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| | | #REDIRECT [[Prasugrel#Clinical Studies]] |
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| __NOTOC__
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| {{Prasugrel}}
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| {{CMG}}; {{AE}} {{SS}}
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| ==Clinical Studies==
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| The clinical evidence for the effectiveness of Effient is derived from the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel) study, a 13,608-patient, multicenter, international, randomized, double-blind, parallel-group study comparing Effient to a regimen of [[clopidogrel]], each added to [[aspirin]] and other standard therapy, in patients with [[ACS]] (UA, [[NSTEMI]], or [[STEMI]]) who were to be managed with [[PCI]]. Randomization was stratified for UA/[[NSTEMI]] and [[STEMI]].
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| Patients with UA/[[NSTEMI]] presenting within 72 hours of symptom onset were to be randomized after undergoing coronary angiography. Patients with [[STEMI]] presenting within 12 hours of symptom onset could be randomized prior to coronary angiography. Patients with [[STEMI]] presenting between 12 hours and 14 days of symptom onset were to be randomized after undergoing coronary angiography. Patients underwent [[PCI]], and for both UA/[[NSTEMI]] and [[STEMI]] patients, the loading dose was to be administered anytime between randomization and 1 hour after the patient left the [[catheterization]] lab. If patients with [[STEMI]] were treated with thrombolytic therapy, randomization could not occur until at least 24 hours (for [[tenecteplase]], [[reteplase]], or [[alteplase]]) or 48 hours (for [[streptokinase]]) after the thrombolytic was given.
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| Patients were randomized to receive Effient (60-mg loading dose followed by 10-mg once daily) or [[clopidogrel]] (300-mg loading dose followed by 75-mg once daily), with administration and follow-up for a minimum of 6 months (actual median 14.5 months). Patients also received [[aspirin]] (75-mg to 325-mg once daily). Other therapies, such as heparin and intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, were administered at the discretion of the treating physician. Oral anticoagulants, other platelet inhibitors, and chronic [[NSAIDs]] were not allowed.
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| The primary outcome measure was the composite of cardiovascular death, nonfatal MI, or nonfatal stroke in the UA/[[NSTEMI]] population. Success in this group allowed analysis of the same endpoint in the overall [[ACS]] and [[STEMI]] populations. Nonfatal MIs included both MIs detected solely through analysis of creatine kinase muscle-brain (CK-MB) changes and clinically apparent (investigator-reported) MIs.
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| The patient population was 92% Caucasian, 26% female, and 39% ≥65 years of age. The median time from symptom onset to study drug administration was 7 hours for patients with [[STEMI]] and 30 hours for patients with UA/[[NSTEMI]]. Approximately 99% of patients underwent [[PCI]]. The study drug was administered after the first coronary guidewire was placed in approximately 75% of patients.
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| Effient significantly reduced total endpoint events compared to [[clopidogrel]] (see Table 5 and Figure 3). The reduction of total endpoint events was driven primarily by a decrease in nonfatal [[MI]]s, both those occurring early (through 3 days) and later (after 3 days). Approximately 40% of [[MI]]s occurred peri-procedurally and were detected solely by changes in CK-MB. Administration of the [[clopidogrel]] loading dose in TRITON-TIMI 38 was delayed relative to the placebo-controlled trials that supported its approval for [[ACS]]. Effient produced higher rates of clinically significant bleeding than [[clopidogrel]] in TRITON-TIMI 38 [see Adverse Reactions (6.1)]. Choice of therapy requires balancing these differences in outcome.
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| The treatment effect of Effient was apparent within the first few days, and persisted to the end of the study (see Figure 3). The inset shows results over the first 7 days.
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| The effect of Effient in various subgroups is shown in Figures 4 and 5. Results are generally consistent across pre-specified subgroups, with the exception of patients with a history of TIA or stroke [see Contraindications (4.2)]. The treatment effect was driven primarily by a reduction in nonfatal MI. The effect in patients ≥75 years of age was also somewhat smaller, and bleeding risk is higher in these individuals [see Adverse Reactions (6.1)]. See below for analyses of patients ≥75 years of age with risk factors.
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| Effient is generally not recommended in patients ≥75 years of age, except in high-risk situations (diabetes mellitus or prior MI) where its effect appears to be greater and its use may be considered. These recommendations are based on subgroup analyses (see Table 6) and must be interpreted with caution, but the data suggest that Effient reduces ischemic events in such patients.
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| The Kaplan-Meier curves (see Figure 3) show the primary composite endpoint of CV death, nonfatal MI, or nonfatal stroke over time in the UA/[[NSTEMI]] and [[STEMI]] populations. In both populations, the curves separate within the first few hours. In the UA/[[NSTEMI]] population, the curves continue to diverge throughout the 15 month follow-up period. In the [[STEMI]] population, the early separation was maintained throughout the 15 month follow-up period, but there was no progressive divergence after the first few weeks.
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| Effient reduced the occurrence of the primary composite endpoint compared to [[clopidogrel]] in both the UA/[[NSTEMI]] and [[STEMI]] populations (see Table 5). In patients who survived an on-study [[myocardial infarction]], the incidence of subsequent events was also lower in the Effient group.
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| Effient is generally not recommended in patients ≥75 years of age, except in high-risk situations (diabetes mellitus or prior MI) where its effect appears to be greater and its use may be considered. These recommendations are based on subgroup analyses (see Table 6) and must be interpreted with caution, but the data suggest that Effient reduces ischemic events in such patients.
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| There were 50% fewer stent thromboses (95% C.I. 32% - 64%; p<0.001) reported among patients randomized to Effient (0.9%) than among patients randomized to [[clopidogrel]] (1.8%). The difference manifested early and was maintained through one year of follow-up. Findings were similar with bare metal and drug-eluting stents.
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| In TRITON-TIMI 38, prasugrel reduced ischemic events (mainly nonfatal MIs) and increased bleeding events [see Adverse Reactions (6.1)] relative to [[clopidogrel]]. The findings are consistent with the intended greater inhibition of platelet aggregation by prasugrel at the doses used in the study [see Clinical Pharmacology (12.2)]. There is, however, an alternative explanation: both prasugrel and [[clopidogrel]] are pro-drugs that must be metabolized to their active moieties. Whereas the pharmacokinetics of prasugrel's active metabolite are not known to be affected by genetic variations in CYP2B6, CYP2C9, CYP2C19, or CYP3A5, the pharmacokinetics of [[clopidogrel]]'s active metabolite are affected by CYP2C19 genotype, and approximately 30% of Caucasians are reduced-metabolizers. Moreover, certain proton pump inhibitors, widely used in the [[ACS]] patient population and used in TRITON-TIMI 38, inhibit CYP2C19, thereby decreasing formation of [[clopidogrel]]'s active metabolite. Thus, reduced-metabolizer status and use of proton pump inhibitors may diminish [[clopidogrel]]'s activity in a fraction of the population, and may have contributed to prasugrel's greater treatment effect and greater bleeding rate in TRITON-TIMI 38. The extent to which these factors were operational, however, is unknown.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5fe9c118-c44b-48d7-a142-9668ae3df0c6 | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5fe9c118-c44b-48d7-a142-9668ae3df0c6 | publisher = | date = | accessdate = 6 February 2014 }}</ref>
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| ==References==
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| {{Reflist|2}}
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| [[Category:Antiplatelet drugs]]
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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