ࡱ>  <bjbjcTcT sB>>vv$   P[< yC"*m&^&&'=()|a*@wxxxxxx${C~$x*9(9(**$xk|&:'4Ay===*''w=*w==hpn'@n6 .kJwWy0y.lB~13H~pnpn~o**=*****$x$xy7***y****~*********v :  National Drug Monograph Prasugrel (Effient"!) April 2010 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current. Executive Summary: Prasugrel is a thienopyridine agent that inhibits platelet activation and aggregation irreversibly for the life of the platelet, similar to clopidogrel. Prasugrel is approved for the reduction of thrombotic cardiovascular (CV) events including stent thrombosis in patients with acute coronary syndromes (ACS) managed with percutaneous coronary intervention (PCI). Like clopidogrel, prasugrel is a pro-drug that requires activation to produce its pharmacologic effect. In contrast to the activation of clopidogrel, conversion to the active metabolite with prasugrel occurs quickly and is more efficient. Prasugrel exhibits more rapid, profound and consistent anti-platelet activity compared to clopidogrel with less inter-subject variability in response. Following a loading dose of 60 mg of prasugrel or 600 mg of clopidogrel, significant differences in inhibition of platelet aggregation (IPA) with 20 umol/L ADP were noted at 30 minutes (31% vs. 5%; p <0.05) and maintained through 24 hours (69% vs. 33%; p <0.05). Similarly, IPA with maintenance doses of 10 mg/day of prasugrel and 150 mg/day of clopidogrel over a 2-week period were greater with prasugrel (61% vs. 47%; p <0.05). The recommended dose of prasugrel is a one-time 60 mg oral loading dose followed by a maintenance dose of 10 mg orally once daily, given with background aspirin therapy (75-325 mg daily). A reduced maintenance dose of 5 mg orally once daily is recommended for patients weighing less than 60 kg due to an increased bleeding risk with higher maintenance doses in this population, although efficacy and safety with this dose has not been prospectively studied. The effects of prasugrel compared to clopidogrel in moderate-to-high risk patients with ACS undergoing PCI were evaluated in the pivotal phase 3 TRITON-TIMI 38 study. Of note, in patients with unstable angina (UA), non-ST-elevation myocardial infarction (NSTEMI) or post-ST-elevation myocardial infarction (STEMI), study drug was not initiated until coronary anatomy was known to be suitable for PCI (and thus coronary artery bypass [CABG] surgery deemed unlikely). Compared to clopidogrel, treatment with prasugrel was associated with a reduction in the composite primary efficacy endpoint of CV death, nonfatal MI, or nonfatal stroke (9.9% vs. 12.1%; HR 0.81; 95% CI 0.73-0.9; p <0.001; NNT 46), which was driven by a reduction in nonfatal MI, evident early on in therapy (within days). In a post-hoc analysis, probable or definite stent thrombosis was also significantly reduced in the prasugrel vs. clopidogrel group (1.1% vs. 2.4%; HR 0.48; 95% CI 0.36-0.64; p <0.001; NNT 77), a finding that was observed with both bare metal and drug eluding stents. The improvement in efficacy outcomes with prasugrel was accompanied by an increased risk of bleeding compared to clopidogrel. The most common adverse events reported with prasugrel are related to bleeding. Significantly more patients on prasugrel discontinued the drug due to adverse events compared to clopidogrel (7.2% vs. 6.3%; p <0.05). In TRITON-TIMI 38, prasugrel was consistently associated with excess bleeding events compared to clopidogrel, including serious and non-serious events, fatal events, and across many subgroups evaluated. TIMI major bleeding occurred in 2.4% of prasugrel vs. 1.8% of clopidogrel treated patients (HR 1.32; 95% CI 1.03-1.68; p=0.03; NNH 167). In the small portion of patients who underwent CABG after treatment with a thienopyridine (3%), prasugrel treatment was associated with significantly higher rates of bleeding vs. clopidogrel (TIMI major bleeding 13.4% prasugrel vs. 3.2% clopidogrel; HR 4.73 [95% CI 1.9-11.82]; p <0.05; ARI 10.2%; NNH 10). Prasugrel was associated with an excess number of newly diagnosed malignancies compared to clopidogrel (1.5% vs. 1.2%), with common sites of the lung, colon, and prostate. It is unclear whether this observation is random or if there may be a causal relationship. Prasugrel is contraindicated in patients with prior transient ischemic attack (TIA) or stroke and in patients with active pathological bleeding. Prescribing information includes a boxed warning on bleeding risk and cautions use in patients 75 years of age and older, those with low body weight of <60 kg (may consider lower maintenance dose), or those likely to undergo CABG. In effort to better define those patients who may or may not benefit from use of prasugrel considering both the efficacy benefit and increased bleeding risk, the net clinical benefit was calculated as part of a post-hoc analysis. No net benefit from prasugrel therapy was observed in patients 75 years of age and older or those with a body weight <60 kg, while those with a previous TIA or stroke were shown to have net harm from prasugrel therapy. On the other hand, statistically significant net clinical benefit was observed with prasugrel in patients with diabetes mellitus (DM) or those presenting with STEMI. In contrast to clopidogrel, prasugrel does not appear to be associated with clinically significant drug interactions via the cytochrome P450 system. Prasugrel has to date only been evaluated in patients with ACS undergoing PCI. The efficacy and safety of prasugrel for use in other situations is unknown at this time. Introduction The spectrum of ACS encompasses an array of clinical symptoms consistent with acute coronary ischemia and includes unstable angina UA and myocardial infarction ([NSTEMI and STEMI]). Management of ACS is based on clinical presentation and risk assessment and may include medical management, PCI, or CABG surgery. UA and NSTEMI are considered closely related conditions that are usually caused by a narrowing of the coronary artery due to a thrombus. The diagnosis of UA is made when there are no elevations of biomarkers (e.g., troponin, creatinine kinase-myocardial bands [CK-MB]). In patients with STEMI, there is a high likelihood of complete occlusion of a coronary artery, and immediate consideration of reperfusion therapy (pharmacological or catheter-based) is indicated. Goals of treatment of UA/NSTEMI are to provide immediate relief of ischemia and prevent serious outcomes including death or MI. In STEMI, the immediate goal is to restore perfusion. Platelet adhesion, activation, and aggregation are stimulated in ACS, and anti-platelet therapy is a key component of therapy. Aspirin, consistently shown to be associated with improvement in outcomes including reductions in MI and/or death, should be administered to all patients with ACS and continued indefinitely, unless contraindicated (e.g., true aspirin allergy). NOTEREF _Ref250920157 \h  \* MERGEFORMAT 1, NOTEREF _Ref250920158 \h  \* MERGEFORMAT 2 For those patients with ACS who undergo PCI, dual anti-platelet therapy with aspirin plus a thienopyridine (ticlopidine, clopidogrel, or prasugrel) has been shown to significantly reduce secondary cardiovascular events compared with aspirin alone and is recommended by current national guidelines. ,,, The use of ticlopidine, the first available thienopyridine in the US, has largely been replaced by clopidogrel, due to less favorable tolerability and adverse event profile with ticlopidine (e.g., gastrointestinal complaints, neutropenia, and rarely, thrombotic thrombocytopenia purpura [TTP]). Clopidogrel has been shown to have a variable response between individuals, may be associated with potentially clinically significant drug interactions, and requires hours to achieve anti-platelet response following a loading dose. Prasugrel is a new thienopyridine agent that exhibits a more rapid onset of action, more potent and consistent platelet aggregation inhibition, although is associated with an increased risk of bleeding. The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to considering prasugrel for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA. Pharmacology Like clopidogrel, prasugrel is a prodrug belonging to the thienopyridine class and inhibits platelet activation and aggregation through specific and irreversible binding of its active metabolite to the platelet adenosine 5-diphosphate (ADP) P2Y12 receptor. Pharmacokinetics/Pharmacodynamics Prasugrel is rapidly hydrolyzed to an inactive thiolactone, which is then converted to the active metabolite (R-138727) in one step via the CYP P450 system, primarily by CYP 3A4 and CYP 2B6, and to a lesser extent by CYP 2C19 and CYP 2C9. NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7, In contrast, activation of clopidogrel involves a 2-step process, both of which are dependent on CYP enzymes. Following oral administration of clopidogrel, the majority of the drug is de-activated (about 85%). The remainder is metabolized to an intermediate compound and then to the active metabolite. At least 79% of the prasugrel dose is absorbed after oral administration. Absorption and activation are rapid, with peak plasma concentrations of the active metabolite occurring in about 30 minutes. The active metabolite is highly protein bound and is inactivated through S-methylation or conjugation with cysteine. The elimination half-life of the active metabolite is about 7 hours (range 2-15 hours). However, similar to clopidogrel, the duration of effect lasts for the life of the platelet, returning to baseline in approximately 5-9 days after discontinuation of prasugrel. Approximately 68% of the dose is excreted in the urine and 27% in the feces as inactive metabolites. NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 Prasugrel is approximately 10-fold more potent than clopidogrel (and 100-fold more potent than ticlopidine); however, the active metabolites of each drug exhibit similar concentration-dependent potency. This suggests that the increased potency of prasugrel is related to the greater exposure of the active metabolite. Results from the PRINCIPLE-TIMI 44 trial, a phase 2, 2-week crossover study in 201 patients undergoing cardiac catheterization and planned PCI, showed that prasugrel (60 mg load and 10 mg daily maintenance) exhibits a more rapid and profound anti-platelet effect than high doses of clopidogrel (600 mg load and 150 mg daily maintenance). At 6 hours following the loading dose, IPA was 75% with prasugrel vs. 32% with clopidogrel (p <0.0001). Significant differences were apparent at 30 minutes following the loading dose (31% with prasugrel vs. 5% with clopidogrel) and persistent throughout the 14-day treatment period (mean IPA 61% with prasugrel vs. 46% with clopidogrel). A smaller number of patients treated with prasugrel were considered hyporesponsive, defined in this study as IPA with 20 umol/L ADP <20% (2.4% vs. 12.8%; p=0.02). Of note, IPA is a surrogate marker and has not been shown to consistently correlate with outcomes. The effects of certain genetic variants of the CYP 450 enzyme system (CYP2C19, CYP2C9, CYP2B6, CYP3A5, and CYP1A2) involved in the activation of clopidogrel and prasugrel were evaluated by Mega et al. In 238 healthy subjects from 6 studies, carriers of a reduced-function allele were not found to have attenuation of the pharmacokinetic or pharmacodynamic response with prasugrel. In a sub-study of 1466 patients from TRITON TIMI-38 where genetic information was available, no statistically significant associations were found between the CYP P450 variants studied (including variants of CYP2C19) and the occurrence of the primary efficacy endpoint (cardiovascular death, nonfatal MI, or stroke), stent thrombosis, or TIMI non-CABG major or minor bleeding in patients that received prasugrel. In contrast, carriers of reduced-function alleles of CYP2C19 have been shown to have an attenuated pharmacokinetic and pharmacodynamic response to clopidogrel and may be at higher risk of subsequent cardiovascular events. Conversion of salt to free base form The hydrochloride (HCl) salt is the approved form of prasugrel. Upon storage, it was found that a portion of the HCl salt form may convert to the free base form (ranging from 45-86%), which has been shown to have reduced bioavailability and delay of IPA effect in the setting of elevated gastric pH (e.g., with the use of proton-pump inhibitors [PPIs], H2 blockers). The delay in effect observed with prasugrel in this scenario is not expected to be clinically significant, and the extent of IPA with prasugrel still exceeds that of clopidogrel at all time points. FDA Approved Indication(s) and Off-label Uses NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 Prasugrel is approved for use in the treatment of ACS to reduce the rate of thrombotic CV events including stent thrombosis who are to be managed with PCI as follows: Patients with UA or NSTEMI Patients with STEMI when managed with primary or delayed PCI Potential areas for off-label use of prasugrel may include non-cardiac stenting, the need for antiplatelet therapy in true aspirin allergy, medical management of ACS (without stenting), and as an alternative to clopidogrel where hyporesponsiveness or failure is suspected despite compliance. Current VA National Formulary Alternatives The current VA National Formulary alternative is clopidogrel, which is restricted to Criteria for Use for the following indications: PCI, UA/NSTEMI, STEMI, CABG, cerebral ischemic events, non-cardiac stenting, need for antiplatelet therapy in patients with a true aspirin allergy or extended release aspirin-dipyridamole therapy induced headaches (see  HYPERLINK "http://vaww.pbm.va.gov" http://vaww.pbm.va.gov or  HYPERLINK "http://www.pbm.va.gov" www.pbm.va.gov for more information on the Clopidogrel Criteria for Use). Dosage and Administration NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 The recommended dose of prasugrel is a one-time 60 mg oral loading dose followed by a maintenance dose of 10 mg orally once daily. Prasugrel may be given without regard to meals and should be used with background aspirin therapy (75-325 mg daily). Low Body Weight: A reduced maintenance dose of 5 mg orally once daily is recommended for patients weighing less than 60 kg due to an increased bleeding risk with higher maintenance doses in this population, although efficacy and safety with this dose has not been prospectively studied. Renal Impairment: Dose adjustments are not needed in patients with mild or moderate renal impairment; however, there is limited experience available in patients with end-stage renal impairment. Hepatic Impairment: Dose adjustments are not needed in patients with mild or moderate hepatic impairment. The effects of prasugrel in patients with severe hepatic disease are unknown; however, these patients are generally at an increased risk of bleeding. Storage and Handling: Dispense product in original container. Keep container closed and do not remove desiccant from bottle (see Pharmacokinetics/Pharmacodynamics section on salt to free base conversion). Discontinuation: Prasugrel should be discontinued in active bleeding, stroke or TIA, and at least 7 days prior to elective surgery. However, premature discontinuation of thienopyridines including prasugrel in patients managed with PCI and stent placement confers an increased risk of cardiac events including stent thrombosis, MI, and death. Efficacy (Pivotal Clinical Trial) Primary Efficacy Endpoint Composite of the following: Death from cardiovascular (CV) causes Nonfatal MI an event distinct from the index event, defined by symptoms suggestive of ischemia/infarction, electrocardiogram (ECG) data, cardiac biomarker, or pathologic evidence of infarction Nonfatal stroke Key Secondary Efficacy Endpoints NOTEREF _Ref250925005 \h  \* MERGEFORMAT 15 Stent thrombosis (not prespecified and was a post-hoc analysis) Composite of CV death, nonfatal MI, nonfatal stroke, or rehospitalization due to cardiac ischemic event 30 and 90 day event rates for the primary endpoint and the composite of CV death, nonfatal MI, or urgent target-vessel revascularization Efficacy in ACS patients undergoing PCI TRITON-TIMI 38 The effects of prasugrel were compared to clopidogrel in the pivotal TRITON-TIMI 38 study (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction), where13,608 patients with moderate-to-high risk ACS (UA, NSTEMI, STEMI) and scheduled PCI were followed for a median duration of 14.5 months. Except for patients with STEMI where primary PCI was planned, randomization did not occur until after the coronary anatomy was known to be suitable for PCI. All patients were given background aspirin therapy and were randomized to receive prasugrel (60 mg oral loading dose and 10 mg orally daily) or standard dose clopidogrel (300 mg oral loading dose and 75 mg orally daily), with loading doses administered to the majority of patients during PCI. The study population was comprised of 74% presenting with UA/NSTEMI and 26% with STEMI. Compared to clopidogrel, treatment with prasugrel was associated with a reduction in the composite primary efficacy endpoint of CV death, nonfatal MI, or nonfatal stroke (9.9% vs. 12.1%; HR 0.81; 95% CI 0.73-0.9; p <0.001), which was driven by a reduction in nonfatal MI, evident early on in therapy (within days). A large part of the treatment benefit observed with prasugrel was noted within the first few weeks, although the treatment effect appeared to persist throughout the duration of the study. NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12, In a post-hoc analysis, probable or definite stent thrombosis was also significantly reduced in the prasugrel vs. clopidogrel group (1.1% vs. 2.4%; HR 0.48; 95% CI 0.36-0.64; p <0.001), a finding that was observed with both bare metal and drug eluding stents. The improvement in efficacy outcomes with prasugrel was accompanied by an increased risk of bleeding compared to clopidogrel (see Adverse Events and Net Clinical Benefit sections for additional details). The treatment benefit of prasugrel with respect to the composite primary efficacy endpoint tended to be greater in younger patients, males, those weighing >60 kg, with a creatinine clearance >60 ml/min, and without prior CABG, while patients with a history of TIA/stroke tended to do worse on prasugrel with an overall net harm (see Net Clinical Benefit section). NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12, NOTEREF _Ref250925005 \h  \* MERGEFORMAT 15 Factors that could have favored prasugrel by the study design include both the loading dose of clopidogrel used (300 mg vs. 600 mg) as well as the timing of the loading dose of study drug (75% of patients received drug during PCI), given the delayed anti-platelet effect of a 300 mg dose of clopidogrel. The validity of the stent thrombosis endpoint has been questioned because events were not confirmed by the clinical event committee through direct angiography review as is the current required standard of the Academic Research Consortium (ARC)., In addition, the definition and significance of nonfatal MI in this trial have been scrutinized., Table 1. Efficacy Outcomes from TRITON-TIMI 38 (at 15 months) EndpointPrasugrel (n=6813)Clopidogrel (n=6795)HR (95% CI)P ValueARRNNTComposite of CV death, nonfatal MI, nonfatal stroke*9.9%12.1%0.81 (0.73-0.9)<0.0012.2%46 CV Death2.1%2.4%0.89 (0.7-1.12)0.310.3%- Nonfatal MI7.3%9.5%0.76 (0.67-0.85)<0.0012.2%46 Nonfatal stroke1%1%1.02 (0.71-1.45)0.93--Stent thrombosis (post-hoc)1.1%2.4%0.48 (0.36-0.64)<0.0011.3%77*Primary Endpoint For further details on the efficacy results of the TRITON-TIMI 38, refer to Appendix. Selected Additional Analyses from TRITON-TIMI 38 Patients with DM A pre-specified sub-group analysis was conducted to compare the effects of prasugrel and clopidogrel in the setting of DM, a condition shown to be associated with worse outcomes in ACS. In the 3146 (23% of the study population) patients with DM, prasugrel was associated with a significant reduction in the composite primary endpoint of CV death, nonfatal MI, or nonfatal stroke (12.2% prasugrel vs. 17% clopidogrel; HR 0.7; 95% CI: 0.58-0.85; p <0.001; pinteraction=0.09; ARR 4.8%; NNT 21), which was of greater magnitude than the reduction seen in patients without DM (9.2% prasugrel vs. 10.6% clopidogrel; HR 0.86; 95% CI 0.76-0.98; p=0.02) or in the whole study population. Similar to the population as a whole, the reduction in the primary endpoint in the DM analysis was driven by the reduction in MI. Non-CABG TIMI major bleeding rates with prasugrel were not significantly different than with clopidogrel in patients with DM, though an overall trend of higher bleeding rates were observed in patients with DM vs. no DM. Patients with STEMI The number of patients with STEMI included in TRITON-TIMI 38 was capped to be reflective of the presentation of ACS in the general population. The trial was not prospectively designed or powered to show superiority of prasugrel to clopidogrel in this population alone. NOTEREF _Ref250986437 \h  \* MERGEFORMAT 13, In the pre-specified analysis of the STEMI sub-population which included 3534 patients, prasugrel was associated with a significant reduction in the composite primary endpoint (CV death, nonfatal MI, or nonfatal stroke) compared to clopidogrel at 30 days (6.5% vs. 9.5%; HR 0.68; 95% CI 0.54-0.87; p=0.0017) and at 15 months; (10% vs. 12.4%; HR 0.79; 95% CI 0.65-0.97; p=0.0221). Effects in the STEMI subgroup were consistent with that of the UA/NSTEMI group, and no significant interaction of presenting syndrome (UA/NSTEMI vs. STEMI) and benefits of prasugrel were noted (p=0.7686). For the individual endpoints of CV death, all-cause death, MI, and stent thrombosis, prasugrel was shown to be statistically superior to clopidogrel at 30 days, while at 15 months, only MI and stent thrombosis remained significantly improved with prasugrel vs. clopidogrel. Of note, bleeding unrelated to CABG surgery was not found to be significantly different between prasugrel and clopidogrel treatments, although this finding should be interpreted cautiously due to some differences in patient characteristics between groups that could account in part for the results. Recurrent Cardiovascular Events In a separate analysis of TRITON-TIMI 38, patients experiencing an initial nonfatal event (MI or stroke) treated with prasugrel were found to have a reduction in recurrent CV events (MI, stroke, CV death) compared to patients on clopidogrel (10.8% vs. 15.4%; HR 0.65; 95% CI 0.46-0.92; p=0.016). Results remained consistent when several sensitivity analyses were performed. However, recurrent bleeding events on prasugrel vs. clopidogrel could not be adequately assessed, as 42% of patients experiencing an initial major bleeding event discontinued therapy. Table 2. Key Endpoints by Sub-Group from TRITON-TIMI 38 (at 15 months) NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12, NOTEREF _Ref250925005 \h  \* MERGEFORMAT 15, NOTEREF _Ref250998774 \h  \* MERGEFORMAT 22, NOTEREF _Ref250998775 \h  \* MERGEFORMAT 24 EndpointTotal PopulationDMSTEMIPrevious TIA/CVAPRAS n=6813CLOP n=6795PRAS n=1576CLOP n=1570PRAS n=1769CLOP n=1765PRAS n=262CLOP n=256Composite of CV death, nonfatal MI, nonfatal stroke9.9%*12.1%12.2%*17%10%*12.4%17.9%13.7% CV Death2.1%2.4%3.4%4.2%2.4%3.4%3.4%5.9% Nonfatal MI7.3%*9.5%8.2%*13.2%6.8%*9%11.1%9.8% Nonfatal stroke1%1%NRNR1.6%1.5%5.7%*0.8%Stent thrombosis1.1%*2.4%2%*3.6%1.6%*2.8%NRNRTIMI Major Bleed (non-CABG)2.4%*1.8%2.5%2.6%2.4%2.1%5%2.9%*p<0.05; data are for patients who received e"1 dose of study drug; ! includes fatal and nonfatal events; CVA >3 mos prior or any TIA history Adverse Events (Safety Data) Safety data for prasugrel were derived primarily from the pivotal TRITON-TIMI 38 study, which included a total of 13,457 subjects with ACS managed by PCI and treated with prasugrel (n=6741) or clopidogrel (n=6716). NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12 Key safety endpoints evaluated were non-CABG TIMI major or life-threatening bleeding, and TIMI major and minor bleeding. Deaths and Other Serious Adverse Events (Sentinel Events) In the TRITON-TIMI 38 study, the occurrence of all-cause death was similar between treatment groups (2.8% prasugrel vs. 2.9% clopidogrel). NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12 The only other deaths reported in the clinical development program were from the JUMBO TIMI-26 trial, a phase 2, dose-ranging safety study (n=904), where three deaths occurred in the prasugrel group versus none in the clopidogrel group, a difference that was not statistically significant. Other serious adverse events that occurred significantly more frequently with prasugrel compared to clopidogrel in TRITON-TIMI 38 included bleeding and neoplasms, which are discussed further below. NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12 Bleeding In TRITON-TIMI 38, prasugrel was consistently associated with excess bleeding events compared to clopidogrel, including serious and non-serious events, fatal events, and across many subgroups evaluated. NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12, NOTEREF _Ref250925005 \h  \* MERGEFORMAT 15 Non-CABG-related bleeding Bleeding events were reported significantly more frequently in patients receiving prasugrel compared to clopidogrel (See Table 3). Many of the events occurred early on in therapy, although the difference in risk persisted throughout the study period (median duration 14.5 months). NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12, NOTEREF _Ref250925005 \h  \* MERGEFORMAT 15 A landmark analysis of the TRITON-TIMI 38 population suggested that excess in major bleeding associated with prasugrel was predominant during the maintenance phase of therapy. NOTEREF _Ref251081477 \h  \* MERGEFORMAT 16 Table 3. Non-CABG-Related Bleeding Events from TRITON-TIMI 38a EndpointPrasugrel (n=6741)Clopidogrel (n=6716)HR (95% CI)P ValueARINNHTIMI majorb or minorc bleeding5%3.8%1.31 (1.11-1.56)0.0021.2%83TIMI majorb bleeding2.4%1.8%1.32 (1.03-1.68)0.030.6%167Life threatening bleedingd1.4%0.9%1.52 (1.08-2.13)0.0150.5%200Fatal bleeding0.4%0.1%4.19 (1.58-11.11)0.0020.3%333a Data shown for patients who received e"1 dose of study drug b Clinically overt (including imaging), hemoglobin drop of e"5 gm/dL, and includes ICH c Clinically overt (including imaging), hemoglobin drop of 3 - <5 gm/dL d TIMI major bleed that is fatal, requires inotropes, surgical intervention, transfusion (e"4 units in 48hrs), or is a symptomatic ICH Bleeding by Subgroup Compared to clopidogrel, the relative increase in bleeding risk with prasugrel remained fairly consistent (approximately 1.3) when examined across subgroups by gender, age, and ethnicity. NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12 Though relative risk of bleeding was similar between clopidogrel and prasugrel in patients e"75 years of age, outcomes secondary to bleeding were worse with prasugrel. Fatal bleeding or ICH occurred in 1% and 0.8% of prasugrel-treated patients e"75, respectively, vs. 0.1% and 0.3% respectively in clopidogrel-treated patients <75. NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12 The number of bleeding events that occurred in patients weighing <60 kg was about doubled in the prasugrel vs. clopidogrel group, though the portion of low weight patients in the study population was small (<5%). NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12 Intracranial hemorrhage (ICH) NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12 ICH occurred in 20 patients (0.29%) treated with prasugrel vs. 16 patients (0.24%) treated with clopidogrel, though twice as many events were fatal with prasugrel (9 events vs. 5 events). CABG-related bleeding NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12, NOTEREF _Ref250925005 \h 15 In the small portion of patients who underwent CABG after treatment with a thienopyridine (3%), prasugrel treatment was associated with significantly higher rates of bleeding than clopidogrel, a risk that was particularly high within the first 3 days of discontinuing prasugrel and persisted through 7 days following a dose of prasugrel (TIMI major bleeding 13.4% prasugrel vs. 3.2% clopidogrel; HR 4.73 [95% CI 1.9-11.82]; p <0.05; ARI 10.2%; NNH 10). Neoplasm Prasugrel treatment was associated with an excess number of newly diagnosed non-benign (malignant or undetermined) neoplasms compared to clopidogrel. NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 Common sites included the lung, colon, and prostate. The overall number of events was small, and the magnitude of the observed difference between treatment groups was sensitive to how the event was classified; however, the trend was consistent (FDA final classification: 1.5% prasugrel vs. 1.2% clopidogrel; RR 1.29; 95% CI: 0.96-1.72). NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12 Cancer deaths were also slightly higher with prasugrel. It is unclear whether this observation is random or if there may be a causal relationship. Additional evaluation of clopidogrel data from previous studies did not reveal a signal with this similar drug, and non-clinical data do not support a tumor promotion effect of prasugrel, per the FDA review. NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12 Common Adverse Events NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 The most frequently reported adverse effects with prasugrel are generally related to bleeding (described above). Other commonly reported adverse events are listed below. Table 4. Non-hemorrhagic events reported more frequently with prasugrel and in more than 2.5% of patients EventPrasugrelClopidogrelHypertension7.5%7.1%Headache5.5%5.3%Dyspnea4.9%4.5%Nausea4.6%4.3%Hypotension3.9%3.8%Bradycardia2.9%2.4%Rash2.8%2.4%Pyrexia2.7%2.2%Other Adverse Events NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 Other important adverse events reported included severe thrombocytopenia, abnormal hepatic function, allergic reactions, and angioedema, all of which occurred rarely in <0.5% of prasugrel and clopidogrel-treated patients. Anemia occurred in 2.2% and 2% of prasugrel- and clopidogrel-treated patients, respectively. Tolerability NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7, NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12 Significantly more patients on prasugrel discontinued the drug due to adverse events than patients on clopidogrel (7.2% vs. 6.3%; p <0.05). Discontinuations due to hemorrhagic events, both serious and non-serious, were also significantly more frequent with prasugrel (2.5% vs. 1.4%; p <0.05). For further details on the safety results of the clinical trials, refer to the Appendix. Contraindications Prasugrel is contraindicated in patients with active pathological bleeding (e.g., peptic ulcer, intracranial bleeding) and in patients with a history of prior TIA or stroke. NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 Patients who received prasugrel with a remote TIA/stroke history (those with recent events within previous 3 months were excluded from clinical trial) were shown to have an increased rate of stroke compared to clopidogrel (6.5% vs. 1.2%). Warnings and Precautions Boxed Warning: Bleeding Risk NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 Prasugrel can cause significant, sometimes fatal bleeding and is contraindicated in patients with active pathological bleeding or a history of TIA or stroke. Prasugrel is generally not recommended for use in patients e"75 years and older due to an increased risk of fatal and intracranial bleeding and an unclear benefit, except in high-risk situations (e.g., DM, history of prior MI) where its effect appears to be greater and its use may be considered. Prasugrel should not be used in patients who are likely to undergo CABG surgery due to an increased bleeding risk. When possible, prasugrel should be discontinued at least 7 days prior to surgery. Additional risk factors for bleeding include body weight <60 kg, propensity to bleed, concomitant use of medications that increase the risk of bleeding (e.g., warfarin, heparin, fibrinolytic therapy, chronic use of non-steroidal anti-inflammatory drugs [NSAIDs]. Bleeding should be suspected in any patient who becomes hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures in the setting of prasugrel. If possible, manage bleeding without discontinuing prasugrel. Discontinuing prasugrel, particularly in the first few weeks after ACS, increases the risk of subsequent cardiovascular events. Thrombotic Thrombocytopenic Purpura (TTP) NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 Although not reported in the clinical development program for prasugrel, TTP has been reported with the use of other thienopyridines, sometimes after brief exposure (<2 weeks). Pregnancy and Lactation NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 Prasugrel is a FDA Pregnancy Category B medication. There are no adequate and well-controlled studies in human pregnancy. Animal reproductive and developmental toxicology studies did not reveal evidence of fetal harm, structural malformations, or effects on behavioral or reproductive development; however, animal studies are not always predictive of a human response. Prasugrel should only be used during pregnancy when the potential benefit to the mother outweighs the potential risk to the fetus. It is not known whether prasugrel is excreted in human milk, although metabolites of prasugrel were found in rat milk. Because many drugs are excreted in human milk, prasugrel should only be used during nursing if the potential benefit to the mother outweighs the potential risk to the nursing infant. Net Clinical Benefit In TRITON-TIMI 38, the efficacy benefit of prasugrel was offset by an increase risk of bleeding compared to clopidogrel. In effort to better define those patients who may or may not benefit from use of prasugrel, the net clinical benefit was calculated as part of a post-hoc analysis. The composite outcome of all-cause mortality, nonfatal MI, nonfatal stroke, or non-CABG-related nonfatal TIMI major bleeding was examined among sub-groups. Although considered exploratory, the following findings were noted. No net benefit from prasugrel therapy was observed in patients 75 years of age and older or those with a body weight <60 kg, while those with a previous TIA or stroke were shown to have net harm from prasugrel therapy. NOTEREF _Ref250925005 \h  \* MERGEFORMAT 15 On the other hand, statistically significant net clinical benefit was observed with prasugrel in patients with DM or those presenting with STEMI (see Table 5). NOTEREF _Ref250998774 \h  \* MERGEFORMAT 22, NOTEREF _Ref250998775 \h  \* MERGEFORMAT 24 Table 5. Net Clinical Benefit Among Selected Subgroups EndpointPrevious TIA/CVAAge e"75, Wt <60 kg, or previous TIA/CVADMSTEMIPRAS n=262CLOP n=256PRAS n=1320CLOP n=1347PRAS n=1576CLOP n=1570PRAS n=1769CLOP n=1765Composite of CV death, nonfatal MI, nonfatal stroke17.9%13.7%16.1%16%12.2%*17%10%*12.4%TIMI Major Bleed (non-CABG, nonfatal)5%2.9%4.3%3.3%2.5%2.6%2.4%2.1%Net clinical benefit: all-cause death, nonfatal MI, nonfatal stroke, non-CABG nonfatal TIMI major bleed23%*16%20.2%19%14.6%*19.2%12.2%*14.6% Absolute risk change ARI 7%n/an/aARR 4.6%ARR 2.4% Number needed to treat or harm NNH 14n/an/aNNT 22NNT 42*p <0.05 Risk Evaluation and Mitigation Strategy (REMS) NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 The REMS approved by the FDA for prasugrel includes a Medication Guide that is to be dispensed to patients with every prescription. In addition, the manufacturer will have a Dear Healthcare Provider Letter and Prescriber Brochure available as part of the communication plan for providers. Look-alike / Sound-alike (LA / SA) Error Risk Potential As part of a JCAHO standard, LASA names are assessed during the formulary selection of drugs. Based on clinical judgment and an evaluation of LASA information from four data sources (Lexi-Comp, USP Online LASA Finder, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LASA confusion: LA/SA for generic name prasugrel: pravachol, praziquantel LA/SA for trade name Effient: Effexor Drug Interactions Drugs that increase gastric pH NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7, NOTEREF _Ref250998770 \h  \* MERGEFORMAT 12 Co-administration of prasugrel with H2 blockers or PPIs resulted in a reduction of Cmax but not AUC of the active metabolite of prasugrel and slight delay in biologic effects (see Pharmacokinetics/ Pharmacodynamics section). In TRITON-TIMI 38, prasugrel was administered without regard to co-administration of H2 blockers or PPIs. About 40% of patients reported PPI use, and no differences in efficacy were seen when compared to those who did not receive a PPI. Inhibitors and inducers of CYP P450 enzyme system NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 Based on pharmacokinetic testing, inducers or inhibitors of CYP P450 enzymes are not expected to have a clinically significant impact on the active metabolite of prasugrel. In addition, in-vitro testing demonstrated that prasugrels main metabolites are not likely to cause clinically significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A, or induction of CYP1A2 or CYP3A. Although prasugrel is a weak inhibitor of CYP2B6, the drug is not anticipated to have a clinically relevant interaction with drugs primarily metabolized by this enzyme. Warfarin and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 Co-administration of warfarin or chronic use of NSAIDs with prasugrel increases the risk of bleeding. Patients receiving these medications were excluded from TRITON-TIMI 38. Other medications that increase the risk of bleeding NOTEREF _Ref250974090 \h  \* MERGEFORMAT 7 Aspirin (75-325 mg/day), heparin, and glycoprotein IIb/IIIa inhibitors were commonly used in clinical trials and can be administered with prasugrel. Acquisition Cost Drug/DoseCost* per dayCost* per yearLoading Dose Prasugrel 60 mg x1$22.44- Clopidogrel 300 mg x1$11.63- Clopidogrel 600 mg x1$23.26-Maintenance Dose Prasugrel 10 mg tablet once daily$3.74$1365.10 Prasugrel 5 mg tablet once daily$3.67$1339.55 Clopidogrel 75 mg tablet once daily$2.93$1069.45*VA Prices as of 1/2/10; check VA pricing sources for update information Pharmacoeconomic Analysis A pharmacoeconomic analysis for prasugrel vs. clopidogrel was conducted from the perspective of the US healthcare system in a pre-specified subgroup from the TRITON-TIMI 38 study including 6705 patients from 8 countries (including US) for a median follow-up period of 14.7 months. Drug costs were estimated at $4.62/day for clopidogrel and $5.45/day for prasugrel using 2009 pricing, and all other resource use was estimated in 2005 US dollars. Overall, the economic study subset showed similar baseline characteristics and primary clinical endpoint results as the entire study population. Mean index hospitalization costs did not differ significantly between treatment groups, with lower costs for peri-procedural MI offset by higher costs for peri-procedural bleeding with prasugrel. Costs associated with re-hospitalization were lower with prasugrel, primarily due to a significantly lower incidence of repeat PCI, even though hospitalizations for bleeding were higher with prasugrel. Cumulative medical care costs (including drug, index, and re-hospitalizations) were found to be $221 per patient lower with prasugrel (95% CI -759 to 299). Life expectancy with prasugrel was projected as 0.102 life-years gained mainly due to reduction in nonfatal MI. Prasugrel remained economically dominant across a number of sensitivity and sub-group analyses. When costs of generic clopidogrel (expected to be available in 2011) were considered (estimated at $1/day), the net cost with prasugrel increased to $996 per patient (no longer cost saving and associated with an incremental cost effectiveness ratio (ICER) of $9277 per life-year gained). Considering more conservative assumptions (generic clopidogrel cost, loss of life expectancy for bleeding, and costs in added years of life), the ICER for prasugrel increased to $18,458. Overall, prasugrel was found to be an economically attractive option in the treatment of ACS with planned PCI in this subset of patients in many scenarios, though cost savings is lost with the availability of generic clopidogrel. Cost savings with prasugrel was primarily driven by fewer re-hospitalizations for PCI; it is unclear whether this economic subset is representative of the entire study population in this regard. Life expectancy estimates for nonfatal MI and the lack of impact on life expectancy estimated with major TIMI bleeding could have influenced the primary results. Conclusions In patients with ACS undergoing PCI, dual anti-platelet therapy with aspirin plus a thienopyridine has been shown to significantly reduce secondary cardiovascular events and is recommended in current national clinical practice guidelines. Clopidogrel is currently the most widely used thienopyridine but requires several hours to achieve a significant anti-platelet effect and is associated with variability in anti-platelet response between individuals. There has also been recent concern of potentially clinically significant drug interactions with clopidogrel, affecting the anti-platelet response. Prasugrel is a new thienopyridine that exhibits a more rapid, consistent, and profound anti-platelet response compared to clopidogrel, although is associated with more bleeding. Prasugrel appears to lack clinically significant drug interactions mediated by the CYP 450 system. In a moderate-to-high risk ACS population undergoing PCI, prasugrel was shown to significantly reduce the composite primary efficacy endpoint of CV death, nonfatal MI, and nonfatal stroke compared to clopidogrel, which was driven by a reduction in nonfatal MI. A significant reduction in stent thrombosis was also demonstrated with prasugrel, though this was not a prespecified analysis (e.g., post-hoc). Although a large treatment benefit was seen early in the study, efficacy appeared to be maintained throughout the duration of the study (median 14.5 months). The early treatment effect differences observed with prasugrel and clopidogrel may have been attributed to the timing of the administration of the drugs (within 1 hr of PCI in 75% of patients), as well as the lower loading dose of clopidogrel used, both of which favor prasugrel. Compared to clopidogrel, prasugrel was overall associated with a significantly higher risk of bleeding, including major and fatal bleeding events. Prescribing information includes a boxed warning regarding bleeding risk. Prasugrel should not be used in patients likely to undergo CABG due to increased risk of bleeding with thienopyridine treatment, which was shown to be several-fold higher with clopidogrel vs. prasugrel. In TRITON-TIMI 38, study drug was not administered in UA/NSTEMI or post-STEMI patients until coronary anatomy was known to be suitable for PCI. An exploratory landmark analysis suggested that there may be an increased risk of bleeding with chronic therapy over time. Considering both the treatment benefit and bleeding risks with prasugrel, net clinical benefit was analyzed. Patients with prior TIA/CVA showed a net harm from prasugrel treatment, and its use is contraindicated in this population. No net benefit was seen in patients 75 years of age and older or those with low body weight of <60 kg. On the other hand, patients with DM or STEMI appeared to achieve a greater net benefit from prasugrel therapy. Place In Therapy Use of prasugrel should follow the evidence currently available. Prasugrel may be considered as an option in the management of patients with moderate-to-high risk patients with ACS and undergoing PCI who do not have any contraindications (TIA, stroke, or active bleeding) or other risk factors for bleeding as identified in or otherwise excluded from TRITON TIMI-38, who have not already been loaded with clopidogrel, and who are not candidates for CABG surgery. In patients with UA/NSTEMI or post-STEMI, coronary anatomy should be known to be suitable for PCI prior to administration of prasugrel. Prasugrel may be considered in the management of definite or probable stent thrombosis in patients documented to be compliant with aspirin and clopidogrel. Prasugrel should be administered in combination with daily aspirin therapy. Duration of use beyond the median of 14.5 months from TRITON TIMI-38 has not been investigated. Other areas of interest for prasugrel use include: Use in aspirin allergy: For patients with ACS and/or undergoing PCI who have an aspirin allergy, dual anti-platelet therapy with aspirin and a thienopyridine has been shown to be superior to aspirin alone and is recommended in national guidelines. NOTEREF _Ref255900010 \h  \* MERGEFORMAT 3, NOTEREF _Ref255900012 \h  \* MERGEFORMAT 4, NOTEREF _Ref255900014 \h  \* MERGEFORMAT 5, NOTEREF _Ref255900016 \h  \* MERGEFORMAT 6 Aspirin desensitization may be considered if possible to provide the known benefits of dual anti-platelet therapy. Use of prasugrel monotherapy has not been studied to date. Prasugrel monotherapy is not recommended over clopidogrel monotherapy in these patients until more information is known about the benefits vs. risks. Use in sub-optimal platelet response to clopidogrel: Prasugrel has been shown to exhibit less variability in anti-platelet effect between individuals than clopidogrel. However, there is no evidence to provide additional guidance on the use of prasugrel as an alternative to clopidogrel in patients with a sub-optimal platelet response at this time. Prasugrel should be used with caution in the absence of safety or efficacy data in these situations. Use when thienopyridine plus proton-pump inhibitor (PPI) is indicated: The evidence for the clopidogrel-PPI interaction is conflicting (See VA PBM Services document on clopidogrel and PPI interaction:  HYPERLINK "http://vaww.national.cmop.va.gov/PBM/Clinical%20Guidance/Clinical%20Recommendations/PBM%20Response%20clopidogrel-omeprazole%20FDA%20alert%20(1%2023%2010).doc" http://vaww.national.cmop.va.gov/PBM/Clinical%20Guidance/Clinical%20Recommendations/PBM%20Response%20clopidogrel-omeprazole%20FDA%20alert%20(1%2023%2010).doc). While prasugrel does not appear to have a clinically significant interaction with drugs that elevate gastric pH or those that affect they cytochrome P450 enzyme system and is an appealing alternative, the use of prasugrel as an alternative to clopidogrel in patients that require PPI therapy cannot be recommended in the absence of data that demonstrates safety of prasugrel, a more potent anti-platelet agent, in this patient population likely at higher baseline bleeding risk. Though there is interest in use for additional indications, prasugrels role in other areas has not yet been determined and its use is not recommended until there is supportive evidence available. Several studies are underway that will help to clarify the place in therapy for prasugrel including TRILOGY-ACS (medical management of ACS), TRIGGER-PCI (sub-optimal platelet response with clopidogrel); GeCCO (genotype evaluation of CYP2C19 extensive metabolizers). Individual cases that are outside of these recommendations should be adjudicated at the local facility according to the policy and procedures of its P&T Committee and Pharmacy Services. Prepared April 2010. Contact person: Lisa Longo, Pharm.D., BCPS, Pharmacy Benefits Management Services References Appendix: Pivotal Clinical Trial. StudyEligibility CriteriaEndpoints/InterventionsResults and ConclusionsWiviott (2007) NOTEREF _Ref250925005 \h  \* MERGEFORMAT 15, NOTEREF _Ref250998774 \h 22, NOTEREF _Ref250998775 \h 24 TRITON-TIMI 38 N=13,608 MC, DB, AC, RCT 706 sites, 30 countries, including US Mean duration 14.5 mos Supported by research grants from Daiichi Sankyo and Eli Lilly Inclusion criteria Age e"18; moderate-to-high riska ACS (UA/NSTEMI d"72hr of symptom onset; STEMI and primary PCI d"12hr of symptom onset; post-STEMI >12hr and d"14 days after symptom onset with planned PCI Exclusion criteria Cardiogenic shock, refractory ventricular arrhythmia, NYHA IV HF, fibrinolytics within 24 hr, active internal bleeding, bleeding diathesis, increased bleeding risk, hemorrhagic stroke, intracranial neoplasm, AV malformation, aneurysm, ischemic stroke d"3 mos, INR >1.5; platelets <100K/mm3; Hgb <10g/dL; thienopyridine d"5 d of PCI; oral anticoagulation or anti-platelet that cannot be discontinued for study duration; daily use of NSAID sor COX-2 inhibitors; pregnant or breastfeeding, severe hepatic dysfunction, intolerance or allergy to ASA or thienopyridinesTreatments PRAS 60mg LD, 10mg/d MD CLOP 300mg LD, 75mg/d MD *LD admin only after coronary anatomy known to be suitable for PCI in UA/NSTEMI, post-STEMI, up to 24h prior to PCI Primary Endpoint Composite of CV death, nonfatal MI, nonfatal CVA Secondary Endpoints Stent thrombosis; Composite of CV death, nonfatal MI, nonfatal CVA, or rehospitalization due to cardiac ischemic event; 30d, 90d event rates for primary endpoint and composite of CV death, nonfatal MI, urgent TVR Efficacy analysis based on ITT; Safety analysis used treated data setBaseline: Mean age 61yr; UA/NSTEMI 74%; STEMI 26%; 99% PCI; 95% stent; LD before PCI 25%, during PCI 74%; >1hr post-PCI 1% Key Efficacy and Safety Endpoints PRAS CLOP HR Efficacy (n=13,608) N=6813 N=6795 Primary-composite of CV death, nonfatal MI, nonfatal CVA 9.9%* 12.1% 0.81 (0.73-0.9) Stent thrombosis (not prespecified) 1.1%* 2.4% 0.48 (0.36-0.64) Composite of CV death, nonfatal MI, nonfatal CVA, rehospitalization for ischemia 12.3%* 14.6% 0.84 (0.76-0.92) Composite of CV death, nonfatal MI, urgent TVR (30 and 90d) NR NR 0.78 (0.69-89) Safety (n=13,457) N=6741 N=6716 Non-CABG TIMI major bleeding 2.4%* 1.8% 1.32 (1.03-1.68) Life-threatening bleeding 1.4%* 0.9% 1.52 (1.08-2.13) Fatal bleeding 0.4%* 0.1% 4.19 (1.58-11.11) TIMI minor or major bleeding 5%* 3.8% 1.31 (1.11-1.56) CABG-related TIMI major bleeding (3% of population) 13.4%* 3.2% 4.73 (1.9-11.82) Net Clinical Benefit Composite of CV death, nonfatal MI, nonfatal CVA, non-CABG nonfatal TIMI major bleeding Prior TIA/CVA (n=518) 23%* 16% 1.54 (1.02-2.32) Age e"75, wt <60 kg, or history of CVA/TIA (n=2667) 20.2% 19% 1.07 (0.9-1.28) STEMI (n=3534) 12.2%* 14.6% 0.81 (0.67-0.97) DM (n=3146) 14.6%* 19.2% 0.74 (0.62-0.89) *p <0.05; difference due to reduction in nonfatal MI with prasugrel (7.3%* vs. 9.5%) Other adverse events: increase in malignancies (lung, colon, prostate) of 1.5% vs. 1.2%; significance unclear Conclusions: Prasugrel treatment led to significant reduction in primary endpoint of CV death, nonfatal MI, or nonfatal CVA compared to clopidogrel, which was offset by an increased risk of bleeding. Patients e"75 yr or wt <60 kg showed no net benefit, patients with prior TIA/CVA showed net harm, and patients with STEMI or DM showed net benefit with prasugrel. Study assessment: Timing of LD and clopidogrel LD used may have favored prasugrel Results driven by nonfatal MI; definition changed during study which resulted in more events, clinical significance of biomarker positive events is controversialAC=active comparator; ASA=aspirin; CAD=coronary artery disease; CV=cardiovascular; CVA=cerebral vascular accident; DB=double-blind; HF=heart failure; LD=loading dose; MC=multicenter; MD=maintenance dose; MI=myocardial infarction; MN=multinational; NYHA=New York Heart Association; NR, Number randomized; RCT=randomized controlled trial; TVR=target vessel revascularization; aModerate-to-high risk=TIMI risk score of e"3; TIMI Risk (one point each): age e"65; e"3 CAD risk factors; known CAD with >50% stenosis; ASA use in past 7 days; severe angina within preceding 24 hrs, elevated cardiac markers     Prasugrel Monograph Updated version may be found at  HYPERLINK "http://www.pbm.va.gov" www.pbm.va.gov or  HYPERLINK "http://vaww.pbm.va.gov" http://vaww.pbm.va.gov  PAGE 11 STRICTLY CONFIDENTIAL PRE-DECISIONAL DELIBERATION INFORMATION Prasugrel Monograph DRAFTUpdated version may be found at  HYPERLINK "http://www.pbm.va.gov" www.pbm.va.gov or vaww.pbm.va.gov PAGE 14Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up to $20,000 for unauthorized disclosure. . Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 Guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction executive summary. J Am Coll Cardiol. 2007;7(50):652-726. . Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA Guidelines for the management of patients with ST-elevation myocardial infarction: a report of the Amercian College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2004; accessed at  HYPERLINK "http://www.acc.org/qualityandscience/clinical/guidelines/stemi/STEMI%20Full%20Text.pdf" http://www.acc.org/qualityandscience/clinical/guidelines/stemi/STEMI%20Full%20Text.pdf (January 10, 2009). . Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med. 1998;339(23):1665-71. . Steinhubl SR, Berger PB, Mann JT, 3rd et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial (CREDO). JAMA. 2002;288-2411-20 . Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358:527- . Kushner FG, Hand M, Smith SC, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update. Circulation. 2009;120:2271-2306. . Prasugrel (Effient) Prescribing Information. Eli Lilly and Company, Indianapolis, IN. July 2009. . Rehmel JLF, Eckstein JA, Farid NA, et al. Interactions of two major metabolits of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab and Dispos. 2006;34:600-7. . Plavix Product Information. Bristol-Myers Squibb/Sanofi Pharmaceuticals. Bridgewater, NJ. May 2009 . US Food and Drug Administration. Pharmacology review for prasugrel. Available at:  HYPERLINK "http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000_Pharm_P1.pdf" http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000_Pharm_P1.pdf (accessed on October 16, 2009. . Wiviott SD, Trenk D, Frelinger AL, 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 2VX\pr4 6 ` r = F ̿zozdzYLChaHhwRCJh6h~SOJQJaJh&{h&{CJaJh3C<6CJ]aJh#6CJ]aJh&{h&{6CJ]aJhr9h#CJOJQJhr9h&`CJOJQJhr9h~SCJOJQJh[OJQJhT!nOJQJhr9h~SCJOJQJhr9hCJOJQJ^Jhr9hHsCJOJQJhMhMOJQJaJhr9h~SOJQJ2\r6 ^ _ fg  qr"gdE="gdv  & F^gdv"gd![gd  & F^gdwRgdwRgdr9gdP7[$d&d-DM NPgdaM -DM gdM   F p  V \ ] ^ _ d ) 8 < D c w NTW&SUVcefgkĻĻĻİĎ~ hGyCJhaHB*CJphhaHhaHB*CJph hvCJ haHCJhaHhvCJhaHh![CJaJhaHhUG4CJhaHh![CJ h CJhaHho_CJhaHh~SCJhaHhwRCJhaHhPmUCJhaHhCJ1kr):<gmnw8; Q/06>   [\^|$=EO_lr|⸬⸬ h[#CJ hCJ h:8CJ h CJ hE=CJh+hvCJ hCJ h+CJ h{gCJh]jhH CJ h 8CJ hGyCJ hC|>CJ hvCJ hH CJ?}257PU^)<>?^_`" 2 4 5 8 W \ b c d žžܸ販~~xr hu CJ h<CJ hy<CJ hCJ h/%oCJ h&CJh%h~SOJQJaJ h+CJh+huCJ huCJ hCJ hu CJ\ hS9?CJ\ h=CJ\hC|>hC|>CJ hC|>CJ hw}CJ h 8CJ hCJ hE=CJ h[#CJ+r|}`ay#z#P%Q%d)e)**++B.gdkgd`  & F^gd+"gdu"gd 8gd"gdC|>gdC|>"gdE=gdwRd e f g "!t!!"""""A#O#Y#l#v#x#z########$l$$ú~ulclcZlZcZh&hiuCJh&h2CJh&h*8CJh&h~UCJh&h GCJh&h`CJh&hI}CJjh&h:{0J!CJUh&hCJh&h<CJh&h0CJh&hwCJh&hy<CJ h 8CJ h&CJ h0CJ hCJ hCJjh0J!CJU!$$% %%%%%%%8%9%I%J%K%L%N%O%Q%d%m%%%%%&+&,&G&y&z&{&|&}&~&񶰪wm^jh.bh&0J!CJUh.bh&CJH*jh.bh0J!CJU hp_CJ hCJ hZCJ hryCJ h-CJ h KCJ huRvCJ hI}CJ h2CJ"j}h&h2CJH*U h)QCJH*"jh&h2CJH*Uh&h2CJH*jh&h2CJH*U"~&&&&&&&&&&'1'f'n''''''''''''C((((((((()#)c)e)**(***;͸͸͸͸Ǧ|oh%hkOJQJaJh7 hkCJ h{gCJh7 h~SCJh7 h7 CJh7 hNpCJ hCJ h.bCJ hLuCJ hQ9CJh7 hryCJ hZCJ hryCJjhp_0J!CJU hZCJH*jh.bh.b0J!CJUh.bh.bCJH******++++++++,3,B,Z,[,\,d,e,f,r,z,~,,,,,,,,ùìwnenene\nVnMeMnMwh*,h3*CJ h 8CJh*,hUXCJh*,hDCJh*,h*OJQJaJ+jh%h]V0J!5>*OJQJUaJ,,,,- - - - - -5-H-O-c-|-------->.?.A.B.C.F.O.q... /翶wne\eS\Sehkh^CJhkh3^CJhkhiCJh*,hiCJjh*,0J!CJUh*,h3^CJ h 8CJh*,hUXCJh*,h:u<z<<====>(?/A////// 00|00000 1 11111!1"1c1e111N2a2b2c2d2e2f2223ƴЦ|sjajhkh?gCJhkhuCJhkhWuCJhkhiCJjhlI0J!CJU h]VCJ hlICJhkhznCJ h)QCJH* hlICJH*"jwhlIhlICJH*UhlIhlICJH*jhlIhlICJH*U h+CJhkh3^CJhkh`5CJhkh\CJ$3333!4r4444j5x55556666(6666666 717H77777778P8p8x8892939q9r99999غ~~~~ hsgCJ hCJ hACJ h(CJ hCJjhsg0J!CJU hCJ hCJ hRdCJ huCJ h{gCJ h;+CJ h+CJ hvCJhkh?gCJ h 8CJhkhuCJjhkh?g0J!CJU/99:::::;:<:>:V:[:::;;;u<y<z<<<<<<<ȵȯveLev0jh%h5>*H*OJQJUaJ!h%h5>*H*OJQJaJ*jh%h5>*H*OJQJUaJh%h~SOJQJaJh},~h},~CJ h},~CJH* hBCJ h},~CJ%jh;+h;+0J!CJOJQJUhk5CJOJQJhT!n5CJOJQJh+ hCJjh0J!CJU hsgCJ hCJ<<<<= =n=q==========*>.>K>c>e>>>>>(?-?d???@ʻvi`W`Q` hCJhhEACJhh6CJh%h~SOJQJaJhhgB*OJQJphh-B*OJQJphhhB*OJQJphhhNB*OJQJphhB*OJQJphhhOB*OJQJph!h%h~S5>*H*OJQJaJ*jh%h5>*H*OJQJUaJh)Q5>*H*OJQJaJ@@@@@@@@@@@@@@A:A;A*H*OJQJaJ0jh%h5>*H*OJQJUaJ!h%h5>*H*OJQJaJ*jh%h5>*H*OJQJUaJh%h~SOJQJaJhhNCJhh6CJj*hhlICJUhhg0JCJjqhhlICJUjhhgCJUhhgCJABB B:BZB~BBBCCdDeDfD{DhEiEE7F8FJF˾ثؘtjZjMBhPB>*CJOJQJh;k%h;k%B*CJphh;k%5B*CJOJQJphh;k%B*CJphh Y5B*CJOJQJphh B*CJphh YB*CJph$h h 5B*CJOJQJph$hh 5B*CJOJQJphhha8B*CJphhhEAB*CJphhh B*CJphhhNB*CJphhhE<B*CJphfDhEiE8FGGGGHHHH:IzIIkJJ:R*OJQJaJh%hOd>*OJQJaJh%hXiOJQJaJh%h~SOJQJaJh 85>*CJOJQJh$5>*CJOJQJh^h^5>*CJOJQJh^5>*CJOJQJGHHHH*HIHHHHHHHHII I#I$I4I5I7I8I9I:IJIKIyIzIKJYJkJͿzoi`Wh{ghoCJh{gh{gCJ h{gCJh)QCJH*OJQJ*j^hOdhOdCJH*OJQJUhOdhOdCJH*OJQJ$jhOdhOdCJH*OJQJUh]jhXi5CJOJQJh]jho5CJOJQJh]jhoCJh]jha8CJh hoCJh ha8CJh hNCJ h CJkJwJJJJJJJKKKKLLLLLLLLM MM:NMNSNbNlNNNNNNO$O%OHOROsOtOιΰΧΰΰzqqqzqzzzkek h`CJ h5oCJh]jheCJh]jhWlCJh]jh5(CJh]jh0CJ hzCJjh( 0J!CJUh]jh~SCJh]jh=!CJjh$90J!CJUh]jhXiCJh]jhCJh]jh~SOJQJh}OJQJh]jhOJQJh]jhXiOJQJ'tOO P1P2PLPMP]P^P`PaPbPcPeP~PPPQQQhQiQkQQQQQQQQQQRR4R5R6R8R9R:R;R¯ysysysymsymsysgss h}CJ hw?CJ h]jCJ h#CJjhZ 0J!CJU hmeCJh]jh2CJh]jh5(CJ h{gCJ h5oCJjh@0J!CJU h)QCJH* h@CJH*"jh@h@CJH*Uh@h@CJH*jh@h@CJH*U h@CJ h:KCJ(;R $$Ifa$gdP<WWW%h$If^h`gdP<kdL $$Ifl֞ ^," F*v. t0644 laytP<WWWWWWW $$Ifa$gdrq> $$Ifa$gdP<WWW%h$If^h`gdP<kdM $$Ifl֞ ^," F*v. t0644 laytP<WWWWWWW $$Ifa$gdrq> $$Ifa$gdP<WWWWWWWWWWWXXX X XXX X!X"X#X$X&X6XAXBXFXGXKXLX\X]XcXdXhXiXkXmX~XXX񴧗|rh}h}5CJh0chNCJOJQJaJh0cCJOJQJaJhP<h|y5CJOJQJaJh_5CJOJQJaJhP<h&5CJOJQJaJhP<h0cCJOJQJaJhP<h=PCJOJQJaJhP<h&CJOJQJaJhP<h|yCJOJQJaJ)WWX%h$If^h`gdP<kdN $$Ifl֞ ^," F*v. t0644 laytP<XX XX!X#X%X $$Ifa$gdrq> $$Ifa$gdP<%X&XBX% $IfgdNkdO $$Ifl֞ ^," F*v. t0644 laytP<BXGXLX]XdXiXlX $$Ifa$gdrq> $$Ifa$gdP<lXmXX% gdNkdP$$Ifl֞ ^," F*v. t0644 laytP<XXXXY YY%]&]:]cc'cXeYefffg g0g $$Ifa$gd gd} ! 0^`0gd1  !gdOdXXXXXXXXXXXYY YYYYYCJ h#3WCJ hoCJh%h~SOJQJaJhhCJOJQJaJhhCJH*OJQJaJhYCJOJQJaJhJKCJOJQJaJhCJOJQJaJh( BCJOJQJaJhJKh( BCJOJQJaJh( Bh( BCJOJQJaJolplllllllmmm:m;mmmmmmmmmmmmmmmnnnnnoożm؛ggaga htCJ hcCJ"j(h%<h%<CJH*Uh%<h%<CJH* h?CJ hQCJ h<CJ h^^CJhr9h`/*OJQJhCOJQJh1OJQJh#3WhNCJ h%<CJ h CJ h)QCJH*jh%<h%<CJH*U h%<CJH*"j(h%<h%<CJH*U!oooo8oiosooooooooooooo p pppppppp0p9p;pմtf`ZT ho8?CJ h.JOCJ heCJhmeh?5CJOJQJhmehme5CJOJQJ h*CJh^Yh1CJ h)QCJH*"j)h^Yh^YCJH*Uh^Yh^YCJH*jh^Yh^YCJH*Uh^YhyjCJh^Yh_vCJh^Yh]CJh^YhtCJ htCJ h^^CJjh%<0J!CJU;p=pJpOp`pjpqp|ppppppppqqqqqqqq2q3qCqDqFqGqHqIqJqdqqq}r~rrrrrrrrüߵգߵߝoߵ"j*hK,hK,CJH*U h%CJ h)GCJ ho8?6CJhOdh1CJ hMw&CJ"j*hK,hK,CJH*U h)QCJH* hK,CJH*"j)hK,hK,CJH*UhK,hK,CJH*jhK,hK,CJH*U h CJ h6CJ h+^CJ+rrrrrrrrrrrs$sssssssssssssssssssǬxng]VOVn h]5CJ h 5CJh=Ph=P5CJ h%5CJh=Ph,m5CJh,mB*phhMw&ho8?CJ hMw&CJH*"j+hMw&hMw&CJH*UhMw&hMw&CJH*jhMw&hMw&CJH*U hCJ hMw&CJ h)QCJH* hK,CJH*"j+hK,hK,CJH*UhK,hK,CJH*jhK,hK,CJH*Ussttt(t/tMtNtXtYtbtctltmtotptttuttttttttttttttt޿ޑrrcVh]5CJOJQJaJhP<hs@~CJOJQJaJhP<hs@~5CJOJQJaJhP<h,mCJOJQJaJhP<h=PCJOJQJaJh%<5CJH*OJQJaJhP<h=P5CJOJQJaJhP<h`/*CJOJQJaJhP<h@5CJOJQJaJhP<h,m5CJOJQJaJh%<h~SCJH* h%<CJH* 1t4t=tEtItMtNtmtptuttttt $IfgdP<h$If^h`gdP<Ff- $$Ifa$gdP< ttt" $Ifgd  kd0$$Ifl֞7 L=]," 8 7 t0644 laytP<ttttttt $Ifgd  $$Ifa$gd  tt"kd1$$Ifl֞7 L=]," 8 7 t0644 laytP<tttttttttt u uuuuuuu(u)u,u-u.u2u3uDuEuJuKuOuPuSuTuǻǻqbqbqbqbqbqbhP<h,mCJOJQJaJhP<h=PCJOJQJaJhP<h,m5CJOJQJaJhP<h=P5CJOJQJaJhP<h]CJOJQJaJh]CJOJQJaJhs@~CJOJQJaJhK,CJOJQJaJhP<h]5CJOJQJaJh%<5CJH*OJQJaJhs@~5CJOJQJaJ tttt uuuu $IfgdP< $$Ifa$gdP<h$If^h`gdP<uu"kd 2$$Ifl֞7 L=]," 8 7 t0644 laytP<u)u.u3uEuKuPuTu $IfgdP< $$Ifa$gdP<h$If^h`gdP<TuUu"kd3$$Ifl֞7 L=]," 8 7 t0644 laytP<TuUuvxvzv|v~vvw$w&w(w*w,wwwww xx"xBxNxPxjxlxxxxxxdz估估伃wwwwwhaWaQ h%<CJhFKh%<6CJ h%<6CJhs@~h1CJOJQJaJh!CJOJQJaJhs@~hs@~CJOJQJaJhs@~h,mCJOJQJaJhs@~h=PCJOJQJaJhs@~CJOJQJaJhs@~CJH*OJQJaJh%<h%<CJOJQJaJh%<CJOJQJaJh%<CJH*OJQJaJhP<h`/*CJOJQJaJUuzv&wwxxx~~7]#$-Ums$Ifgd1gd%< Z^Z`gds@~ Zgds@~ ZZ^Z`gd%<dzfzzzzzzzT}V}\}^}}}}}}}}~~~~~~~~~~!"23567 $o"j5hK,hK,CJH*U h%<6CJhFKh%<CJ"j5hK,hK,CJH*U hK,CJ"j4hK,hK,CJH*U h_CJ h%<CJ h)QCJH* hK,CJH*"j4hK,hK,CJH*UhK,hK,CJH*jhK,hK,CJH*U)$%5689:;UVWYZ\]d"#$-y‚ǻǬλ|slf`ZTZ hLgCJ h"CJ hxCJ hX)_CJ h16CJhFKh)GCJh1h%<CJ h:8CJ hRCJ hCJ hbCJhmeh%<CJ h%<CJj6hbCJH*UjhbCJH*U hbCJH* h)QCJH*jhK,hK,CJH*UhK,hK,CJH*"j 6hK,hK,CJH*U‚Â݂ނ&)*OPfs}σ؃ك#EF`aqrtuwτ !kۅ܅ hmCJ hX)_CJ h5CJ"j7hhCJH*U h[#CJ hiCJ h*)0CJ hLgCJ hCJ h"CJ h)QCJH* hCJH*"j7hhCJH*UhhCJH*jhhCJH*U+ %&@AQRSTU^rĆņujfbf^f^b^ZbVbRh~Sh^Yh[#hth]h h)Q5H*OJQJ)j}8h^Yh^Y5H*OJQJUh^Yh^Y5H*OJQJ#jh^Yh^Y5H*OJQJUhr9h~SOJQJ h1CJ hX)_CJ h"CJhh"CJH* h)QCJH*jhhCJH*U hCJH*"j8hhCJH*U lm,@A[\lmnop"DqӉԉ·wsssoZw)j>h^Yh^Y5H*OJQJUh~Sh^Yh)Q5H*OJQJ)jd>h^Yh^Y5H*OJQJUh^Yh^Y5H*OJQJ#jh^Yh^Y5H*OJQJUhr9h~SOJQJh=a%hU->CJOJQJaJh=a%hU->5CJOJQJaJhU->h~S5CJhU->hU->5CJ h%5CJhU->"s}?9$Ifkd8$$IflF ,"     t06    44 lapyty $$Ifa$gd=a%qk__ $$Ifa$gd=a%$Ifkd9$$IflF ,"    t06    44 laytyÇȇqk__ $$Ifa$gd=a%$Ifkd:$$IflF ,"   t06    44 laytyȇɇЇՇڇqk__ $$Ifa$gd=a%$Ifkd;$$IflF ,"   t06    44 laytyڇۇqk__ $$Ifa$gd=a%$Ifkd;$$IflF ,"   t06    44 laytyqk__ $$Ifa$gd=a%$Ifkd0<$$IflF ,"   t06    44 layty qk__ $$Ifa$gd=a%$Ifkd<$$IflF ,"   t06    44 layty!&+qk__ $$Ifa$gd=a%$IfkdJ=$$IflF ,"   t06    44 layty+,p@Az{qomommgmemo !kd=$$IflF ,"   t06    44 layty ӊ؊?AGOZ[uvʿʷyj`NGj h^YCJH*"j?h^Yh^YCJH*Uh^Yh^YCJH*jh^Yh^YCJH*U heCJ h}9CJ hd&>*\h}h^Y6CJh}h~S6CJh~Sh hmehr9h~SOJQJhmeOJQJh)Q5H*OJQJ#jh^Yh^Y5H*OJQJUh^Yh^Y5H*OJQJ)j^?h^Yh^Y5H*OJQJǓ"5yz{͍΍ލߍwdV@Vd*jX@h^Yh^YCJH*OJQJUh^Yh^YCJH*OJQJ$jh^Yh^YCJH*OJQJUhHu5CJOJQJhw}5CJOJQJhHuhHu5CJOJQJ hHuCJhHuh~S>*CJOJQJaJhHuh>*CJOJQJaJh}>*CJOJQJaJh@h+b-CJ h.wQCJ heBCJ h@CJjh^Yh^YCJH*U h)QCJH*{rsz{SNEFuvwgdQgdOvo&$d %d &d 'd N O P Q gd=ngdHuߍ6>ʎ̎ 4N#$>?OPQR¼¼­ȧugQguu*j@h h CJH*OJQJUh h CJH*OJQJ$jh h CJH*OJQJUha5CJOJQJh1 5CJOJQJhhCJ hOvoCJ heCJh=nh}9CJ h}9CJ h=nCJ hHuCJ hCJhHuhHuCJOJQJ$jh^Yh^YCJH*OJQJUh)QCJH*OJQJRS 9:JKLMNxDEuvwȽȪ{pjdjd^djPh}5>*CJOJQJ\ hXKCJ h>CJ hG CJh+b-5CJOJQJh)QCJH*OJQJ*jRAh h CJH*OJQJUh h CJH*OJQJ$jh h CJH*OJQJUhG 5CJOJQJh1 h}95CJOJQJh1 haCJ h1 CJ ho8?CJ haCJh1 h1 5CJOJQJw46؝(.: $$Ifa$gd=a%gdQ wŘ̘8CKPbFHKgh,lpҽ~un heBCJ\h)QCJH*\hICJH*\%jAhIhICJH*U\hIhICJH*\jhIhICJH*U\ hICJ\ h7N]CJ\ heCJ\ hkCJ\ ho=nCJ\ h CJ\ hQCJ\ h CJ\!heBhQ5>*OJQJ\aJ$prȜʜΜМҜԜ *,0246D֝؝&(,:<>欄{k^k^k^kOkhaUhNOCJOJQJaJhNO5CJOJQJaJhaUhNO5CJOJQJaJhkhkCJOJQJ\aJhk5CJ\h%5CJ\ hNOCJ\ hkCJ\%jBhq?hq?CJH*U\h)QCJH*\hq?CJH*\%jLBhq?hq?CJH*U\hq?hq?CJH*\jhq?hq?CJH*U\:<>HT^jtJ>>>>>> $$Ifa$gd=a%kdFC$$Iflr H<# T t0H$44 laytNO>RThjȞʞdnpz|  ǸǙ|hNO5CJOJQJaJhaUhNO5CJOJQJaJhaUhNOCJOJQJaJhNOhNO6CJOJQJaJhNOhNOCJOJQJaJhRhNOCJOJQJaJhGhNOCJOJQJaJhhNOCJOJQJaJhNOCJOJQJaJ0tʞԞdp| FfG $Ifgd=a%FfD $$Ifa$gd=a%!&+, ٠ $IfgdNOFfM $Ifgd=a%FfJ $$Ifa$gd=a% !%&*+, à٠:;CDEstɺɺ񭝐m_I_m*jYQh%hq?H*OJQJUaJh%hq?H*OJQJaJ$jh%hq?H*OJQJUaJh%hXK5>*OJQJaJhq?5>*CJOJQJhq?hQCJOJQJ\aJhq?CJOJQJ\aJhNOhNOCJOJQJaJhNO5CJOJQJaJhRhNOCJOJQJaJhNOCJOJQJaJhaUhNOCJOJQJaJ$7." $$Ifa$gd=a% $IfgdNOkdO$$Iflֈ Hr<# ** t0H$44 laytNO$(,3: $$Ifa$gd=a%:;DEŢ72000gdQkdP$$Iflֈ Hr<# ** t0H$44 laytNOס(KRiâĢŢ<>?IyѤſ˹˹ų||sehosnhosn5CJOJQJho=nho=nCJhq?ho=nCJhq?h~SCJ ho=nCJho=nh~SCJho=nhUCJh%h~SOJQJaJ h nCJ h'CJ hCJ hiCJ hxCJh%hXK5>*OJQJaJ$jh%hq?H*OJQJUaJh)QH*OJQJaJ!Ţ>?z2eɫ׫ $$$Ifa$gdp$$IfgdowѤҤ-.012WXYv(ߨ휖uokg\Q\h_\5CJOJQJhow5CJOJQJh~Sh+b- ho=nCJhe.he.CJH* he.CJ hgCJH*hghgCJH* hgCJhosnh~S5OJQJ*jSRhq?hq?CJH*OJQJUh)QCJH*OJQJ*jQhq?hq?CJH*OJQJUhq?hq?CJH*OJQJ$jhq?hq?CJH*OJQJU(056PQabcde ϩЩdȲ֧顛q֧ևkek[hiphip5CJ h);*CJ hipCJ*jMShq?hq?CJH*OJQJUhip5CJOJQJh_\howCJ h_\CJ howCJh)QCJH*OJQJ*jRhq?hq?CJH*OJQJUhq?hq?CJH*OJQJ$jhq?hq?CJH*OJQJUhow5CJOJQJh_\5CJOJQJ!+ɫΫԫիɾɳr^L=.=hp5CJOJQJ\aJh{5CJOJQJ\aJ"h>4h>45CJOJQJ\aJ'h%h~S>*B*OJQJ\aJph'h%h>4>*B*OJQJ\aJphh%h>4OJQJaJh_\how5CJOJQJ h_\CJ hpCJ hf\CJhe.5CJOJQJh)QCJH*OJQJ$jhq?hq?CJH*OJQJUhq?hq?CJH*OJQJ*jShq?hq?CJH*OJQJUի֫׫۫ +,02346QSTUWghkló}}p`}h{h{6CJOJQJaJh{6CJOJQJaJh>4h{CJOJQJaJh CJOJQJaJh{CJOJQJaJh>4h>4CJOJQJaJhKvh>46CJOJQJaJhKv6CJOJQJaJh{5CJOJQJ\aJ"h>4h>45CJOJQJ\aJhp5CJOJQJ\aJ%RJ<< $$$Ifa$gd{$$IfkdGT$$IflFjrb 0    4 lapyt{ ufXX $$$Ifa$gd{$ h$Ifgd{kd@U$$IflFjrb0    4 layt>4,35ufXX $$$Ifa$gd{$ h$Ifgd{kdU$$IflFjrb0    4 layt>456MTVufXX $$$Ifa$gd{$ h$Ifgd{kdV$$IflFjrb0    4 layt>4VWhijum__ $$$Ifa$gd{$$IfkdVW$$IflFjrb0    4 layt>4jkufXX $$$Ifa$gd{$ q$Ifgd{kdX$$IflFjrb0    4 layt>4ƬϬufXX $$$Ifa$gd{$ q$Ifgd{kdX$$IflFjrb0    4 layt>4ŬƬάЬѬ .MNOPj}ݭ'TҿҿҬyysgaa[ h1)CJ hNRvCJjh0J!CJU hDCJ hHhCJ h?CJ hCJh%h~SOJQJaJ'h&h~S5>*B*CJOJQJph%h&h~SB*CJOJQJaJph%h&hpB*CJOJQJaJph%h&h{B*CJOJQJaJphh>4h>4CJOJQJaJh{CJOJQJaJ#ϬЬwhZZ $$$Ifa$gd{$ q$Ifgd{kdlY$$IflFjrb0    4 layt>4OPjno9:Kwuusqsqqllexgdv67gdZkdZ$$IflFjrb0    4 layt>4 o~ 0Ʋ`|سٳڳ}1@C lzȷڷMsQkκuŻ⾱~~ h9CJ heBCJ hPBCJ hp_CJhh~SCJ hZCJ hDV/CJ h1CJhVXh~SOJQJaJ h+b-CJ h yCJ hCJ hUCJ h>CJ h#ICJ hUAtCJ hA^CJ hDCJ h1)CJ hNRvCJ0Żǻֻ$CD12QdfR[uxzv*acg689:KmľĵľӾөөӑөӑ{u{ hCJ h>ICJhv67hv675>*OJQJaJ h@CJ hMw&CJ hPBCJ hw}CJ hCJ hF6CJhZh:KCJ hZCJhh:KCJ h:\CJ h9CJh_h:\CJh_h9CJ h_CJh_h_CJ hRCJ-:@FG :B"$%&?9:JKLMNOijz{|}ܺv"jE[h>Ih>ICJH*U h>ICJH*"jZh>Ih>ICJH*Uh>Ih>ICJH*jh>Ih>ICJH*Uh{ch{cCJ hgR5CJ h,CJ hCJ h 0`CJ h>ICJ h:CJ hOCJ hCJ hv67CJ hLCJ.K%&%&xyz0$Ifgd%$d&dNP"gd: $ & F"a$gdgR 7$8$H$gdh & F"7$8$H$gdgR 7$8$H$^gdgR & F"gdgdZ}~ 4PS#%&-\]߻鵬ymf h8,CJ]hhh:5CJ]hhhgR5CJ]hgRhgRB*CJ^Jph h>CJ hA{CJ hCJ h 0`CJh{ch{cCJ h>ICJ"j?\h>Ih>ICJH*U"j[h>Ih>ICJH*Uh>Ih>ICJH*jh>Ih>ICJH*U h>ICJH*%]F6uvdeY"mtswxy···xqkekek_[h~S hCJ h,CJ hCJ h:5CJhh:5CJOJQJhh0J5CJOJQJ$jhh5CJOJQJUhh5CJOJQJh5CJOJQJh:hgR5CJOJQJh:CJOJQJ hgRCJ]hhhhCJ]hhhC!zCJ]hhhgRCJ]yz0:H_aopܮssfSEh$9hu5H*OJQJaJ$jh$9hu5H*OJQJUaJh$9hu5OJQJaJhu55OJQJ\aJh$9hu55OJQJ\aJh%h%h~SaJ h%aJ haJ h~S>*h~Sh5B*OJQJphhh5B*OJQJphhf5B*OJQJph hr9h~S5B*OJQJph#hr9h~S5>*B*OJQJph0H`akd\$$Ifl4\) ~2LJ  t(064 lap(ytu5 $IfgdC$If PRWɾɳ}pfpf\RfpheOJQJaJh*OJQJaJhu5OJQJaJh$9hu5OJQJaJ$j^h^S\H*OJQJUaJ$jp^h^S\H*OJQJUaJjh^S\H*OJQJUaJh^S\H*OJQJaJh)QH*OJQJaJ$jh$9hu5H*OJQJUaJh$9hu5H*OJQJaJ*j]h$9hu5H*OJQJUaJa 34KLMNOPQRSTUVWXpr$If<>FHNp $%0./0]Ϳܿܭܢ}p}p}p}pcUphrThu5H*OJQJaJhrThVOJQJaJhrThu5OJQJaJhrThu55OJQJaJhL?hu5OJQJaJhu5OJQJaJhu55OJQJaJ#h$9hu5H*OJQJaJmH PsH Phq {OJQJaJmH PsH Phq {H*OJQJaJmH PsH P h$9hu5OJQJaJmH PsH P#h$9hu55OJQJaJmH PsH P! !:;% $$Ifa$gdrTK$$IfK$ $IfgdZ$If $Ifgd$9,$$IfK$kdj_$IfK$L$l\vJdqF  t(0644 lap(ytrT06<LFkd`$IfK$L$l\vJdqF t0644 laytrT$IfK$ $$Ifa$gdrTK$LMqw|\TFFT $$Ifa$gdrTK$$IfK$kd3a$IfK$L$l\vJdqF t0644 laytrT]pPbJ6Pp<=>UvvkaTkI?hHOJQJaJhH5OJQJaJhJhJOJQJaJhJOJQJaJhJ5OJQJaJhVOJQJaJhu5OJQJaJhrTh1BOJQJaJhrTh^S\CJOJQJaJhrTh^S\OJQJaJhrTh^S\5OJQJaJhrThVOJQJaJhrThu55OJQJaJhrThdQaOJQJaJhrThu5OJQJaJhx:OJQJaJ\TFFT $$Ifa$gdrTK$$IfK$kda$IfK$L$l\vJdqF t0644 laytrT:=@O\TFFT $$Ifa$gdrTK$$IfK$kdb$IfK$L$l\vJdqF t0644 laytrTOPbipq\TFFT $$Ifa$gdrTK$$IfK$kdOc$IfK$L$l\vJdqF t0644 laytrTqr\TFFT $$Ifa$gdrTK$$IfK$kdd$IfK$L$l\vJdqF t0644 laytrT\TFFT $$Ifa$gdrTK$$IfK$kdd$IfK$L$l\vJdqF t0644 laytrT\TFFT $$Ifa$gdrTK$$IfK$kdke$IfK$L$l\vJdqF t0644 laytrT/38I\TFFT $$Ifa$gdrTK$$IfK$kdf$IfK$L$l\vJdqF t0644 laytrTIJ~\TFFT $$Ifa$gdrTK$$IfK$kdf$IfK$L$l\vJdqF t0644 laytrT\VN@@N $$Ifa$gdrTK$$IfK$$Ifkdg$IfK$L$l\vJdqF t0644 laytrTFPXz\TFFT $$Ifa$gdrTK$$IfK$kd;h$IfK$L$l\vJdqF t0644 laytrTz|\TFFT $$Ifa$gdrTK$$IfK$kdh$IfK$L$l\vJdqF t0644 laytrT6DPr\TFFT $$Ifa$gdrTK$$IfK$kdi$IfK$L$l\vJdqF t0644 laytrTrt\TFFT $$Ifa$gdrTK$$IfK$kdWj$IfK$L$l\vJdqF t0644 laytrT=>BDh\VVMMMMM $IfgdH$Ifkd k$IfK$L$l\vJdqF t0644 laytrT @BDh ->N}ɿyqfZfRh'ROJQJhps!h~SH*OJQJhps!h~SOJQJhps!OJQJhCOJQJhH0OJQJhL?OJQJh$9OJQJhps!hps!OJQJh$9hu5OJQJaJh]R:h]R:5OJQJaJh]R:OJQJaJh hH5OJQJaJhH5OJQJaJh^S\OJQJaJhHOJQJaJh OJQJaJh611gd'Rkdk$$Ifl\) ~2LJ t064 laytu5 & FL$If^`Lgd]R: & FL$If^`LgdH z78[\jkopƽznzd^d h&0Jjh&0JUh  hT!n0J6] hT!n6]jhT!n6U]hIh&0J6]jh&6U] h&6] h&CJh&6CJ]h&h&5CJ\ha@jha@U h~SCJh$9OJQJhq {h$9OJQJhq {OJQJh'Rh$9H*OJQJ$gd8,bkdl$$IflF/j' 6    4 layt+ $$Ifa$gd+ $Ifgd+lc $Ifgda7kd m$$IflF"[ 'S t06    4 la $$Ifa$$If>?bcqrmnopqst澳斃{p{p{p{papjh= Lh&CJUaJh= Lh&CJaJh= LCJaJ$jh= Lh&0J!CJH*UaJha@ h&]h h&0Jhdh&0J6]jh&6U] h&6] h&CJh&6CJ]h'R6CJ]h&5CJ\h&jh&0JUhA{0JmHnHu&{ywnh\ $$Ifa$gd'R$If $IfgdLkdm$$IflF"[ 'S t06    4 la $$Ifa$$Ifgd'Rbkdln$$IflF 3 6    4 laytx{rlc $$Ifa$$If $IfgdRekdn$$IflF') 3S t06    4 lamE$={yywwjjjjjjj ^`gd= Lkdo$$IflF') 3S t06    4 la /0EFGHI$%&'(=>?@AjklmnŽؽŽؽصتؗyyŽؽŽؽŽؽŽؽh= Lhp_CJaJ$jh= Lhp_0J!CJH*UaJ$jh= Lh.b0J!CJH*UaJh= Lh.bCJaJh+CJaJh= LCJaJ$jh= Lh&0J!CJH*UaJh= Lh&CJaJh= Lh&0JCJaJjh= Lh&CJUaJ/jn,,x-./0K15233445e6789 ;<<<gd'R ^`gd ^`gd ^`gd= L(),m,n,o,q,,,x-y-z-{-|---#.$.ƻvcƻTTjhh&CJUaJ$jhh0J!CJH*UaJhhsgCJaJhhCJaJ$jhhsg0J!CJH*UaJUhh&B*CJaJphhh&CJaJhh= LCJaJ$jhh&0J!CJH*UaJh= Lh&0JCJaJjh= Lh&CJUaJh= Lh&CJaJactivation and aggregation thrombolysis in myocardial infarction 44 trial. Circulation. 2007;116:2923-2932. . Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel. Circulation. 2009;119:2553-2560. . Clopidogrel (Plavix) prescribing information. Bristol Myers Squibb/Sanofi Pharmaceuticals, Bridgewater NJ. March 2010. . US Food and Drug Administration. Summary review for prasugrel. Available at:  HYPERLINK "http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000_SumR.pdf" http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000_SumR.pdf (accessed on October 16, 2009). . Wiviott SD, Antman EM, Gibson CM, et al. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel thrombolysis in myocardial infarction 38 (TRITON-TIMI 38). Am Heart J. 2006;152:627-35. . Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284(7):835-42. . Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-15. . Antman EM, Wiviott SD, Murphy SA, et al. Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention. A TRITON-TIMI 38 analysis. J Am Coll Cardiol. 2008;51:2028-33. . Wiviott SD, Braunwald E, McCabe CH, et al. Intensive oral antiplatelet therapy for reduction of ischemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomized trial. Lancet. 2008;371:1353-63. . Pasceri V, Patti G, DiSciascio GD. Prasugrel vs. clopidogrel. N Engl J Med. 2008;358(12):1298-99. Letter. . Mauri L, Hsieh W, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluding stents. N Engl J Med. 2007;356:1020-9. . Serebrauny V. Prasugrel versus clopidogrel. N Engl J Med. 2008;358(12):1298. Letter . Serebrauny V. Excess rates of nonfatal myocardial infarction in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel (preventing clinical events or chasing enzymatic ghosts). Am J Cardiol. 2008;101:1364-66. . Donahoe SM, Stewart GC, McCabe CH et al. Diabetes and mortality following acute coronary syndromes. JAMA. 2007;298(7):765-75. . Wiviott SD, Braunwald E, Angiolillo DJ, 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 prasugrel thrombolysis in myocardial infarction 38. Circulation. 2008;118:1626-36. . Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomized controlled trial. Lancet. 2009;373:723-31. . Murphy SA, Antman EM, Wiviott SD, 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. . Wiviott SD, Antman EM, Winters KJ, et al. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention. Results of the joint utilization of medications to block platelets optimally (JUMBO)-TIMI 26 Trial. Circulation. 2005;111:3366-3373. . Mahoney EM, Wang K, Arnold SV, et al. Cost-effectiveness of prasugrel versus clopidogrel in patients with acute coronary syndromes and planned percutaneous coronary intervention. Results from the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction (TRITON-TIMI 38). Circulation. 2010;121:71-79. $.n.o....../////00000K1L1M1N1O15262728292333333333344444444445ƾپƾپƾپ٫ƾپٍƾپƾپh= LhZ CJaJ$jh= LhZ 0J!CJH*UaJh= Lh@CJaJ$jh= Lh@0J!CJH*UaJh= LCJaJ$jh= Lh&0J!CJH*UaJh= Lh&CJaJjhh&CJUaJhh&0JCJaJ055555e6f6g6h6i6777778888899999; ; ; ; ; ;<<<孼弩 h~SCJha@h= Lh&B*CJaJphh= Lh&CJaJ$jh= Lh&0J!CJH*UaJh= LhT.CJaJh= LCJaJ$jh= LhT.0J!CJH*UaJ!61+:p8,BP/ =!8"8#$%@^ 9&P1+0:p'R= /!"#$%] }DyK _Ref250920157}DyK _Ref250920158}DyK _Ref250974090}DyK _Ref250974090}DyK _Ref250974090DyK yK Hhttp://vaww.pbm.va.gov/yX;H,]ą'cDyK yK Fhttp://www.pbm.va.gov/yX;H,]ą'c}DyK _Ref250974090}DyK _Ref250925005}DyK _Ref250998770}DyK _Ref250998770}DyK _Ref250925005$$If!vh5 5F555*5v5.#v #vF#v#v#v*#vv#v.:V l  tF065 5F555*5v5.pFytyTkdR$$Ifl֞ ^," F*v.  tF0644 lapFyty$$If!vh5 5F555*5v5.#v #vF#v#v#v*#vv#v.:V l t065 5F555*5v5.ytP<$$If!vh5 5F555*5v5.#v #vF#v#v#v*#vv#v.:V l t065 5F555*5v5.ytP<$$If!vh5 5F555*5v5.#v #vF#v#v#v*#vv#v.:V l t065 5F555*5v5.ytP<$$If!vh5 5F555*5v5.#v #vF#v#v#v*#vv#v.:V l t065 5F555*5v5.ytP<$$If!vh5 5F555*5v5.#v #vF#v#v#v*#vv#v.:V l t065 5F555*5v5.ytP<}DyK _Ref250986437}DyK _Ref250998770}DyK _Ref250925005}DyK _Ref250998774}DyK _Ref2509987750$$If!vh55555#v#v#v:V l  t20555p2ytyD$$If!v h55555555*5 #v#v#v*#v :V l t0555*5 pZyty\kd$$Ifl p@ PzJ* t0$$$$44 lapZyty$$If!v h55555555*5 #v#v#v*#v :V l t0555*5 ytkd$$Ifl p@ PzJ* t0$$$$44 layt$$If!v h55555555*5 #v#v#v*#v :V l t0555*5 ytkd$$Ifl p@ PzJ* t0$$$$44 layt$$If!v h55555555*5 #v#v#v*#v :V l t0555*5 ytkdl$$Ifl p@ PzJ* t0$$$$44 layt$$If!v h55555555*5 #v#v#v*#v :V l t0555*5 ytkdV$$Ifl p@ PzJ* t0$$$$44 layt$$If!v h55555555*5 #v#v#v*#v :V l t0555*5 ytkd@"$$Ifl p@ PzJ* t0$$$$44 layt$$If!v h55555555*5 #v#v#v*#v :V l t0555*5 ytkd*%$$Ifl p@ PzJ* t0$$$$44 layt}DyK _Ref250998770}DyK _Ref250998770}DyK _Ref250998770}DyK _Ref250998770}DyK _Ref250925005}DyK _Ref250998770}DyK _Ref250925005}DyK _Ref251081477$$If!vh5 55855 557#v #v#v8#v#v #v#v7:V l  tF065 55855 557pFytyYkd+$$Ifl֞7 L=]," 8 7  tF0644 lapFyty$$If!vh5 55855 557#v #v#v8#v#v #v#v7:V l t065 55855 557ytP<$$If!vh5 55855 557#v #v#v8#v#v #v#v7:V l t065 55855 557ytP<$$If!vh5 55855 557#v #v#v8#v#v #v#v7:V l t065 55855 557ytP<$$If!vh5 55855 557#v #v#v8#v#v #v#v7:V l t065 55855 557ytP<}DyK _Ref250998770}DyK _Ref250998770}DyK _Ref250998770}DyK _Ref250998770}DyK _Ref250998770}DyK _Ref250925005}DyK _Ref250974090}DyK _Ref250998770}DyK _Ref250998770}DyK _Ref250974090$$If!vh5 5 5 #v :V l  t065 / / pyty$$If!vh5 5 5 #v :V l t065 / yty$$If!vh5 5 5 #v :V l t065 yty$$If!vh5 5 5 #v :V l t065 yty$$If!vh5 5 5 #v :V l t065 yty$$If!vh5 5 5 #v :V l t065 yty$$If!vh5 5 5 #v :V l t065 yty$$If!vh5 5 5 #v :V l t065 yty$$If!vh5 5 5 #v :V l t065 yty}DyK _Ref250974090}DyK _Ref250974090}DyK _Ref250998770}DyK _Ref250974090}DyK _Ref250974090}DyK _Ref250974090}DyK _Ref250974090}DyK _Ref250925005}DyK _Ref250998774}DyK _Ref250998775$$If!vh5 55T55#v #v#vT#v:V l t0H$5 55T5ytNO$$If!v h5 555*5*5555 #v #v#v*#v :V l t0H$5 55*5 ytNOkdD$$Ifl xHrl< !# ** t0H$$$$$44 laytNO$$If!v h5 555*5*5555 #v #v#v*#v :V l t0H$5 55*5 ytNOkdF$$Ifl xHrl< !# ** t0H$$$$$44 laytNO$$If!v h5 555*5*5555 #v #v#v*#v :V l t0H$5 55*5 ytNOkdI$$Ifl xHrl< !# ** t0H$$$$$44 laytNO$$If!v h5 555*5*5555 #v #v#v*#v :V l t0H$5 55*5 ytNOkdL$$Ifl xHrl< !# ** t0H$$$$$44 laytNO$$If!vh5 55*5*55#v #v#v*#v:V l t0H$5 55*5ytNO$$If!vh5 55*5*55#v #v#v*#v:V l t0H$5 55*5ytNO}DyK _Ref250974090}DyK _Ref250974090}DyK _Ref250998770}DyK _Ref250974090}DyK _Ref250974090}DyK _Ref250974090$$If!vh555b#v#v#vb:V l 0555b4pyt{$$If!vh555b#v#v#vb:V l0555b4yt>4$$If!vh555b#v#v#vb:V l0555b4yt>4$$If!vh555b#v#v#vb:V l0555b4yt>4$$If!vh555b#v#v#vb:V l0555b4yt>4$$If!vh555b#v#v#vb:V l0555b4yt>4$$If!vh555b#v#v#vb:V l0555b4yt>4$$If!vh555b#v#v#vb:V l0555b4yt>4$$If!vh555b#v#v#vb:V l0555b4yt>4}DyK _Ref255900010}DyK _Ref255900012}DyK _Ref255900014}DyK _Ref2559000165$$If!vh5555|#v#v#v#v|:V l4  t(06,55L5J5 4p(ytu5}DyK _Ref250925005}DyK _Ref250998774}DyK _Ref250998775$IfK$L$q!vh5q555F#vq#v#vF:V l  t(065q55Fp(ytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$IfK$L$q!vh5q555F#vq#v#vF:V l t065q55FytrT$$If!vh5555|#v#v#v#v|:V l t0655L5J5 4ytu5|$$If!vh55;5b#v#v;#vb:V l65 554yt+$$If!vh5595q#v#v9#vq:V l t065S554$$If!vh5595q#v#v9#vq:V l t065S554|$$If!vh5}55h#v}#v#vh:V l65 554ytx$$If!vh5a(55 #va(#v#v :V l t065S554$$If!vh5a(55 #va(#v#v :V l t065S554^) 2 0@P`p2( 0@P`p 0@P`p 0@P`p 0@P`p 0@P`p 0@P`p8XV~_HmH nH sH tH <`< xNormalCJ_HmH sH tH J@J (U Q Heading 1$xx@&5>*OJQJL@L  Heading 2$x@&5CJOJQJ88  Heading 3$@&5@@  Heading 4$@& 6B*phTT &M Heading 6 <@&5OJPJQJ\^JaJLRL  Heading 7$<@&5CJOJQJ88  Heading 8$@&5DA`D Default Paragraph FontVi@V  Table Normal :V 44 la (k (No List @>@@ 'Title$a$5B*OJQJphJJ@J Subtitle$a$5B*CJOJQJph:B@: Body Text CJOJQJ:@":  Footnote TextCJ0U@10 Hyperlink>*B*4@B4 Header  !8OR8 Table B*CJphF6@bF wR List Bullet 2 & F^@ @r@ Footer  ! CJOJQJ.)@. Page NumberHH % Balloon TextCJOJQJ^JaJ6OQ6 TableFootnoteD"@D Caption $x5CJOJQJ\^O^ `Style Heading 1 + Black xx B*\phFVF NFollowedHyperlink >*B* phT^@T &{ Normal (Web)dd[$\$B* CJaJph8+@8  dE Endnote TextCJ:: dEEndnote Text Char>*@> dEEndnote ReferenceH*L@"L 6 List Paragraph "^m$CJaJj3j 8j Table Grid7:V#0#HYBH %'R Document Map$CJOJQJ^JaJNQN $'RDocument Map CharCJOJQJ^JaJRaR MHeading 6 Char5CJOJPJQJ\^JaJDqD M Title Char5B*CJOJQJphFF MHeading 1 Char5>*CJOJQJPK![Content_Types].xmlj0Eжr(΢Iw},-j4 wP-t#bΙ{UTU^hd}㨫)*1P' ^W0)T9<l#$yi};~@(Hu* Dנz/0ǰ $ X3aZ,D0j~3߶b~i>3\`?/[G\!-Rk.sԻ..a濭?PK!֧6 _rels/.relsj0 }Q%v/C/}(h"O = C?hv=Ʌ%[xp{۵_Pѣ<1H0ORBdJE4b$q_6LR7`0̞O,En7Lib/SeеPK!kytheme/theme/themeManager.xml M @}w7c(EbˮCAǠҟ7՛K Y, e.|,H,lxɴIsQ}#Ր ֵ+!,^$j=GW)E+& 8PK!Ptheme/theme/theme1.xmlYOo6w toc'vuر-MniP@I}úama[إ4:lЯGRX^6؊>$ !)O^rC$y@/yH*񄴽)޵߻UDb`}"qۋJחX^)I`nEp)liV[]1M<OP6r=zgbIguSebORD۫qu gZo~ٺlAplxpT0+[}`jzAV2Fi@qv֬5\|ʜ̭NleXdsjcs7f W+Ն7`g ȘJj|h(KD- dXiJ؇(x$( :;˹! I_TS 1?E??ZBΪmU/?~xY'y5g&΋/ɋ>GMGeD3Vq%'#q$8K)fw9:ĵ x}rxwr:\TZaG*y8IjbRc|XŻǿI u3KGnD1NIBs RuK>V.EL+M2#'fi ~V vl{u8zH *:(W☕ ~JTe\O*tHGHY}KNP*ݾ˦TѼ9/#A7qZ$*c?qUnwN%Oi4 =3ڗP 1Pm \\9Mؓ2aD];Yt\[x]}Wr|]g- eW )6-rCSj id DЇAΜIqbJ#x꺃 6k#ASh&ʌt(Q%p%m&]caSl=X\P1Mh9MVdDAaVB[݈fJíP|8 քAV^f Hn- "d>znNJ ة>b&2vKyϼD:,AGm\nziÙ.uχYC6OMf3or$5NHT[XF64T,ќM0E)`#5XY`פ;%1U٥m;R>QD DcpU'&LE/pm%]8firS4d 7y\`JnίI R3U~7+׸#m qBiDi*L69mY&iHE=(K&N!V.KeLDĕ{D vEꦚdeNƟe(MN9ߜR6&3(a/DUz<{ˊYȳV)9Z[4^n5!J?Q3eBoCM m<.vpIYfZY_p[=al-Y}Nc͙ŋ4vfavl'SA8|*u{-ߟ0%M07%<ҍPK! ѐ'theme/theme/_rels/themeManager.xml.relsM 0wooӺ&݈Э5 6?$Q ,.aic21h:qm@RN;d`o7gK(M&$R(.1r'JЊT8V"AȻHu}|$b{P8g/]QAsم(#L[PK-![Content_Types].xmlPK-!֧6 +_rels/.relsPK-!kytheme/theme/themeManager.xmlPK-!Ptheme/theme/theme1.xmlPK-! ѐ' theme/theme/_rels/themeManager.xml.relsPK] d{}! $>%b)*-1;1>BCbGhH:L2MMMPRxUN[ccDAe Z QR9@!/fB8B &&(( kd $~&*, /39<@AJFGkJtO;R3VWXZx^e0gh{iolo;prstTudz$‚ߍRwp> Ѥ(իŻ}]y]$.5<|~   rB.fDVWWWWWX%XBXlXX0g2gUhhui1tttttuuTuUusȇڇ+{w:t$:Ţ5VjϬK0aLOqIzrh<}   IK#$ $'((333777777U888@4@7@1G]G`GJJJJKKGUsUvU\\\\\\]-]0]2]^]a]`(a+ambbbdddeeeeee%gQgTgVggg7hchfh0l\l_lmmmnnno0o3op3p6p8pTpWprrrCtotrtuvv#vOvQv>xjxlxyyyyzzX|||}}}!MOHJe6begqϑ+.3_a͖HJLxz|شڴbmۿ޿HtHtHtHtHtXXHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtHtXHtHtHtJn}QuXX!X!GC ' XXX@  @ 0(  B S  ?H0(   _Ref80503453 _Ref250920157 _Ref250920158 _Ref255900010 _Ref255900012 _Ref255900014 _Ref255900016 _Ref250974090 _Ref250924867 _Ref250998770 _Ref250986437 _Ref250925005 _Ref251081477 _Ref250998774 _Ref250998775d{}!*;1>CbGPxU e|~!*<1>CcGPyU$+n.}.00Q1T111 5(555P@\@QQrrۨbmǵҵ#.x}_f7;<ABIJOPTU\ 3<vzLUpw%*/%V\ aglsKRW` 4<\g $y}{hpS4V4BBeGgGJJMMSSY\a\\\eeihqhii;j@KLx3Dhm#6:@LQZeh~=^_kpy@A}OX":B]bgk 33333333333333333333333333333333333333333333333333333333333333333333333333333333333333333389)<>?bcL# $'(33U88<>@>@8@1GaGJJJKP PPPGUwU\\\]]1]2]b]`,ambbddeeee%gUgVgg7hgh0l`lmmnno4op7p8pXpqqrrCtstu v#vRv>xmxyyyzX||}}!PKe6fgqϑ/3b͖ŨŨѲѲQZ[Dvv޾m߿ *599;Z",7;B`89)<>?bcL# $'(33U88<>@>@8@1GaGJJJKP PPPGUwU\\\]]1]2]b]`,ambbddeeee%gUgVgg7hgh0l`lmmnno4op7p8pXpqqrrCtstu v#vRv>xmxyyyzX||}}!PKe6fgqϑ/3b͖ŨŨѲѲQZ[Dvv޾m߿ 4499[",bTjklmGGHabcdeL ]"1{BZZ@7SG  ,4 nARfD2n|1%nc!)RZ|*ZZ@4,4Ww- b2nrfG31tx4^djw6̜F\7h*(\&:䚱=8"2l<@nq@ b];BxJHRhNn6_OL.X&kU^d"V^d dYZZ@ZR]Aa>D9;bjMS"gR0eiZZ@pp$ ^`OJQJo(- hh^h`OJQJo(hh^h`56B*CJOJQJo(hh^h`o(.^`B*OJQJo(hh^h`56B*CJOJQJo(h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hH^`B*OJQJo(hh^h`56B*CJOJQJo(hh^h`56B*CJOJQJo(h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hHhh^h`o(.h ^`OJQJo(-h ^`OJQJo(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJQJo(oh ^`OJQJo(h ^`OJQJo(h ^`OJQJo(oh PP^P`OJQJo(^`CJOJQJo(q^`OJQJ^Jo(o p^p`OJQJo( @ ^@ `OJQJo(^`OJQJ^Jo(o ^`OJQJo( ^`OJQJo(^`OJQJ^Jo(o P^P`OJQJo( ^`OJQJo(h8^8`OJQJo(hHh^`OJQJ^Jo(hHoh ^ `OJQJo(hHh ^ `OJQJo(hHhx^x`OJQJ^Jo(hHohH^H`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh ^`OJQJo(-h ^`OJQJo(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJQJo(oh ^`OJQJo(h ^`OJQJo(h ^`OJQJo(oh PP^P`OJQJo(h ^`OJQJo(-h ^`OJQJo(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJQJo(oh ^`OJQJo(h ^`OJQJo(h ^`OJQJo(oh PP^P`OJQJo(h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hH^`B*OJQJo(h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hHhh^h`56B*CJOJQJo(^`B*OJQJo(h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hH ^`OJQJo( ^`OJQJo(hh^h`56B*CJOJQJo(hh^h`56B*CJOJQJo(^`OJQJo(hH ^`hH. pp^p`hH. @ @ ^@ `hH. ^`hH. ^`hH. ^`hH. ^`hH. PP^P`hH.h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hHhh^h`56B*CJOJQJo(hh^h`56B*CJOJQJo(h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hH#AX&kUS"g"VxJHx4Z|1%,4 hNZ|*0ei2l<@{Bc!)Ww-7SG dY\7\&:b2D9;bfG3=];Bpp4,jw66_O]Aa* ]AafDq@""                  YB                 $        :a        YB                                                                        uuNeE& 5Xm(@3sM3s`Ewxk|U5~.-R3^ke'~U*>&Te}(AMYjrET6nCdEH 1| 1  , G2 G u y K }| ~ h$X|E<dXK`u_v[*8L?Q}3 }c<m(]j q) 2#{=kF6]8ja3;hS2 dW ps!y!jC"#[#%=a%;k%&%&d&Mw&+Z'5(x )*`/*3*);*1N*b+;+[+*,K,+b-D.T.\2/DV/0*)07R02=2>4UG4u5`5v67wB7a7n7 8<8}Q8$9Q9r9}9:]R:U:x:r;y<9<3C<]f<k<E=yT=U->rq>C|>o8?S9?I?q?@EAmA( BPB'B1B6BeB7EG G)G ;G@HaH>I'KJK= L~ M?]!aM^ 8,Zg$@SBOVOdyjNp yOx( "`tu>o-:ww-DnS.XZCDJ pQ y>c31?D] niO%<=nuCDI,m2 z Li:mw;a{\u\1=a[!9'1H1)9P<"A:KB#"6lIb"pVv@Б]^_`ijkm}~$$$$pp@pfp@pjp@pvpxpzp@pp @pp@@pp@pp@pp@pp@pX@Unknown G* Times New Roman5Symbol3. * Arial7.{ @Calibri7Kartika5. *aTahoma;Wingdings?= * Courier NewA BCambria Math"1h;fHtf͒&>jyjy#8n4d 2qHX ?%2!xx+National PBM Monograph Template Rev20091005 F. GoodmanLisa"                           ! Oh+'0(8 HT t   ,National PBM Monograph Template Rev20091005 F. Goodman 02/10/05 Added legal statementNormalLisa8Microsoft Office Word@J@fP@4c@0՜.+,D՜.+,` hp   VHA PBM SHGyj ,National PBM Monograph Template Rev20091005 Titlet P,Lh _PID_HLINKS_AdHocReviewCycleID_NewReviewCycle_EmailSubject _AuthorEmail_AuthorEmailDisplayName_ReviewingToolsShownOnceA6j5http://vaww.national.cmop.va.gov/PBM/Clinical Guidance/Clinical Recommendations/PBM Response clopidogrel-omeprazole FDA alert (1 23 10).doc l.http://www.pbm.va.gov/ 58http://vaww.pbm.va.gov/ l. http://www.pbm.va.gov/ 58http://vaww.pbm.va.gov/ l.http://www.pbm.va.gov/ BHKhttp://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000_SumR.pdf P;Ohttp://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000_Pharm_P1.pdf w>Shttp://www.acc.org/qualityandscience/clinical/guidelines/stemi/STEMI Full Text.pdf OI8Please Post: Revised National Drug Monograph TEMPLATEFrancine.Goodman@va.govGoodman, Francine  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ\]^_`abcdefghijklmnopqrstuvwxyz{|}~Root Entry F0);Data "Lp1Table[sWordDocument sBSummaryInformation(DocumentSummaryInformation8MsoDataStore/@n6YRNXL02ID0Q==2/@n6Item  PropertiesUCompObj y   F'Microsoft Office Word 97-2003 Document MSWordDocWord.Document.89qRoot Entry FO@ Data "Lp1Table[sWordDocument sB  !"#$%&'()*+, ,National PBM Monograph Template Rev20091005 Title( _PID_HLINKS_AdHocReviewCycleID_NewReviewCycle_EmailSubject _AuthorEmail_AuthorEmailDisplayName_ReviewingToolsShownOnceA6j5http://vaww.national.cmop.va.gov/PBM/Clinical Guidance/Clinical Recommendations/PBM Response clopidogrel-omeprazole FDA alert (1 23 10).doc l.http://www.pbm.va.gov/ 58http://vaww.pbm.va.gov/ l. http://www.pbm.va.gov/ 58http://vaww.pbm.va.gov/ l.http://www.pbm.va.gov/ BHKhttp://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000_SumR.pdf P;Ohttp://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000_Pharm_P1.pdf w>Shttp://www.acc.org/qualityandscience/clinical/guidelines/stemi/STEMI Full Text.pdf SummaryInformation(DocumentSummaryInformation8 MsoDataStore/@n6YRNXL02ID0Q==2/@n6xmlformats.org/officeDocument/2006/bibliography"/>  F'Microsoft Office Word 97-2003 Document MSWordDocWord.Document.89q՜.+,D՜.+,` hp   VHA PBM SHGyj