CardioSource WorldNews | Page 26
CLINICAL
NEWS
American College of Cardiology Extended Learning
Despite the gain of 101 minutes in time to first troponin, the primary
endpoint was just a little shorter in patients randomized to POCtroponin compared with UC.
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 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% prasug rel, 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)]
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 patient s 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).
So, in this pragmatic trial conducted in a broad population of
patients with chest pain, prehospital
POC-troponin testing shortened the
time from first medical contact to
final disposition in the ED with no
difference in clinical outcomes.
The authors added that future
randomized controlled trials evaluating the utility
of POC testing
in the ambulance should
consider the use
of ultrasensitive troponin,
To listen to the
randomization,
interview with Justin
A. Ezekowitz, MD,
which might
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have an impact
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grating troponin
testing into an
algorithm that
crosses health
care boundaries.
In PROACT-4,
for example,
patient data
were measured across five different
hospitals varying in size, volume, and
expertise, as well as across emergency personnel and ED staff.
Overall, based on the data, the
news is encouraging: it appears that
enhanced and more cost effective
early ED discharge of the majority of
patients with chest pain delivered by
ambulance is viable.
REFERENCES:
1. Wong WM, Lam KF, Cheng C, et al. World J
Gastroenterol. 2004;10:707-12.
2. Eslick GD, Jones MP, Talley NJ. Aliment Pharmacol Ther. 2003;17:1115-24.
3. Ezekowitz JA, Welsh RC, Gubbels C, et al. Can
J Cardiol. 2014;30:1208-15.
4. Ezekowitz JA, Welsh RC, Weiss D, et al. J Am
Heart Assoc. 2015;4(12). pii: e002859.
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
June 2016