibrin to form platelet aggregates. These aggregates cause mechanical disruption of flow and may embolize downstream, causing microvasculature obstruction that results in myocardial ischemia and infarction.The important role of antiplatelet agents in the management and prevention of the complications after ACS and percutaneous coronary intervention (PCI) is related directly to the physiological events noted above.3–7 Thienopyridine antiplatelet agents interfere with platelet activation and aggregation induced by ADP. There are 3 members of the thienopyridine class of antiplatelet agents currently available for clinical use: ticlopidine, clopidogrel, and the subject of this review, prasugrel. All 3 agents are prodrugs and require conversion to an active metabolite to exhibit an antiplatelet effect (Figure 1). The active metabolite of the thienopyridine binds irreversibly to the P2Y12 receptor, blocking the binding of ADP and thereby inhibiting platelet activation and aggregation8 and leading to the clinical benefits and risks of these agents. The benefits of ticlopidine were shown in a series of trials comparing dual antiplatelet therapy with aspirin plus an oral anticoagulant.9,10 Ticlopidine is limited by the need to take the drug twice daily, by poor tolerability, notably gastrointestinal distress, but most important by severe side effects, including bone marrow aplasia.11 Clopidogrel plus aspirin dual antiplatelet therapy has become the standard of care for the support of patients undergoing PCI with stenting largely on the basis of a better tolerability profile.12,13 Clinical trials established the benefits of clopidogrel across the spectrum of ACS, including unstable angina (UA), non–ST-elevation MI (NSTEMI), and ST-elevation MI (STEMI).14–16 American College of Cardiology/American Heart Association guidelines recommend dual antiplatelet therapy with aspirin and clopidogrel in patients with ACS for up to 1 year regardless of syndrome type or treatment strategy (medical, PCI, or surgery).6Download figureDownload PowerPointFigure 1. Schematic representation of the relationship between thienopyridine metabolism, pharmacological effects, and clinical outcomes.Pharmacological Limitations of ClopidogrelDespite the major benefits of clopidogrel alone and in combination with aspirin for patients with ACS and for those undergoing PCI, important pharmacological limitations are associated with its use.17 The antiplatelet effects of clopidogrel have a delayed onset (several hours after ingestion), and there is substantial variability in response among patients. A growing number of studies have linked poor antiplatelet response to clopidogrel to adverse clinical outcomes, particularly coronary ischemia and stent thrombosis.18–21 From these limitations, the evaluation of more intensive and consistent antiplatelet therapy compared with clopidogrel has been fostered. One such agent, prasugrel, a third-generation thienopyridine, is the focus of this review.Pharmacology of PrasugrelPrasugrel requires enzymatic metabolism to exert its antiplatelet effects (Figure 1).22 The parent molecule, prasugrel, is rapidly hydrolyzed by esterases, such as those located in the intestine and blood, to a thiolactone intermediate metabolite R-95913. The parent molecule is therefore not detectable in the plasma. This intermediate metabolite undergoes subsequent activation by a single cytochrome P450 (CYP)–dependent step (predominantly CYP3A and CYP2B6) to form the sulfhydryl-containing active metabolite R-138727. This active metabolite binds irreversibly to the platelet P2Y12 receptor by covalent linkage of a sulfhydryl group to inhibit platelet activation and aggregation. Prasugrel metabolism differs from clopidogrel metabolism in that the initial hydrolysis of the parent clopidogrel compound results in inactivation of a substantial fraction (≈85%) of the absorbed drug, and the subsequent activation requires 2 CYP-dependent steps (Figure 1).22 The CYP enzymes involved in the metabolism of clopidogrel and prasugrel are polymorphic, differing between individuals, and are responsible in part for the interpatient variability of clopidogrel response.23,24 The prasugrel active metabolite concentration peaks in the plasma at ≈30 minutes, and the concentration is proportional to a dose between 5 and 60 mg. When not bound to platelets, the active metabolite of prasugrel has an elimination half-life of ≈7 hours.25 Prasugrel does not have clinically relevant interactions with inducers or inhibitors of the cytochrome P450 system.26 The active metabolite concentration and pharmacodynamic response of prasugrel were not affected by moderate renal impairment compared with healthy subjects.27 In patients with end-stage renal disease, active metabolite concentrations were ≈40% lower, but similar platelet inhibition was noted. In patients with moderate liver disease, no effects on prasugrel pharmacokinetics or pharmacodynamics have been observed. Prasugrel has not been tested in severe hepatic disease.28In clinical pharmacology studies of healthy subjects, no effect of age on prasugrel pharmacokinetics or pharmacodynamics was observed with age between 20 and 80 years.29 In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction 38 (TRITON–TIMI 38), however, patients ≥75 years had 19% higher exposure to the active metabolite of prasugrel compared with those <75 years of age and 25% higher exposure compared with patients <60 years of age. In both clinical pharmacology studies and TRITON–TIMI 38, prasugrel pharmacokinetics were affected by body weight, with higher exposure in subjects with lower body weight. In TRITON–TIMI 38, patients <60 kg had 30% higher exposure than patients ≥60 kg and 42% higher exposure than patients ≥85 kg. In the analysis of TRITON–TIMI 38, pharmacokinetics were not appreciably affected by diabetes, smoking, or renal impairment.30In equimolar concentrations, the active metabolites of prasugrel and clopidogrel have similar antiplatelet effects.31 Therefore, the more rapid and consistent conversion of prasugrel from the inactive prodrug to its active metabolite and the ability of patients to generate higher concentrations of the active metabolite provide the mechanistic basis for the differences in the pharmacological profiles of the 2 drugs.32 A 2-phase crossover study comparing loading doses of prasugrel (60 mg) and clopidogrel (300 mg) in healthy subjects showed higher maximal levels and less variable inhibition of ADP-induced platelet aggregation with prasugrel (79±9%) than with clopidogrel (35±25%).32 A difference in platelet inhibition was apparent between the 2 drugs by 30 minutes and persisted to 24 hours, the duration of measurement. This same study also demonstrated several patients with low-level (<20% induced platelet aggregation) response to clopidogrel but no such patients with prasugrel. These observations resulted from the ≈10-fold higher levels of prasugrel active metabolite than clopidogrel active metabolite.32Many physicians in clinical practice use higher doses of clopidogrel than the standard approved dose. This practice is supported in part by clinical practice guidelines,12 small clinical outcomes studies, observational studies, and meta-analyses.33–35 The Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT OASIS 7) trial36 compared high-loading- and -maintenance-dose clopidogrel (600-mg loading dose followed by 150 mg/d for 7 days) with standard dosing (300-mg loading dose followed by 75 mg/d) in ≈25 000 patients with ACS treated with or without coronary angiography. The trial did not meet its primary end point of a reduction of cardiovascular death, MI, or stroke in the overall cohort of ACS patients, and more CURRENT major bleeding was observed with the higher-dose clopidogrel strategy. Lower ischemic event rates were observed with the combination of high-dose clopidogrel and high-dose aspirin (300 to 325 mg daily). In a postrandomization subgroup of patients who underwent PCI, there was a reduction of ischemic events, including MI and stent thrombosis, with higher-dose clopidogrel compared with the standard dose.36The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation (PRINCIPLE)–TIMI 44 trial compared prasugrel and clopidogrel using the CURRENT OASIS 7 clopidogrel dose regimen (600-mg loading dose followed by 150 mg daily). This was a 2-phase crossover study in patients with coronary artery disease undergoing cardiac catheterization with planned PCI. Prasugrel 60-mg loading dose showed higher levels of platelet inhibition than 600 mg clopidogrel, and 10 mg prasugrel showed greater levels of platelet inhibition than 150 mg clopidogrel daily37 (Figure 2). A significant difference in induced platelet aggregation emerged as soon as 30 minutes and persisted throughout the first 24 hours. In fact, by 30 minutes, the levels of inhibition with prasugrel 60 mg were similar to the maximal inhibition achieved with clopidogrel 600-mg loading dose (Figure 2A). In a crossover design, higher levels of induced platelet aggregation were also observed with 10 mg prasugrel compared with 150 mg clopidogrel after 2 weeks of therapy (Figure 2B). Download figureDownload PowerPointFigure 2. The main results of PRINCIPLE–TIMI 44. Prasugrel 60 mg resulted in higher levels of platelet inhibition than 600 mg clopidogrel in the acute phase, and 10 mg prasugrel resulted in higher levels of platelet inhibition than 150 mg clopidogrel in the chronic phase. IPA indicates inhibition of platelet aggregation. Data derived from Wiviott et al.37Clinical Outcomes Trials of PrasugrelThe Joint Utilization of Medications to Block Platelets Optimally (JUMBO)–TIMI 2638 trial was a phase II, dose-ranging, safety study of prasugrel compared with clopidogrel in patients undergoing PCI. In this study, 904 subjects were randomized to 1 of 3 prasugrel dosing strategies with 2 prasugrel loading doses and 3 prasugrel maintenance doses (40/7.5 mg, 60/10 mg, and 60/15 mg) compared with clopidogrel (300/75 mg) and followed up for 30 days. Bleeding rates overall were low, and there were no statistically significant differences among treatment groups for the primary safety end point of TIMI major or minor bleeding. However, numerically more patients had bleeding in the combined prasugrel group (hazard ratio [HR], 1.42; 95% confidence interval [CI] 0.40 to 5.08) compared with clopidogrel, and the 60/15 mg prasugrel arm tended to have higher rates of TIMI minimal bleeding. The study was not powered for efficacy end points, and a nonsignificant difference (HR, 0.76; 95% CI, 0.46 to 1.24) was observed for the primary end point of major adverse cardiovascular events in favor of prasugrel-treated patients compared with clopidogrel-treated patients. The combination of clinical data from JUMBO–TIMI 26 and platelet function data in healthy volunteers32 and patients39 served as the basis for dose selection for the pivotal phase II, registration pathway trial of prasugrel.EfficacyThe majority of clinical outcomes data for prasugrel comes from the phase III TRITON–TIMI 38 trial. In this trial, 13 608 subjects with moderate- to high-risk ACS, including UA, NSTEMI, and STEMI with planned PCI, were randomized to receive either clopidogrel 300-mg loading dose followed by 75 mg daily or prasugrel 60-mg loading dose followed by 10 mg daily. Subjects with UA/NSTEMI or STEMI treated initially with medical therapy could be randomized and treated only after the coronary anatomy was known to be suitable for PCI; subjects with STEMI and planned primary PCI could be randomized and treated on first contact. Subjects with recent clopidogrel use, known bleeding diathesis, or other high-risk features for bleeding were excluded.40 Subjects were treated for a median of 14.5 months.The primary end point was the composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. Subjects randomized to prasugrel had fewer primary end-point events (9.9% versus 12.1%; HR, 0.81; 95% CI, 0.73 to 0.90; P<0.001) compared with clopidogrel, as shown in Figure 3A and Table 1.41Download figureDownload PowerPointFigure 3. A, TRITON–TIMI 38 main results in the overall cohort. B, Main results figure in core clinical cohort (no history of stroke/transient ischemic attack, age <75 years, and weight ≥60 kg). CV indicates cardiovascular; C, clopidogrel; P, prasugrel; NNT, number needed to treat; NNH, number needed to harm. Data derived from Wiviott et al.41Table 1. Key Efficacy and Safety Results From TRITON–TIMI 38End PointClopidogrel, %Prasugrel, %Absolute Risk Difference, %HR95% CIPCVD indicates cardiovascular death; CVA, cerebrovascular accident (stroke); and TVR, target vessel revascularization.*Not related to coronary artery bypass surgery.Data derived from Wiviott et al.41CVD/MI/CVA12.19.92.20.810.73–0.90<0.001MI9.77.42.30.760.67–0.85<0.001Urgent TVR3.72.51.20.660.54–0.81<0.001TIMI major bleeding*1.82.40.61.321.03–1.680.03TIMI major or minor bleeding*3.85.01.21.311.11–1.560.002Bleeding requiring transfusion*3.04.01.01.341.11–1.63<0.001All-cause death, MI, stroke, TIMI major bleeding*13.912.21.70.870.79–0.950.004The primary efficacy end point (Table 1) was driven by a 24% reduction in MI including both fatal and nonfatal MI. Cardiovascular death and total mortality were numerically but not statistically lower (total mortality, 3.0% versus 3.2%; HR, 0.95; 95% CI, 0.78 to 1.16; in STEMI, 3.3% versus 4.3%; HR, 0.76; 95% CI, 0.54 to 1.07; in UA/NSTEMI, 2.9% versus 2.8%; HR, 1.08; 95% CI, 0.84 to 1.38), and no effect was seen on total stroke. Additional analyses of reduction in MI using the American College of Cardiology/American Heart Association/European Society of Cardiology universal MI definition showed similar reductions in procedural MI and spontaneous MI, small and large MIs (based on peak biomarkers), investigator reported MIs, and MIs both early (within 30 days) and after 30 days.42 The reduction in clinical ischemic events was also notable for a reduction in urgent target vessel revascularization (2.5% versus 3.7%; HR, 0.66; 95% CI, 0.54 to 0.81; P<0.001). A key finding from TRITON–TIMI 38 was a marked reduction in stent thrombosis among patients receiving prasugrel. Overall for the duration of the trial, Academic Research Consortium–defined definite or probable stent thrombosis was reduced by 52% (1.1% versus 2.4%; HR, 0.48; 95% CI, 0.36 to 0.64; P<0.001) and definite (angiographic or autopsy proven) stent thrombosis by 58% (0.9% versus 2.0%; HR, 0.42; 95% CI, 0.31 to 0.59; P<0.001; Figure 4A)43 in patients who received prasugrel. These findings were similar whether patients received bare metal stents or drug-eluting stents. The reduction in stent thrombosis was also noted both early, ie, within 30 days after randomization (0.64% versus 1.56%; HR, 0.41; 95% CI, 0.29 to 0.59; P<0·0001), and after 30 days (0.49% versus 0.82%; HR, 0.60; 95% CI, 0.37 to 0.97; P=0·03; Figure 4B). Download figureDownload PowerPointFigure 4. Stent thrombosis in TRITON–TIMI 38. A, Stent thrombosis in the overall cohort for the duration of the trial. B, Academic Research Consortium definite or probable stent thrombosis by timing. Data derived from Wiviott et al.43SafetyConsistent with the more potent antiplatelet effects observed with prasugrel in TRITON–TIMI 38, higher rates of bleeding were observed. The key safety end point of non–coronary artery bypass graft (CABG)–related TIMI major bleeding was observed more frequently with prasugrel (2.4% versus 1.8%; HR, 1.32; 95% CI, 1.03 to 1.68; P=0.03; Figure 3A).41 In addition to the key safety end point of TIMI major bleeding, there was an excess of non-CABG–related TIMI major or minor bleeding (5.0% versus 3.8%; HR, 1.31; 95% CI, 1.11 to 1.56; P=0.002) and bleeding requiring transfusion (4.0% versus 3.0%; HR, 1.34; 95% CI, 1.11 to 1.63; P<0.001). Among non-CABG–related bleeding, the excess was driven predominantly by an increase in spontaneous bleeding (1.6% versus 1.1%; HR, 1.51; 95% CI, 1.09 to 2.08; P=0.01). Instrumented bleeding and bleeding related to trauma were less frequent in both groups, and rates were similar between the 2 treatment arms. Among the non-CABG major bleeds, there was an excess of life-threatening bleeding and, though rare, fatal bleeding. Intracranial bleeding was not increased among the patients treated with prasugrel (0.3% of both treatment arms).The relative bleeding excess with prasugrel tended to be similar among major subgroups and tended to continue to accumulate over time; no significant difference in TIMI major bleeding was observed by 30 days (1.03% versus 0.87%; HR, 1.19; 95% CI, 0.84 to 1.68; P=0.34), and bleeding in this time period was most often procedure related with both agents. However, after 30 days, a significant excess in TIMI major bleeding was observed (1.42% versus 0.97%; HR, 1.48; 95% CI, 1.04 to 2.09; P=0.03) and was more commonly spontaneous bleeding, particularly gastrointestinal bleeding. No significant interaction between time of follow-up and treatment was observed. Because TRITON–TIMI 38 was designed as a PCI trial in which coronary anatomy had to be known to be suitable for PCI before randomization, CABG was infrequent. TIMI major bleeding was identified in 13% of prasugrel-treated patients who underwent CABG (0.4% of the total cohort) compared with 3% of clopidogrel-treated patients who underwent CABG (0.1% of the total cohort; HR, 4.73; 95% CI, 1.90 to 11.82; P<0.001).To assess the balance between safety and efficacy, a prespecified net outcome end point of all-cause death, MI, stroke, and non-CABG TIMI major bleeding was evaluated in TRITON–TIMI 38. In the overall cohort, this end point favored prasugrel (12.2% versus 13.9%; HR, 0.87; 95% CI, 0.79 to 0.95; P=0.004). This net outcome was robust to sensitivity analyses, including less severe bleeding episodes (such as TIMI minor bleeding).44 In addition to the prespecified safety end points, a careful assessment of reported adverse events identified a slight excess in patients with new or worsened malignancies, particularly colon cancers, which may have resulted from ascertainment bias caused by earlier identification in the prasugrel group as a result of evaluations for bleeding or anemia. The US Food and Drug Administration determined that there was not sufficient biological evidence to suggest that prasugrel was a carcinogen or a tumor promoter and requested additional studies to assess the potential cancer risk.45SubgroupsSeveral subgroups of patients in TRITON–TIMI 38 are of both scientific and clinical interest. Three groups were highlighted as being of particular concern: those with previously known stroke, elderly patients, and patients with low body weight. Patients with a self-reported or known history of stroke or transient ischemic attacks (n=518) before enrollment in TRITON–TIMI 38 had a higher rate of primary efficacy events (19.1% versus 14.4%; HR, 1.37; P=0.15) driven by an increase in stroke, which differed significantly from the nonstroke cohort (P for interaction=0.02). Coupled with a high rate of bleeding, including more intracranial hemorrhage in this subgroup, the net outcome significantly favored clopidogrel (23.0% versus 16.0%; HR, 1.54; P=0.04).In patients ≥75 years of age (n=1809), a smaller (but directionally consistent) relative reduction in primary efficacy events (17.2% versus 18.3%; HR, 0.94; P=0.60), coupled with higher absolute TIMI major bleeding rates (4.2% versus 3.4%; HR, 1.36; P=0.24), resulted in a balance between efficacy and safety and a neutral net outcome (21.7% versus 21.5%; HR, 0.99; P=0.92). Of particular concern in the elderly patients was the higher rate of spontaneous fatal hemorrhage compared with younger patients. In patients ≥75 years of age, 9 spontaneous fatal hemorrhages were observed with prasugrel and 0 with clopidogrel. In patients <75 years of age, 5 fatal spontaneous hemorrhages were observed with prasugrel and 4 with clopidogrel.Patients with low body weight (<60 kg; n=668), in whom pharmacokinetic modeling demonstrated an overexposure to the prasugrel active metabolite,30,41 had an efficacy similar to that of the overall cohort (10.5% versus 12.6%; HR, 0.86; P=0.54), had higher rates of bleeding (6.0% versus 3.5%; HR, 1.90; P=0.09), and had a neutral net outcome (15.9% versus 15.7%; HR, 1.03; P=0.89). It should be recognized that the relative efficacy and safety of prasugrel appear to be optimized in TRITON–TIMI 38 in patients 60 kg, but it is also likely that the general principle holds that this balance worsens with advancing age and decreasing body weight beyond these precise thresholds (Tables I and II in the online-only Data Supplement).In contrast, patients with diabetes mellitus had a greater reduction in cardiovascular death/MI/stroke (12.2% versus 17.0%; HR, 0.70; P<0.001) than those without diabetes mellitus (9.2% versus 10.6%; HR, 0.86; P=0.02; P for interaction=0.09) without an excess in TIMI major bleeding, resulting in a greater improvement in the net outcome.46 There were consistent benefits among patients presenting with STEMI47 and those with UA/NSTEMI, although there appeared to be less bleeding excess in patients with STEMI. There were consistent benefits of prasugrel compared with clopidogrel among patients who received varying doses of aspirin,48 patients with or without glycoprotein IIb/IIIa inhibitors,49 and those with or without proton pump inhibitors.50A pharmacokinetic substudy of TRITON–TIMI 38 demonstrated that patient groups who had less favorable outcomes, patients who were either <60 kg or ≥75 years of age, had higher levels of the active metabolite of the drug than did subjects without those characteristics.30 Modeling data suggest that decreasing the maintenance dose of prasugrel to 5 mg in these subjects would reduce exposure to the active metabolite to levels consistent with those observed in the subjects <75 years of age and ≥60 kg. The efficacy and safety of the 5-mg doses in this population have not been established in a clinical trial but are being tested in the ongoing Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) NCT00699998 trial, which is also testing the efficacy of prasugrel compared with clopidogrel in patients with ACS without intended PCI.Clinical GeneticsAs noted above, for clopidogrel or prasugrel to exert an antiplatelet effect, metabolism from an inactive parent compound to the active metabolite that interacts with the P2Y12 receptor is required (Figure 1). The CYP enzymes involved in these conversions are known to be subject to common genetic variation resulting in differential function. The combination of the need for metabolism for action and the interpatient variability in metabolic efficiency sets the stage for a pharmacogenomic treatment interaction with clopidogrel. Indeed, several studies have reported that patients who are carriers of a reduced-function allele of CYP 2C19 are at increased risk of recurrent cardiovascular events, including recurrent MI and stent thrombosis, while being treated with clopidogrel.24,51–53 In the genetic analysis of TRITON–TIMI 38, ≈30% of subjects tested were carriers of at least 1 common reduced-function allele for CYP 2C19. Among the clopidogrel subjects, carriers had an excess of cardiovascular ischemic events, including a 3-fold higher rate of stent thrombosis.24 These data were supported by consistent effects of the reduced function alleles of CYP 2C19 showing less generation of active metabolite and less inhibition of platelets in clopidogrel-treated patients.24 In support of the mechanistic importance of the CYP 2C19 enzyme, a genome-wide association study identified loci associated with genes encoding CYP 2C19 associated with reduced antiplatelet effect of clopidogrel.54 In contrast to the consistent observations of pharmacogenomic effects on clopidogrel, none of the common variants in the CYP genes tested showed consistent reductions in prasugrel active metabolite generation and the antiplatelet effects of prasugrel.23 Consequently, subjects assigned to prasugrel in the TRITON–TIMI 38 genetic analysis had no difference in the rates of cardiovascular ischemic events by genotype, suggesting that the more efficient metabolism of prasugrel may render patients less susceptible to such genetic variation.23Regulatory Action and Anticipated Clinical UseLargely on the basis of the aforementioned TRITON–TIMI 38 trial, prasugrel received approval by both the US Food and Drug Administration and the European Medicines Agency for use in patients with ACS (including STEMI and UA/NSTEMI) undergoing planned PCI (Table 2). Both agencies provided warnings of the bleeding risk with prasugrel, including a "black box" warning by the Food and Drug Administration, and provided contraindications for its use in patients with prior stroke or transient ischemic attack. On the basis of regulatory action, the core clinical cohort recommended for treatment with prasugrel at the studied doses (60 mg and 10 mg) included patients without prior stroke or transient ischemic attack who were <75 years of age and weighed ≥60 kg. This group of patients, who represented 79.4% of the TRITON–TIMI 38 population, exhibited a greater benefit of prasugrel on ischemic end points and had less absolute bleeding difference (Figure 3B). The American and European regulatory agencies approved both 10- and 5-mg tablets of prasugrel and recommended the 5-mg tablet for patients weighing <60 kg (132 lb). For patients ≥75 of age, the US Food and Drug Administration indicated that prasugrel is generally not recommended, but its use may be considered in patients at high risk for recurrent ischemic events such as those with diabetes mellitus or prior MI; it also recommended that when prasugrel is used in the elderly weighing ≥60 kg, prasugrel should be used with its standard dosing regimen. The European Medicines Agency took a slightly different approach, also recommending that prasugrel should generally be avoided in the elderly, but if used, the dose should be lowered to 5 mg. Table 2. Summary of Regulatory Action Related to PrasugrelUS Food and Drug AdministrationEuropean Medicines AgencyASA indicates acetylsalicylic acid.IndicationReduction of thrombotic cardiovascular events (including stent thrombosis) in patients with ACS who are to be managed with PCIPrevention of atherothrombotic events in patients with ACS undergoing primary or delayed PCIDose and administrationInitiate treatment with a single 60-mg oral loading dose and continue at 10 mg once daily with or without foodShould be initiated with a single 60-mg loading dose and then continued at 10 mg once a dayPremature discontinuation of any antiplatelet agent, including prasugrel, could result in an increased risk of thrombosis, MI, or death resulting from the patient's underlying diseaseTreatment of up to 12 mo is recommended unless the discontinuation of prasugrel is clinically indicatedContraindicationsActive pathological bleedingHypersensitivity to the active substance or to any of the excipientsPrior stroke or transient ischemic attackActive pathological bleedingHistory of stroke or transient ischemic attackSevere hepatic impairment (Child Pugh class C)Warnings and precautionsCan cause significant, sometimes fatal, bleeding Increased risk in patients likely to undergo CABG Premature discontinuation increases the risk of stent thrombosis, MI, and deathPatients with ACS undergoing PCI treated with prasugrel and ASA showed an increased risk of major and minor bleeding; therefore, the use of prasugrel in patients at increased risk of bleeding should be considered only when the benefits in terms of prevention of ischemic events are deemed to outweigh the risk of serious bleedingsAge ≥75 yGenerally not recommended except in high-risk patients (diabetes mellitus or prior MI) in whom its effect appears to be greater and its use may be consideredGenerally not recommended and sho
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