CLINICAL
NEWS
American College of Cardiology Extended Learning
and the obesity paradox seems largely limited to
patients with low fitness, whereas those with better fitness have a good prognosis, period, and no
clear obesity paradox is apparent.5 Indeed, in one
analysis of 10 studies jointly assessing the impact
of cardiorespiratory fitness and BMI on all-cause
mortality, fitness was more important than fatness
for long-term mortality.6
women.4 Even after adjusting for age, sex, blood
urea nitrogen, blood pressure, creatinine, sodium,
heart rate, and dyspnea at rest, BMI quartile still
predicted mortality risk. For every 5 U increase in
BMI, the odds of risk-adjusted mortality were 10%
lower.
While there is still considerable debate, the
issue appears to be one of both fitness and fatness
Effient® (prasugrel) tablets
Brief Summary of Prescribing Information
BRIEF SUMMARY. Please see Full Prescribing Information for additional information about
Effient.
WARNING: BLEEDING RISK
• Effient can cause significant, sometimes fatal, bleeding [see Warnings and
Precautions (5.1, 5.2) and Adverse Reactions (6.1)].
• Do not use Effient in patients with active pathological bleeding or a history of
transient ischemic attack or stroke [see Contraindications (4.1, 4.2)].
• In patients ≥75 years of age, Effient is generally not recommended, because of
the increased risk of fatal and intracranial bleeding and uncertain benefit, except
in high-risk situations (patients with diabetes or a history of prior MI) where its
effect appears to be greater and its use may be considered [see Use in Specific
Populations (8.5)].
• Do not start Effient in patients likely to undergo urgent coronary artery
bypass graft surgery (CABG). When possible, discontinue Effient at least
7 days prior to any surgery [see Warnings and Precautions (5.2)].
• 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]) [see Warnings and Precautions (5.1)].
• Suspect bleeding in any patient who is hypotensive and has recently
undergone coronary angiography, percutaneous coronary intervention (PCI),
CABG, or other surgical procedures in the setting of Effient [see Warnings and
Precautions (5.1)].
• If possible, manage bleeding without discontinuing Effient. Discontinuing
Effient, particularly in the first few weeks after acute coronary syndrome,
increases the risk of subsequent cardiovascular events [see Warnings and
Precautions (5.3)].
1 INDICATIONS AND USAGE
1.1 Acute Coronary Syndrome: Effient® is indicated to reduce the rate of thrombotic
cardiovascular (CV) events (including stent thrombosis) in patients with acute coronary
syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) as
follows:
• Patients with unstable angina (UA) or non–ST-elevation myocardial infarction
(NSTEMI).
• Patients with ST-elevation myocardial infarction (STEMI) when managed with
primary or delayed PCI.
Effient has been shown to reduce the rate of a combined endpoint of cardiovascular death,
nonfatal myocardial infarction (MI), or nonfatal stroke compared to clopidogrel. The difference
between treatments was driven predominantly by MI, with no difference on strokes and little
difference on CV death [see Clinical Studies (14) in full Prescribing Information].
2 DOSAGE AND ADMINISTRATION
Initiate Effient treatment as a single 60-mg oral loading dose and then continue at 10-mg
orally once daily. Patients taking Effient should also take aspirin (75-mg to 325-mg) daily
[see Drug Interactions (7.3) and Clinical Pharmacology (12.3) in full Prescribing Information].
Effient may be administered with or without food [see Clinical Pharmacology (12.3) in full
Prescribing Information and Clinical Studies (14) in full Prescribing Information].
Timing of Loading Dose
In the clinical trial that established the efficacy and safety of Effient, the loading dose of Effient
was not administered until coronary anatomy was established in UA/NSTEMI patients and
in STEMI patients presenting more than 12 hours after symptom onset. In STEMI patients
presenting within 12 hours of symptom onset, the loading dose of Effient was administered at
the time of diagnosis, although most received Effient at the time of PCI [see Clinical Studies
(14) in full Prescribing Information]. For the small fraction of patients that required urgent
CABG after treatment with Effient, the risk of significant bleeding was substantial.
Although it is generally recommended that antiplatelet therapy be administered promptly in
the management of ACS because many cardiovascular events occur within hours of initial
presentation, in a trial of 4033 NSTEMI patients, no clear benefit was observed when Effient
loading dose was administered prior to diagnostic coronary angiography compared to at the
time of PCI; however, risk of bleeding was increased with early administration in patients
undergoing PCI or early CABG.
Dosing in Low Weight Patients: Compared to patients weighing ≥60 kg, patients weighing
<60 kg have an increased exposure to the active metabolite of prasugrel and an increased
risk of bleeding on a 10-mg once daily maintenance dose. 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 Warnings and Precautions (5.1), Adverse Reactions (6.1), and
Clinical Pharmacology (12.3) in full Prescribing Information].
4 CONTRAINDICATIONS
4.1 Active Bleeding: Effient is contraindicated in patients with active pathological bleeding
such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions (5.1) and
Adverse Reactions (6.1)].
4.2 Prior Transient Ischemic Attack or Stroke: Effient is contraindicated in patients with
a history of prior transient ischemic attack (TIA) or stroke. In TRITON-TIMI 38 (TRial to Assess
Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel),
patients with a history of TIA or ischemic stroke (>3 months prior to enrollment) had a
higher rate of stroke on Effient (6.5%; of which 4.2% were thrombotic stroke and 2.3% were
intracranial hemorrhage [ICH]) than on clopidogrel (1.2%; all thrombotic). In patients without
such a history, the incidence of stroke was 0.9% (0.2% ICH) and 1.0% (0.3% ICH) with Effient
and clopidogrel, respectively. Patients with a history of ischemic stroke within 3 months of
screening and patients with a history of hemorrhagic stroke at any time were excluded from
TRITON-TIMI 38. Patients who experience a stroke or TIA while on Effient generally should
have therapy discontinued [see Adverse Reactions (6.1) and Clinical Studies (14) in full
Prescribing Information].
4.3 Hypersensitivity: Effient is contraindicated in patients with hypersensitivity
(e.g., anaphylaxis) to prasugrel or any component of the product [see Adverse Reactions (6.2)].
5 WARNINGS AND PRECAUTIONS
5.1 General Risk of Bleeding: Thienopyridines, including Effient, increase the risk of
bleeding. With the dosing regimens used in TRITON-TIMI 38, TIMI (Thrombolysis in Myocardial
Infarction) Major (clinically overt bleeding associated with a fall in hemoglobin ≥5 g/dL, or
intracranial hemorrhage) and TIMI Minor (overt bleeding associated with a fall in hemoglobin
of ≥3 g/dL but <5 g/dL) bleeding events were more common on Effient than on clopidogrel
[see Adverse Reactions (6.1)]. The bleeding risk is highest initially, as shown in Figure 1
(events through 450 days; inset shows events through 7 days).
Figure 1: Non-CABG-Related TIMI Major or Minor Bleeding Events.
Effient
5
Non-CABG-Related TIMI
Major or Minor Bleeding Events (%)
Subsequently, Fonarow and colleagues evaluated waist circumference, an alternative anthropometric index of obesity that is more specific to
abdominal adiposity.3 Again, the obesity paradox
was apparent: bigger waist circumference, high
BMI, and the combination of both were each associated with improved outcomes in an advanced HF
cohort and the effect was seen in both men and
4
Clopidogrel
3
3
2
2
1
1
0
0
0
Number at risk:
Effient
6741
Clopidogrel 6716
90
6042
6023
0
1
2
3
4
5
6
7
180
270
360
450
5707
5764
4813
4883
4078
4138
2747
2792
Days from Randomization
Suspect bleeding in any patient who is hypotensive and has recently undergone coronary
angiography, PCI, CABG, or other surgical procedures even if the patient does not have overt
signs of bleeding. Do not use Effient in patients with active bleeding, prior TIA or stroke
[see Contraindications (4.1, 4.2)].
Other risk factors for bleeding are:
• Age ≥75 years. Because of the risk of bleeding (including fatal bleeding) and uncertain
effectiveness in patients ≥75 years of age, use of Effient is generally not recommended in
these patients, except in high-risk situations (patients with diabetes or history of myocardial
infarction) where its effect appears to be greater and its use may be considered [see
Adverse Reactions (6.1), Use in Specific Populations (8.5), Clinical Pharmacology (12.3) in
full Prescribing Information, and Clinical Studies (14) in full Prescribing Information].
• CABG or other surgical procedure [see Warnings and Precautions (5.2)].
• Body weight <60 kg. Consider a lower (5-mg) maintenance dose [see Dosage and
Administration (2), Adverse Reactions (6.1), and Use in Specific Populations (8.6)].
• Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal
(GI) bleeding, active peptic ulcer disease, severe hepatic impairment, or moderate to severe
renal impairment) [see Adverse Reactions (6.1) and Use in Specific Populations (8.7, 8.8)].
• Medications that increase the risk of bleeding (e.g., oral anticoagulants, chronic use of
non-steroidal anti-inflammatory drugs [NSAIDs], and fibrinolytic agents). Aspirin and
heparin were commonly used in TRITON-TIMI 38 [see Drug Interactions (7.1, 7.2, 7.3), and
Clinical Studies (14) in full Prescribing Information].
Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7-10 days), so
withholding a dose will not be useful in managing a bleeding event or the risk of bleeding
associated with an invasive procedure. Because the half-life of prasugrel’s active metabolite
is short relative to the lifetime of the platelet, it may be possible to restore hemostasis by
administering exogenous platelets; however, platelet transfusions within 6 hours of the loading
dose or 4 hours of the maintenance dose may be less effective.
5.2 Coronary Artery Bypass Graft Surgery-Related Bleeding: The risk of bleeding is
increased in patients receiving Effient who undergo CABG. If possible, Effient should be
discontinued at least 7 days prior to CABG.
Of the 437 patients who underwent CABG during TRITON-TIMI 38, the rates of CABG-related
TIMI Major or Minor bleeding were 14.1% in the Effient group and 4.5% in the clopidogrel
group [see Adverse Reactions (6.1)]. The higher risk for bleeding events in patients treated
with Effient persisted up to 7 days from the most recent dose of study drug. For patients
receiving a thienopyridine within 3 days prior to CAGB, the frequencies of TIMI Major or
Minor bleeding were 26.7% (12 of 45 patients) in the Effient group, compared with 5.0%
(3 of 60 patients) in the clopidogrel group. For patients who received their last dose of
thienopyridine within 4 to 7 days prior to CABG, the frequencies decreased to 11.3% (9 of
80 patients) in the prasugrel group and 3.4% (3 of 89 patients) in the clopidogrel group.
Do not start Effient in patients likely to undergo urgent CABG. CABG-related bleeding
may be treated with transfusion of blood products, including packed red blood cells and
platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the
maintenance dose may be less effective.
5.3 Discontinuation of Effient: Discontinue thienopyridines, including Effient, for active
bleeding, elective surgery, stroke, or TIA. The optimal duration of thienopyridine therapy
is unknown. In patients who are managed with PCI and stent placement, premature
discontinuation of any antiplatelet medication, including thienopyridines, conveys an increased
risk of stent thrombosis, myocardial infarction, and death. Patients who require premature
discontinuation of a thienopyridine will be at increased risk for cardiac events. Lapses in
therapy should be avoided, and if thienopyridines must be temporarily discontinued because
of an adverse event(s), they should be restarted as soon as possible [see Contraindications
(4.1, 4.2) and Warnings and Precautions (5.1)].
5.4 Thrombotic Thrombocytopenic Purpura: Thrombotic thrombocytopenic purpura
(TTP) has been reported with the use of Effient. TTP can occur after a brief exposure
(<2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment,
including plasmapheresis (plasma exchange). TTP is characterized by thrombocytopenia,
microangiopathic hemolytic anemia (schistocytes [fragment red blood cells] seen on peripheral
smear), neurological findings, renal dysfunction, and fever [see Adverse Reactions (6.2)].
5.5 Hypersensitivity Including Angioedema: Hypersensitivity including angioedema has
been reported in patients receiving Effient, including patients with a history of hypersensitivity
reaction to other thienopyridines [see Contraindications (4.3) and Adverse Reactions (6.2)].
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience: The following serious adverse reactions are also discussed
elsewhere in the labeling:
• Bleeding [see Boxed Warning and Warnings and Precautions (5.1, 5.2)]
• Thrombotic thrombocytopenic purpura [see Warnings and Precautions (5.4]
Safety in patients with ACS undergoing PCI was evaluated in a clopidogrel-controlled study,
TRITON-TIMI 38, in which 6741 patients were treated with Effient (60-mg loading dose and
10-mg once daily) for a median of 14.5 months (5802 patients were treated for over 6 months;
4136 patients were treated for more than 1 year). The population treated with Effient was
27 to 96 years of age, 25% female, and 92% Caucasian. All patients in the TRITON-TIMI 38
study were to receive aspirin. The dose of clopidogrel in this study was a 300-mg loading dose
and 75-mg once daily.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials cannot be directly compared with the rates observed in other
clinical trials of another drug and may not reflect the rates observed in practice.
Drug Discontinuation: The rate of study drug discontinuation because of adverse reactions
was 7.2% for Effient and 6.3% for clopidogrel. Bleeding was the most common adverse
reaction leading to study drug discontinuation for both drugs (2.5% for Effient and 1.4%
for clopidogrel).
Bleeding: Bleeding Unrelated to CABG Surgery – In TRITON-TIMI 38, overall rates of TIMI Major
or Minor bleeding adverse reactions unrelated to coronary artery bypass graft surgery (CABG)
were significantly higher on Effient than on clopidogrel, as shown in Table 1.
Table 1: Non-CABG-Related Bleedinga (TRITON-TIMI 38)
Effient (%)
(N=6741)
4.5
2.2
1.3
0.3
0.3
0.3
0.3
0.7
2.4
Clopidogrel (%)
(N=6716)
3.4
1.7
0.8
0.1
0.3
0.1
0.3
0.5
1.9
TIMI Major or Minor bleeding
TIMI Major bleedingb
Life-threatening
Fatal
Symptomatic intracranial hemorrhage (ICH)
Requiring inotropes
Requiring surgical intervention
Requiring transfusion (≥4 units)
TIMI Minor bleedingb
a
Patients may be counted in more than one row.
b
See 5.1 for definition.
Figure 1 demonstrates non-CABG-related TIMI Major or Minor bleeding. The bleeding rate is
highest initially, as shown in Figure 1 (inset: Days 0 to 7) [see Warnings and Precautions (5.1)].
Bleeding by Weight and Age – In TRITON-TIMI 38, non-CABG-related TIMI Major or Minor
bleeding rates in patients with the risk factors of age ≥75 years and weight <60 kg are
shown in Table 2.
Table 2: Bleeding Rates for Non-CABG-Related Bleeding by Weight and Age
(TRITON-TIMI 38)
Major/Minor
Fatal
Effienta Clopidogrelb Effienta Clopidogrelb
(%)
(%)
(%)
(%)
Weight <60 kg
(N=308 Effient, N=356
10.1
6.5
0.0
0.3
clopidogrel)
Weight ≥60 kg (N=6373
Effient, N=6299
4.2
3.3
0.3
0.1
clopidogrel)
Age <75 years (N=5850
Effient, N=5822
3.8
2.9
0.2
0.1
clopidogrel)
Age ≥75 years (N=891
Effient, N=894
9.0
6.9
1.0
0.1
clopidogrel)
a
10-mg Effient maintenance dose.
b
75-mg clopidogrel maintenance dose.