Review of Prasugrel for the Secondary Prevention of Atherothrombosis

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1 SUBJECT REVIEW Review of Prasugrel for the Secondary Prevention of Atherothrombosis Sarah A. Spinler, PharmD, FCCP, BCPS, and Catherine Rees, BHB, BA ABSTRACT What is presently known about this subject from this review BACKGROUND: The role of platelets in atherothrombotic disease is well established, and antiplatelet therapy is now recommended for the short- Dual antiplatelet therapy with clopidogrel and aspirin significantly and long-term management of patients with acute coronary syndromes reduces the risk of an adverse outcome after acute coronary syn- (ACS), with and without percutaneous coronary intervention (PCI). The dromes (ACS). Dual antiplatelet therapy is not recommended for thienopyridine clopidogrel is accepted as a key component of antiplatelet primary prevention in patients without symptomatic cardiovascu- management and is recommended in current treatment guidelines as add- on therapy to aspirin in secondary prevention to reduce coronary risk in lar disease. patients with ACS and/or following PCI. The FDA Cardiovascular and Renal In the Trial to Assess Improvement in Therapeutic Outcomes by Drugs Advisory Committee met on February 3, 2009, and recommended Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in approval of prasugrel, but with guidance to physicians about increased risk Myocardial Infarction (TRITON-TIMI) 38 trial, 13,608 patients in low-weight or elderly patients and avoidance of use (a) around coronary with moderate-to-high risk ACS with scheduled percutaneous cor- artery bypass graft (CABG) or other surgical or invasive procedures and (b) onary intervention (PCI) showed prasugrel superior to clopidogrel in patients with prior or current stroke or transient ischemic attack (TIA). at a median follow-up of 14.5 months. The occurrence of the pri- OBJECTIVE: To review the published literature examining primarily the clini- mary end point (combined outcome of death from cardiovascular cal efficacy and safety of prasugrel in ACS patients. causes, nonfatal myocardial infarction [MI], or nonfatal stroke) was METHODS: The PubMed database was searched for English language stud- 9.9% of prasugrel patients versus 12.1% for clopidogrel (HR=0.81, ies involving the use of prasugrel in human subjects published up to April 2009 using the keyword prasugrel. The review focused on randomized, 95% CI=0.73-0.90, P

2 Review of Prasugrel for the Secondary Prevention of Atherothrombosis A ntiplatelet therapy has been shown to significantly reduce commonly prescribed thienopyridine.16 the risk of serious vascular events in high-risk patients, While effective in the prevention of atherothrombotic disease, including those with a prior acute ischemic event.1 The there are risks and trade-offs associated with long-term antiplate- long-term use of antiplatelet agents is thus a key component of let therapy, since all antiplatelet agents carry an increased risk secondary prevention measures following acute coronary syn- of bleeding. The absolute benefits of aspirin therapy have been dromes (ACS). found to substantially outweigh its risks in moderate- to high- Platelets play a fundamental role in the pathophysiology of risk patients (those with a 3% or greater annual risk of a vascular unstable angina and acute myocardial infarction (MI) as plaque event), however.1 A meta-analysis of 4 primary prevention trials rupture is followed by adhesion, activation and aggregation of indicated that aspirin is safe and worthwhile when the annual risk platelets, and formation of a coronary thrombus.2 Platelet activa- of coronary events is 1.5% or more.17 Furthermore, benefits were tion also plays a role in the development of secondary ischemia found to greatly outweigh hazards in patients with chronic stable following an initial ACS event and is more pronounced following angina, prior MI, or unstable angina in an analysis of randomized intracoronary stent implantation than after coronary balloon trial data.18 The benefit in terms of number needed to be treated angioplasty alone.3 Secondary ischemia, which may include MI (NNT) to avoid 1 event per year ranged from 20 to 100, compared and stroke, is a significant hazard for patients who have already with the number needed to harm (NNH) of 500 to 1,000 to cause experienced an acute event.4,5 1 major gastrointestinal bleeding event each year.18 Some of the strongest evidence available for long-term preven- When a second antiplatelet agent is added to aspirin, the tion of adverse cardiac events in patients with coronary disease bleeding risk may be increased. Therefore, the overall risk-benefit pertains to the use of aspirin.1,6 Current treatment guidelines profile of dual antiplatelet therapy in patients with ACS, including from the American College of Chest Physicians (ACCP) and those undergoing coronary artery bypass grafting (CABG), should jointly issued guidelines from the American Heart Association be considered.19 Of note, a post-hoc analysis of the subgroup of (AHA) and American College of Cardiology (ACC) recommend patients with prior ischemic events in the Clopidogrel for High that aspirin therapy be continued indefinitely for secondary pre- Atherothrombotic Risk and Ischemic Stabilization, Management, vention of ischemic events following ACS, with the thienopyri- and Avoidance (CHARISMA) study suggests that the increase in dine clopidogrel to be added for up to 12 months for the majority bleeding risk with dual antiplatelet therapy versus aspirin alone of patients with unstable angina, non-ST segment elevation MI occurs predominantly during the first few months of treatment (NSTEMI), or ST segment elevation MI (STEMI),7-10 or longer in and decreases after 12 months.20 the case of patients receiving drug-eluting stents (Table 1).9,11 At the time that this review was completed (May 2009), there were Methods 2 thienopyridines (ticlopidine and clopidogrel) approved by the Literature searches were conducted by one author (Rees), and the U.S. Food and Drug Administration (FDA) for use in patients results confirmed by the lead author (Spinler), in August 2008 with ACS. and April 2009 using the keyword prasugrel for publications On February 3, 2009, a new thienopyridine, prasugrel, was indexed on the National Library of Medicines PubMed database. recommended for approval as an addition to aspirin for patients No lower date limit was set, and all studies that were identi- with ACS by the FDA Cardiovascular and Renal Drugs Advisory fied through August 2008 were evaluated for inclusion in this Committee.12 This article reviews the published data on the review. The search identified 125 published papers, of which 29 pharmacologic and clinical profile of prasugrel. The purpose is to were studies involving the use of prasugrel in human subjects. describe what is known about prasugrel from the published lit- Forty-six publications were discarded on the basis that they erature and the FDA review compared with the current standard were news items (15) or general reviews of antiplatelet therapy of add-on antiplatelet therapy (clopidogrel) in the United States. (31). Bibliographies from prasugrel-specific reviews (9 identified) or comments/editorials/letters to the editor (24 identified) were Current Recommendations for Thienopyridines scanned for papers that may not have been identified in our as Add-On Antiplatelet Therapy search. Relevant information regarding limitations of current data Briefly, dual antiplatelet therapy with aspirin and a thienopyri- was extracted from these papers, but they were not otherwise dine for at least 1 year is now recommended for all patients considered for inclusion. Similarly, in vitro/ex vivo (11 papers) or with non-ST segment elevation ACS with or without stents animal studies (6) were excluded from this review. at hospital discharge.6 Ticlopidine was used in the past for The 28 prasugrel reports involving research in humans prevention of subacute stent thrombosis,13 but the adverse comprised 21 pharmacology reports and 7 reports with clinical effects of the drug (principally rash and diarrhea, but also the end points. The phase II studies included: (1) the Prasugrel in potential for neutropenia [reported in approximately 2.4% of Comparison to Clopidogrel for Inhibition of Platelet Activation patients]) limit its utility.14,15 Therefore, clopidogrel, which and Aggregation-Thrombolysis in Myocardial Infarction lacks the adverse effect of neutropenia,15 has become the most (PRINCIPLE-TIMI) 44 trial,21 a cross-over study of laboratory- 384 Journal of Managed Care Pharmacy JMCP June 2009 Vol. 15, No. 5 www.amcp.org

3 Review of Prasugrel for the Secondary Prevention of Atherothrombosis TABLE 1 Antiplatelet Therapy Recommendations for Patients With ACS6,8,10,11 AHA/ACC Recommendations Aspirin Clopidogrel ACCP Recommendations Unstable Angina and NSTEMI Without stenting Aspirin 162-325 mg (loading) then Clopidogrel 300-600 mg (loading) Aspirin 162-325 mg initially, then 75-100 mg per day 75-162 mg per day indefinitely then 75 mg per day for at least 1 indefinitely month and ideally for at least 1 Clopidogrel 300 mg (loading) then 75 mg per day for 12 year months Bare-metal stent Aspirin 162-325 mg (loading) then Clopidogrel 300-600 mg (loading) Aspirin 75-100 mg per day for 12 months 162-325 mg per day for at least 1 then 75 mg per day for at least 1 Clopidogrel 300-600 mg (loading) then 75 mg per day for month, then 75-162 mg per day month and ideally for longer than 12 months indefinitely 1 year Drug-eluting stent Aspirin 162-325 mg (loading) Clopidogrel 300-600 mg (loading) Aspirin 75-100 mg per day for at least 12 months then 162-325 mg per day for 3-6 then 75 mg per day for at least 1 Clopidogrel 300-600 mg (loading) then 75 mg per day for months, then 75-162 mg per day year at least 12 months indefinitely Combination to be given indefinitely in absence of bleed- ing or tolerability issues STEMI PCI with stenting Aspirin 75-325 mg (loading) Clopidogrel (generally 600 mg) Aspirin 160-325 mg (loading) then 75-100 mg per day then 162-325 mg per day for 1-6 then 75 mg per day Clopidogrel 300 mg (loading) then 75 mg per day months (depending on stent type), Bare-metal stent: for 1-12 months then 75-162 mg per day indefi- Bare-metal stent: combination to be given for 12 months nitely Drug-eluting stent: for at least 12 Drug-eluting stent: combination to be given for at least 12 months months; indefinitely if no excess risk of bleeding or toler- ability issues Without stenting Aspirin 162-325 mg (loading) then Clopidogrel 300 mg (loading) Aspirin 160-325 mg (loading) then 75-162 mg initially, 75-162 mg per day indefinitely then 75 mg per day for at least 14 then 75-100 mg per day indefinitely days; long-term therapy (1 year) is Clopidogrel 300mg (loading) if aged

4 Review of Prasugrel for the Secondary Prevention of Atherothrombosis TABLE 2 Summary of the Key Pharmacokinetic Properties of Prasugrel and Clopidogrel29-45,58 Prasugrel Clopidogrel Absorption and Prodrug is rapidly and extensively metabolized to the active Prodrug is rapidly and extensively metabolized to the inactive metabolism metabolite (R-138727) and several inactive metabolites metabolite (SR266334) and via 2-step CYP-dependent process to Metabolism to R-138727 is primarily via CYP 3A4 and CYP2B6 active metabolite (R-130946) Exposure to the active metabolite and clinical outcomes are not Metabolism to R-130946 is primarily via CYP 3A4, 2B6 and 1A2, affected by CYP 2C19 and 2C9 polymorphism with lesser contributions from 2C9 and 2C19 Rapid conversion of the parent drug to active metabolite (median Exposure to the active metabolite is affected by CYP 2C19 and 2C9 time to peak plasma concentration in approximately 30 minutes) polymorphism loss-of-function polymorphism increases the risk of poor cardiovascular outcome Rapid conversion of the parent drug to active metabolite (mean time to peak plasma concentration approximately 1 hour) Disposition Linear pharmacokinetics at doses up to 75 mg Linear pharmacokinetics at doses of 50 to 150 mg Elimination Median elimination half-life of the active metabolite in Elimination half-life of active metabolite not properly characterized approximately 7.4 hours but reported to be a mean of 1.9 hours in 1 analysis Excretion is primarily urinary (approximately 70%); fecal Excretion is 50% urinary and 46% fecal excretion

5 Review of Prasugrel for the Secondary Prevention of Atherothrombosis TABLE 3 Comparison of End Point Events With Prasugrel and Clopidogrel, Given as Dual Antiplatelet Therapy With Aspirin, in the TRITON-TIMI 38 Trial23 and the Bleeding Rates From This Study as Adjudicated by the CEC and Reported in the FDA Briefing Document12 Prasugrel Clopidogrel Study and Design Patients (n) Treatment End Point + Aspirin + Aspirin OR (95% CI) P Value TRITON-TIMI Patients with Prasugrel 60 mg, Efficacy (n=6,813) (n=6,795) 38 (2007) ACS (n=13,608) then 10 mg/day CV death, nonfatal MI, or 643 (9.9) 781 (12.1) 0.81 (0.73-0.90)

6 Review of Prasugrel for the Secondary Prevention of Atherothrombosis FIGURE 1 The Incidence of the Primary Composite End Point of Cardiovascular Death, Nonfatal MI or Nonfatal Stroke in Subgroups of Patients in TRITON-TIMI 38 P

7 Review of Prasugrel for the Secondary Prevention of Atherothrombosis FIGURE 2 The Incidence of the Primary Safety End Point of Non-CABG-Related Major TIMI Bleeding in the Primary (Overall) TRITON-TIMI 38 Study and the Published Patient Subgroup Analyses P=0.114 3.1 P=0.81 P=0.067 P=0.02 P=0.34 3 P=0.03 P=0.645 P=0.06 P=0.09 2.6 2.5 2.5 2.5 Major non-CABG bleeding 2.5 2.4 2.4 2.4 2.4 2.3 2.1 2.1 2 1.9 1.9 (% patients) 1.8 1.6 1.6 1.5 1 0.9 .5 0 Overall All STEMI Primary PCI Secondary PCI No diabetes Diabetes Any stent BMS DES (n=13,457) (n=3,534) (n=2,438) (n=1,094) (n=10,462) (n=3,146) (n=12,844) (n=6,461) (n=5,743) Wiviott et al. Montalescot et al. Wiviott et al. Wiviott et al. (NEJM 2007)23 23 (Lancet 2009)28 (Circulation 2008)26 (Lancet 2008)27 Clopidogrel Prasugrel BMS=bare-metal stent only; CABG=coronary artery bypass graft; DES=drug-eluting stent; PCI=percutaneous coronary intervention; STEMI=ST segment elevation myocardial infarction; TIMI=thombolysis in myocardial infarction; TRITON=Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel. P=0.006), and the incidence of target vessel revascularization was ST segment elevation. The results of this trial showed that statisti- 0.54% versus 0.83% (HR=0.66, 95% CI=0.43-0.99, P=0.047). cally significant reductions in clinical end points with clopidogrel From day 3 to the end of the trial, the corresponding incidence were accompanied by significant increases in bleeding risk.5 of stent thrombosis was 0.80% versus 1.74% (HR=0.45, 95% However, the benefit-risk ratio favored treatment, with an NNT of CI=0.32-0.64, P

8 Review of Prasugrel for the Secondary Prevention of Atherothrombosis who received prasugrel followed by clopidogrel. No TIMI major efficacy outcomes with adverse events (both ischemic and bleed- bleeding events were observed through day 29 of this study.21 ing events). Overall, prasugrel was associated with a net clini- Another phase II study, JUMBO-TIMI 26, was designed pri- cal benefit (combination of clinical efficacy and nonfatal major marily to assess prasugrel safety.22 In this study, 904 patients bleeding events) in 13.9% of patients compared with 12.2% of undergoing elective or urgent PCI were randomized to standard clopidogrel recipients (P=0.004). In the main study, the NNT for therapy with clopidogrel (loading dose of 300 mg with 75 mg per prasugrel was 46 to prevent 1 primary efficacy end point during day maintenance dosage) or to 1 of 3 prasugrel regimens (load- 15 months of treatment, relative to clopidogrel, and the NNH was ing dose of 40 or 60 mg followed by maintenance with 7.5, 10, or 167 to cause 1 non-CABG-related TIMI major bleeding event for 15 mg per day).22 The primary clinical end point was clinically prasugrel relative to clopidogrel (Table 4).23 However, post-hoc significant (TIMI major and minor) non-CABG-related bleeding analysis identified 3 subgroups of patients from TRITON-TIMI at 30 days.22 There were no significant differences between clopi- 38 in whom prasugrel was associated with either no net clinical dogrel and prasugrel in terms of clinically significant bleeding benefit or net harm. There was no clinical benefit from prasugrel and nonsignificant higher rates of minor and minimal bleeding versus clopidogrel in ACS patients with scheduled PCI who (a) in patients treated with prasugrel, particularly at the highest had a body weight below 60 kg or (b) were aged 75 years or dosage.22 There were 3 deaths in the high-dose (15 mg per day) older, and there was net harm in those with a history of stroke prasugrel group and none in the clopidogrel arm. The authors or transient ischemic attack (TIA; HR=1.54, 95% CI=1.02-2.32, note that the incidence of bleeding in the clopidogrel arm of the P=0.004).23 study was lower than expected, rendering the study underpow- Patients with a history of cerebrovascular events had no evi- ered to detect statistically significant differences in bleeding rates dence of benefit from prasugrel and showed a significant interac- between the treatment groups; therefore, more pertinent safety tion (P=0.02) between such a history and degree of net clinical information can be derived from the TRITON study, which was benefit of prasugrel as opposed to clopidogrel. For example, the larger and had longer follow-up. net clinical benefit (incidence of the primary composite efficacy The reduction in ischemic events with prasugrel observed in end point plus the primary safety end point of non-CABG-related TRITON-TIMI 38 was not associated with a reduction in overall major bleeding) was 23.0% with prasugrel versus 16.0% with mortality and was associated with increases in rates of non- clopidogrel in patients with a history of stroke/TIA (HR=1.54, CABG-related major bleeding compared with clopidogrel (2.4% 95% CI=1.02-2.32, P=0.04). However, in those without such vs. 1.8%; HR=1.32, 95% CI=1.03-1.68, P=0.03).23 CABG-related history, the corresponding net clinical benefit rates were 11.8% major bleeding events occurred in 24 prasugrel recipients (13.4%) for prasugrel versus 13.8% for clopidogrel (HR=0.84, 95% and 6 clopidogrel recipients (3.2%; HR=4.73, 95% CI=1.90- CI=0.76-0.93, P

9 Review of Prasugrel for the Secondary Prevention of Atherothrombosis TABLE 4 Net Clinical Benefit of Prasugrel Relative to Clopidogrel (Follow-Up to a Maximum of 15 Months) Composite End Point Including non-CABG-Related Major Bleedinga HR Patient Population N Prasugrel + Aspirin Clopidogrel + Aspirin (95% CI) P Value Overall23 13,608 831b (12.2%) 945b (13.9%) 0.87(0.79-0.95) 0.004 STEMI patients28 3,534 211 (12.2%) 256 (14.6%) 0.81 (0.67-0.97) 0.022 Patients without diabetes26 10,462 602b (11.5%) 643b (12.3%) 0.92(0.82-1.03) 0.16 c Patients with diabetes26 3,146 230b (14.6%) 301b (19.2%) 0.74 (0.62-0.89) 0.001 Stent recipients27 Any stent 12,844 771b (12.0%) 880b (13.7%) 0.86 (0.77-0.95) 0.002 Only BMS 6,461 388b (12%)d 451b (14%)d 0.88(0.77-1.01) 0.07c Only DES 5,743 315b (11%)d 374b (13%)d 0.84(0.72-0.98) 0.025 a Expressed as the incidence of all adverse outcomes (death from any cause, nonfatal MI, nonfatal stroke or non-CABG-related major TIMI bleeding in the overall TRITON-TIMI 38 study population,23 and in the patient subgroup analyses.26-28 bN values were estimated from published percentages, because the number of cases was not provided in the published papers. cThis P value reported to only 2 decimal places in the published paper. d Percentage rates in Wiviott et al.27 were expressed in whole numbers only. BMS=bare-metal stent; CABG=coronary artery bypass graft; CI=confidence interval; DES=drug-eluting stent; HR=hazard ratio; MI=myocardial infarction; STEMI=ST segment elevation myocardial infarction; TIMI=thrombolysis myocardial infarction; TRITON=Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel. intracranial hemorrhage was higher in patients aged 75 years and day) versus clopidogrel ([300 mg] 75 mg per day) in patients with older receiving prasugrel compared with clopidogrel. Fatal hem- non-ST segment elevation ACS not undergoing PCI.68 orrhage occurred in 9 of 891 prasugrel recipients aged 75 years or The currently available data on prasugrel indicate that it is older (1.0%) compared with 1 of 894 clopidogrel recipients in this effective when used in combination with aspirin, in reducing age group (0.1%); the corresponding rates of intracranial hemor- the risk of adverse cardiovascular outcomes in patients with ACS rhage were 7 (0.8%) and 3 (0.3%), respectively. Coupled with the undergoing PCI, at the expense of an increased risk of major modest clinical benefits of prasugrel in patients aged 75 years or bleeding events. It would appear that the clinical differences older, these data prompted the FDA advisory committee to sug- between prasugrel and clopidogrel may be related to differences gest that prasugrel use should be discouraged in this age group. in pharmacokinetic and pharmacodynamic properties, including Thus, identification of patients at higher risk of bleeding events in vivo antiplatelet effects, although this has yet to be confirmed. and attention to discontinuation of therapy before surgery may The NNT to prevent 1 primary outcome event with prasugrel help to guide therapeutic decisions and optimize outcomes. compared with clopidogrel in TRITON TIMI 38 is 46, and the An evaluation of the relative contribution of the loading and NNH for prasugrel compared with clopidogrel is 167, showing a maintenance phases on events in TRITON-TIMI 38 suggests net clinical benefit. The benefit appears to be greatest in patients that excess major bleeding with prasugrel occurred mainly in with diabetes mellitus but controversial in patients aged 75 years the maintenance phase.24 The authors of that study suggested or older or who weigh less than 60 kg and with net harm in maintenance dosage reduction in high-risk patients as a potential patients with a history of TIA/stroke. strategy to minimize bleeding events,24 although the efficacy of lower maintenance doses have not been studied. Dose-ranging Limitations studies have found that, compared with [loading] maintenance Currently, the clinical benefits of prasugrel are derived from a doses of clopidogrel [300 mg] 75 mg per day, inhibition of platelet single study (TRITON TIMI 38), albeit a large and robust one. aggregation was not significantly greater with prasugrel [loading] Further studies are needed to clarify the clinical profile of pra- maintenance doses of [20 mg] 5 mg per day or [30 mg] 7.5 mg per sugrel in other patient groups, such as those with ACS who are day59 but was significantly (P

10 Review of Prasugrel for the Secondary Prevention of Atherothrombosis (only 12% of the population had creatinine clearance

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