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CLINICAL NEWS American College of Cardiology Extended Learning reason for decreased athletic performance with age. Add in the fact that beta-blockers limit heart rate reserve and oxygen becomes a challenge inhibiting life in general and exercise in particular. Likewise, aging causes a crippling of one of the key means for boosting oxygen utilization during exercise. Exercise does increase stroke volume (by about 30%), making it one way for the body to increase oxy- 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 Bleedinga (TRITON-TIMI 38) Effient (%) Clopidogrel (%) (N=213) (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 repo rted 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 Hypertension Hypercholesterolemia/Hyperlipidemia Headache Back pain Dyspnea Nausea Dizziness Cough Hypotension Fatigue Non-cardiac chest pain Atrial fibrillation Bradycardia Leukopenia (<4 x 109 WBC/L) Rash Pyrexia Peripheral edema Pain in extremity Diarrhea Effient (%) (N=6741) 7.5 7.0 5.5 5.0 4.9 4.6 4.1 3.9 3.9 3.7 3.1 2.9 2.9 2.8 2.8 2.7 2.7 2.6 2.3 Clopidogrel (%) (N=6716) 7.1 7.4 5.3 4.5 4.5 4.3 4.6 4.1 3.8 4.8 3.5 3.1 2.4 3.5 2.4 2.2 3.0 2.6 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)] This may help explain the results of a meta-analysis of randomized clinical trials (RCT) evaluating exercise training in patients with HFpEF.1 Compared to controls, To listen to an interexercise training was associview with Sheldon E. Litwin, MD, on ated with clinically significant why exercise works improvements in in HF with preserved cardiorespiratory ejection fraction, scan the code. fitness and QOL without signifi10.2 Recommendations about Specific Treatment: Platelet transfusion may restore clotting ability. The prasugrel active metabolite is not likely to be removed by dialysis. cant changes in 13 NONCLINICAL TOXICOLOGY LV systolic or 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis – No diastolic funccompound-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 tion. In another (based on plasma exposures to the major circulating human metabolite). There was an recent study, increased incidence of tumors (hepatocellular adenomas) in mice exposed for 2 years to high doses (>250 times the human metabolite exposure). investigators Mutagenesis – Prasugrel was not genotoxic in two in vitro tests (Ames bacterial gene reported, contrary to their hypothesis, mutation test, clastogenicity assay in Chinese hamster fibroblasts) and in one in vivo test that 1 year of endurance training (micronucleus test by intraperitoneal route in mice). Impairment of Fertility – Prasugrel had no effect on fertility of male and female rats at oral failed to show any favorable effects on doses up to 300 mg/kg/day (80 times the human major metabolite exposure at daily dose cardiovascular stiffness or function in of 10-mg prasugrel). HFpEF.2 (It should be noted that this 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) was the first study with invasive presBenefits and Risks sure measurements in seven patients • Summarize the effectiveness features and potential side effects of Effient. and 13 controls.) • Tell patients to take Effient exactly as prescribed. • Remind patients not to discontinue Effient without first discussing it with the Dr. Litwin also mentioned that if physician who prescribed Effient. you look across the available litera• Recommend that patients read the Medication Guide. ture, training in patients with HFpEF Bleeding: Inform patients that they: • will bruise and bleed more easily. leads to minimal or no change in • will take longer than usual to stop bleeding. peak heart rate and no change in • should report any unanticipated, prolonged, or excessive bleeding, or blood in their stool or urine. peak blood pressure compared to conOther Signs and Symptoms Requiring Medical Attention trols. Arterial stiffness is increased • Inform patients that TTP is a rare but serious condition that has been reported with in HFpEF, but there have been mixed Effient. • Instruct patients to get prompt medical attention if they experience any of the findings on vasodilator reserve in following symptoms that cannot otherwise be explained: fever, weakness, HFpEF: there is some evidence that extreme skin paleness, purple skin patches, yellowing of the skin or eyes, o r neurological changes. exercise training in HFrEF (HF with • Inform patients that they may have hypersensitivity reactions including rash, reduced ejection fraction) does imangioedema, anaphylaxis, or other manifestations. Patients who have had hypersensitivity reactions to other thienopyridines may have hypersensitivity prove arterial function. Also, exercise reactions to Effient. does not seem to impact brachial Invasive Procedures: Instruct patients to: flow mediated dilatation (endothelial • inform physicians and dentists that they are taking Effient before any invasive procedure is scheduled. function) or carotid distensibility. gen utilization, along with increasing peripheral oxygen extraction (150% to 300%). If you compare elite athletes versus age-matched nonathletes, there is no difference in peak heart rate, but there is mildly higher stroke volume in the athletes and—importantly—higher and more efficient muscle oxygen utilization compared to the nonathletes. 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 H2 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 r elevant 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. • 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 MUSCLES MATTER While improved diastolic function or diastolic filling was presumed to be one reason why exercise might work in HFpEF, that did not seem to be the case. So, what else might apply? The list of potential factors includes improved chronotropic responsiveness, improved endothelial function (reduced afterload), reduced inflammation, metabolic adaptations (such as more efficient energy production), and skeletal muscle adaptations. Let’s look at the problem from a different perspective: what are the mechanisms of exercise intolerance in HFpEF? Investigators performed upright cardiopulmonary exercise testing with hemodynamic monitoring in patients with HFpEF, elevated August 2016