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care because many patients who were subsequently revascularized received initial imaging for reasons considered inappropriate by our expert panel . […] Given that carotid imaging is a fairly commonly ordered test , targeting carotid imaging using decision support tools to
Bleeding Related to CABG – In TRITON-TIMI 38 , 437 patients who received a thienopyridine underwent CABG during the course of the study . The rate of CABG-related TIMI Major or Minor bleeding was 14.1 % for the Effient group and 4.5 % in the clopidogrel group ( see Table 3 ). The higher risk for bleeding adverse reactions in patients treated with Effient persisted up to 7 days from the most recent dose of study drug .
Table 3 : CABG-Related Bleeding a ( TRITON-TIMI 38 )
Effient (%) ( N = 213 )
Clopidogrel (%) ( N = 224 )
TIMI Major or Minor bleeding
14.1
4.5
TIMI Major bleeding
11.3
3.6
Fatal
0.9
0
Reoperation
3.8
0.5
Transfusion of ≥5 units
6.6
2.2
Intracranial hemorrhage
0
0
TIMI Minor bleeding
2.8
0.9
a
Patients may be counted in more than one row .
Bleeding Reported as Adverse Reactions – Hemorrhagic events reported as adverse
reactions in TRITON-TIMI 38 were , for Effient and clopidogrel , respectively : epistaxis ( 6.2 %,
3.3 %), gastrointestinal hemorrhage ( 1.5 %, 1.0 %), hemoptysis ( 0.6 %, 0.5 %), subcutaneous
hematoma ( 0.5 %, 0.2 %), post-procedural hemorrhage ( 0.5 %, 0.2 %), retroperitoneal
hemorrhage ( 0.3 %, 0.2 %), pericardial effusion / hemorrhage / tamponade ( 0.3 %, 0.2 %), and
retinal hemorrhage ( 0.0 %, 0.1 %).
Malignancies : During TRITON-TIMI 38 , newly-diagnosed malignancies were reported
in 1.6 % and 1.2 % of patients treated with prasugrel and clopidogrel , respectively . The
sites contributing to the differences were primarily colon and lung . In another Phase 3
clinical study of ACS patients not undergoing PCI , in which data for malignancies were
prospectively collected , newly-diagnosed malignancies were reported in 1.8 % and 1.7 % of
patients treated with prasugrel and clopidogrel , respectively . The site of malignancies
was balanced between treatment groups except for colorectal malignancies . The rates
of colorectal malignancies were 0.3 % prasugrel , 0.1 % clopidogrel and most were
detected during investigation of GI bleed or anemia . It is unclear if these observations
are causally-related , are the result of increased detection because of bleeding , or are
random occurrences .
Other Adverse Events : In TRITON-TIMI 38 , common and other important non-hemorrhagic
adverse events were , for Effient and clopidogrel , respectively : severe thrombocytopenia
( 0.06 %, 0.04 %), anemia ( 2.2 %, 2.0 %), abnormal hepatic function ( 0.22 %, 0.27 %), allergic
reactions ( 0.36 %, 0.36 %), and angioedema ( 0.06 %, 0.04 %). Table 4 summarizes the
adverse events reported by at least 2.5 % of patients .
Table 4 : Non-Hemorrhagic Treatment-Emergent Adverse Events Reported by at
Least 2.5 % of Patients in Either Group
Effient (%) ( N = 6741 )
Clopidogrel (%) ( N = 6716 )
Hypertension
7.5
7.1
Hypercholesterolemia / Hyperlipidemia
7.0
7.4
Headache
5.5
5.3
Back pain
5.0
4.5
Dyspnea
4.9
4.5
Nausea
4.6
4.3
Dizziness
4.1
4.6
Cough
3.9
4.1
Hypotension
3.9
3.8
Fatigue
3.7
4.8
Non-cardiac chest pain
3.1
3.5
Atrial fibrillation
2.9
3.1
Bradycardia
2.9
2.4
Leukopenia (< 4 x 10 9 WBC / L )
2.8
3.5
Rash
2.8
2.4
Pyrexia
2.7
2.2
Peripheral edema
2.7
3.0
Pain in extremity
2.6
2.6
Diarrhea
2.3
2.6
6.2 Postmarketing Experience : The following adverse reactions have been identified during post approval use of Effient . Because these reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure .
Blood and lymphatic system disorders – Thrombocytopenia , Thrombotic thrombocytopenic purpura ( TTP ) [ see Warnings and Precautions ( 5.4 ) and Patient Counseling Information ( 17 )]
Immune system disorders – Hypersensitivity reactions including anaphylaxis [ see Contraindications ( 4.3 )] reduce inappropriate use may be a good approach to improve the value of health care without compromising quality .”
They also cautioned that there currently is no guidance on the ordering of carotid ultrasounds within the VA , or in most other clinical
7 DRUG INTERACTIONS
7.1 Warfarin : Coadministration of Effient and warfarin increases the risk of bleeding [ see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
7.2 Non-Steroidal Anti-Inflammatory Drugs : Coadministration of Effient and NSAIDs ( used chronically ) may increase the risk of bleeding [ see Warnings and Precautions ( 5.1 )].
7.3 Other Concomitant Medications : Effient can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
Effient can be administered with aspirin ( 75-mg to 325-mg per day ), heparin , GPIIb / IIIa inhibitors , statins , digoxin , and drugs that elevate gastric pH , including proton pump inhibitors and H 2 blockers [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy : Pregnancy Category B – There are no adequate and well-controlled studies of Effient use in pregnant women . Reproductive and developmental toxicology studies in rats and rabbits at doses of up to 30 times the recommended therapeutic exposures in humans ( based on plasma exposures to the major circulating human metabolite ) revealed no evidence of fetal harm ; however , animal studies are not always predictive of a human response . Effient should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus .
In embryo fetal developmental toxicology studies , pregnant rats and rabbits received prasugrel at maternally toxic oral doses equivalent to more than 40 times the human exposure . A slight decrease in pup body weight was observed ; but , there were no structural malformations in either species . In prenatal and postnatal rat studies , maternal treatment with prasugrel had no effect on the behavioral or reproductive development of the offspring at doses greater than 150 times the human exposure [ see Nonclinical Toxicology ( 13.1 )].
8.3 Nursing Mothers : It is not known whether Effient is excreted in human milk ; however , metabolites of Effient were found in rat milk . Because many drugs are excreted in human milk , prasugrel should be used during nursing only if the potential benefit to the mother justifies the potential risk to the nursing infant .
8.4 Pediatric Use : Safety and effectiveness in pediatric patients have not been established [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
8.5 Geriatric Use : In TRITON-TIMI 38 , 38.5 % of patients were ≥65 years of age and 13.2 % were ≥75 years of age . The risk of bleeding increased with advancing age in both treatment groups , although the relative risk of bleeding ( Effient compared with clopidogrel ) was similar across age groups .
Patients ≥75 years of age who received Effient 10-mg had an increased risk of fatal bleeding events ( 1.0 %) compared to patients who received clopidogrel ( 0.1 %). In patients ≥75 years of age , symptomatic intracranial hemorrhage occurred in 7 patients ( 0.8 %) who received Effient and in 3 patients ( 0.3 %) who received clopidogrel . Because of the risk of bleeding , and because effectiveness is uncertain in patients ≥75 years of age [ see Clinical Studies ( 14 ) in full Prescribing Information ], use of Effient is generally not recommended in these patients , except in high-risk situations ( diabetes and past history of myocardial infarction ) where its effect appears to be greater and its use may be considered [ see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.3 ) in full Prescribing Information , and Clinical Studies ( 14 ) in full Prescribing Information ].
8.6 Low Body Weight : In TRITON-TIMI 38 , 4.6 % of patients treated with Effient had body weight < 60 kg . Individuals with body weight < 60 kg had an increased risk of bleeding and an increased exposure to the active metabolite of prasugrel [ see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.1 ), and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ]. Consider lowering the maintenance dose to 5-mg in patients < 60 kg . The effectiveness and safety of the 5-mg dose have not been prospectively studied [ see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
8.7 Renal Impairment : No dosage adjustment is necessary for patients with renal impairment . There is limited experience in patients with end-stage renal disease , but such patients are generally at higher risk of bleeding [ see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
8.8 Hepatic Impairment : No dosage adjustment is necessary in patients with mild to moderate hepatic impairment ( Child-Pugh Class A and B ). The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease have not been studied , but such patients are generally at higher risk of bleeding [ see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
8.9 Metabolic Status : In healthy subjects , patients with stable atherosclerosis , and patients with ACS receiving prasugrel , there was no relevant effect of genetic variation in CYP2B6 , CYP2C9 , CYP2C19 , or CYP3A5 on the pharmacokinetics of prasugrel ’ s active metabolite or its inhibition of platelet aggregation .
10 OVERDOSAGE
10.1 Signs and Symptoms : Platelet inhibition by prasugrel is rapid and irreversible , lasting for the life of the platelet , and is unlikely to be increased in the event of an overdose . In rats , lethality was observed after administration of 2000 mg / kg . Symptoms of acute toxicity in dogs included emesis , increased serum alkaline phosphatase , and hepatocellular atrophy . Symptoms of acute toxicity in rats included mydriasis , irregular respiration , decreased locomotor activity , ptosis , staggering gait , and lacrimation .
10.2 Recommendations about Specific Treatment : Platelet transfusion may restore clotting ability . The prasugrel active metabolite is not likely to be removed by dialysis .
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis , Mutagenesis , Impairment of Fertility : Carcinogenesis – No compound-related tumors were observed in a 2-year rat study with prasugrel at oral doses up to 100 mg / kg / day (> 100 times the recommended therapeutic exposures in humans ( based on plasma exposures to the major circulating human metabolite ). There was an increased incidence of tumors ( hepatocellular adenomas ) in mice exposed for 2 years to high doses (> 250 times the human metabolite exposure ).
Mutagenesis – Prasugrel was not genotoxic in two in vitro tests ( Ames bacterial gene mutation test , clastogenicity assay in Chinese hamster fibroblasts ) and in one in vivo test ( micronucleus test by intraperitoneal route in mice ).
Impairment of Fertility – Prasugrel had no effect on fertility of male and female rats at oral doses up to 300 mg / kg / day ( 80 times the human major metabolite exposure at daily dose of 10-mg prasugrel ).
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Medication Guide ) Benefits and Risks
• Summarize the effectiveness features and potential side effects of Effient .
• Tell patients to take Effient exactly as prescribed .
• Remind patients not to discontinue Effient without first discussing it with the physician who prescribed Effient .
• Recommend that patients read the Medication Guide .
Bleeding : Inform patients that they :
• will bruise and bleed more easily .
• will take longer than usual to stop bleeding .
• should report any unanticipated , prolonged , or excessive bleeding , or blood in their stool or urine .
Other Signs and Symptoms Requiring Medical Attention
• Inform patients that TTP is a rare but serious condition that has been reported with Effient .
• Instruct patients to get prompt medical attention if they experience any of the following symptoms that cannot otherwise be explained : fever , weakness , extreme skin paleness , purple skin patches , yellowing of the skin or eyes , or neurological changes .
• Inform patients that they may have hypersensitivity reactions including rash , angioedema , anaphylaxis , or other manifestations . Patients who have had hypersensitivity reactions to other thienopyridines may have hypersensitivity reactions to Effient .
Invasive Procedures : Instruct patients to :
• inform physicians and dentists that they are taking Effient before any invasive procedure is scheduled .
• tell the doctor performing the invasive procedure to talk to the prescribing health care professional before stopping Effient .
Concomitant Medications : Ask patients to list all prescription medications , over-thecounter medications , or dietary supplements they are taking or plan to take so the physician knows about other treatments that may affect bleeding risk ( e . g ., warfarin and NSAIDs ).
Additional information can be found at www . effienthcp . com
Effient ® is a registered trademark of Eli Lilly and Company . Manufactured by Eli Lilly and Company , Indianapolis , IN 46285 , USA Marketed by Daiichi Sankyo , Inc . and Lilly USA , LLC Copyright © 2009 , 2015 Daiichi Sankyo , Inc . and Eli Lilly and Company . All rights reserved .
PGHCPBS13AUG2015
settings . “ Our study demonstrates that developing such decision support is needed ,” they concluded .
In an accompanying editorial , Larry B . Goldstein , MD , wrote that the high proportion of imaging for uncertain indications is not entirely

There is a tension between appropriate screening and appropriate revascularization that necessitates further comment .

surprising and that the proportion of patients who did not undergo revascularization and who have tests done for inappropriate or uncertain reasons may even be higher than those who underwent revascularization , like the study population .
“ Specific educational programs , the use of alerts embedded into the electronic health record , and audits with feed-back , among other interventions , may be helpful in reducing inappropriate testing ,” Goldstein writes . “ The more difficult issue is addressing the large number of tests conducted for purposes considered by the expert panel to be uncertain . In this situation , physicians face a dilemma when caring for individual patients . […] In the setting of uncertainty , however , a conservative approach to screening and referral to a center participating in a relevant clinical trial seems the most appropriate strategy . ■
Keyhani S , Cheng EM , Naseri A , et al . JAMA Intern Med . 2016 ; doi : 10.1001 / jamainternmed . 2016.0678 .
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