Antiplatelet Options for ACS: The Changing Landscape
EFIENT : Review of current guidance
of NICE and SMC
Dr Harald Vangerow
Medical Advisor Cardiovascular
Eli Lilly
Prescribing Information can be found at the end of this presentation
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Disclosure:
I am a full-time employee of
Eli Lilly UK, presenting on
behalf of the alliance between
Lilly and Daiichi-Sankyo
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Background
Antithrombotic therapy for PCI
ASPIRIN
x
Thromboxane
A2
Coagulation
HEPARINS
BIVALIRUDIN
x
5HT
Collagen
GPVI
Thrombin
TPa
5HT
ADP
5HT2A
ADP
ATP
ADP CLOPIDOGREL
PRASUGREL
ATP
P2Y1
P2X1
PAR-4
ACTIVE
METABOLITE
PAR-1
Dense
granule
Thrombin
generation
Shape
change
PLATELET
ACTIVATION
x
P2Y12
Amplification
Alpha
granule
aIIb b3
Coagulation factors
Inflammatory mediators
aIIb b3
Fibrinogen
Aggregation
x
aIIb b3
GP IIb/IIIa ANTAGONISTS
GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.
Adapted from Storey RF. Curr Pharm Des. 2006;12:1255-1259.
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Is this clinically relevant?
Clopidogrel response variability and increased
risk of ischaemic events (1,2)
Primary PCI for STEMI (N=60)
5 µM ADP induced plt agg
120
Clop resist
40
40
Q1
80
Q2
60
Q3
40
Q4
20
P = 0.007
30
Percent
Baseline (%)
100
20
10
6.7
Quartiles of response
0
1
2
3
4
Days
5
The range of variability to clopidogrel ranges from 4% to 56% of
subjects showing some degree of non-responsiveness (3,4). There
are many different definitions of poor-/nonresponse and various
techniques to measure inhibition of platelet aggregation.
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Death/ACS/CVA by 6 m
6
0
0
0
Q1
Q2
Q3
Q4
N=15
N=15
N=15
N=15
1. Matetzky S, et al. Circulation 2004;109:3171-3175
2. Wiviott SD, Antman EM. Circulation 2004 109:3064-3067
3. Serebruany VL, J. Am Coll Cardiol 2005; 45: 246-51
4. O’Donoghue M et al. Circulation 2006; 114(22): e600-e606
TRITON
TRITON-TIMI 38 Study Design
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
N = 13,608
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Planned median duration of therapy - 12 months
1o endpoint:
2o endpoints:
Safety endpoints:
Key sub-studies:
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CV death, MI, stroke
CV death, MI, stroke, rehosp, Rec Isch CV death,
UTVR, Stent thrombosis (ARC definite/prob.)
TIMI major bleeds, life-threatening bleeds
Pharmacokinetic, genomic
Wiviott SD et al. Am Heart J 2006;152:627-635
TRITON
TRITON-TIMI 38: Rates of Key Study
End Points (All ACS)
15
12.1
(781)
9.9
(643)
End Point (%)
clopidogrel + aspirin
CV Death, MI, Stroke
10
prasugrel + aspirin
P<0.001
↓138 events
P=0.03
↑ 35 events
5
prasugrel + aspirin
Non-CABG
TIMI Major Bleeds
2.4
(146)
1.8
(111)
clopidogrel + aspirin
0
0
30
60
90 120
180
270
360
450
Days After Randomisation
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CABG = Coronary Artery Bypass Graft surgery
CV = Cardiovascular
MI = Myocardial Infarction
TIMI = Thrombolysis In Myocardial Infarction
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
TRITON
Bleeding Events: Safety Cohort
Clopidogrel
n = 13,457
Prasugrel
ICH in patients with
prior stroke/TIA
(n = 518)
Events (%)
4
Clopidogrel 0 (0%)
Prasugrel 6 (2.3%)
(P = 0.02)
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0
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TIMI Major
Non-CABG
Bleeding
ARD 0.6%
HR 1.32
P = 0.03
NNH = 167
Lifethreatening
Non-fatal
Fatal
ARD 0.5%
HR 1.52
P = 0.01
ARD 0.2%
P = 0.23
ARD 0.3%
P = 0.002
0.3
0.3
ICH
ARD 0%
P = 0.74
Antman EM et al. AHA Scientific Sessions; 2007, Nov 4-7; Orlando, FL
http://www.clinicaltrialresults.org/Slides/TRITON%20TIMI%2038%20AHA%2007.ppt
TRITON
Net Clinical Benefit: Bleeding Risk Subgroups
Post-hoc analysis
Prior
Stroke / TIA
Risk (%)
+ 37
Yes
No
-16
Pint = 0.006
-1
>75
Age
Wgt
-16
Pint = 0.18
< 75
+3
< 60 kg
>60 kg
Pint = 0.36
-14
-13
OVERALL
0.5
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prasugrel better
1
clopidogrel better
2
HR
Antman EM et al. AHA Scientific Sessions; 2007, Nov 4-7; Orlando, FL
http://www.clinicaltrialresults.org/Slides/TRITON%20TIMI%2038%20AHA%2007.ppt
TRITON
Therapeutic Considerations
16%
4%
MD
10 mg
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Significant
Net Clinical Benefit
with Prasugrel
80%
Antman EM et al. AHA Scientific Sessions; 2007, Nov 4-7; Orlando, FL
http://www.clinicaltrialresults.org/Slides/TRITON%20TIMI%2038%20AHA%2007.ppt
Appropriate Use
Appropriate Use of EFIENT
Loading Dose
Maintenance Dose
≥ 60kg and < 75 years
60mg
10mg
< 60kg
60mg
5mg*
≥ 75 years
60mg
5mg*
Generally not recommended
After Careful Risk-Benefit Evaluation
ANY prior TIA/Stroke
Contraindicated
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The evidence for a 5mg dose is based only on PK/PD analyses and no
clinical data currently exist on the safety of this dose in the at risk sub groups.
*
European SmPC
SMC
Scottish Medicines Consortium
7th August 2009
Prasugrel (Efient) co-administered with aspirin is
accepted for restricted use within NHS Scotland for
the prevention of athero-thrombotic events in patients
with acute coronary syndrome under-going primary or
delayed percutaneous coronary intervention.
Use is restricted to patients who are eligible to
receive the 10mg dose of prasugrel.
(...)
Alternative treatments are available at a lower drug
acquisition cost.
http://www.scottishmedicines.org.uk/files/prasugrel%205%20and%2010%20mg%20tablets%20(Efient)%20FINAL
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%20August%202009%20Revised%20Sept%202009.doc%20website.pdf
TRITON
Balance of Efficacy and Safety in Patients
<75 Yrs, ≥60 kg, and Without TIA/Stroke
16
n=10 804
CV Death / NF MI / NF Stroke
14
Endpoint (%)
12
NNT
37
Hazard Ratio, 0.75
(95% CI, 0.66-0.84)
P<0.001
10
Clopidogrel 11%
8
Prasugrel 8.4%
6
Non-CABG TIMI Major Bleeding
Hazard Ratio, 1.240
(95% CI, 0.91-1.69)
P=0.17
4
2
NNH
222
Prasugrel 1.95%
Clopidogrel 1.50%
0
0
30
90
180
Days
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270
360
450
FDA Briefing Document,
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMa
terials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm12921
9.pdf
NICE
NICE TA 182
Issued October 2009
Review September 2010
Guidance
1.1 Prasugrel in combination with aspirin is
recommended as an option for preventing
atherothrombotic events in people with acute
coronary syndromes having percutaneous
coronary intervention, only when:
•
immediate primary percutaneous coronary
intervention for ST-segment-elevation
myocardial infarction is necessary
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http://guidance.nice.org.uk/TA182/Guidance/pdf/English
TRITON-STEMI
STEMI Cohort (N= 3534)
15
Clopidogrel
CV death / MI / stroke
12.4%
Endpoint (%)
9.5%
10.0%
10
Prasugrel
6.5%
HR 0.68
(0.54 - 0.87)
P = 0.002
5
TIMI major
non-CABG bleeds
HR 0.79
(0.65 - 0.97)
P = 0.02
NNT = 42
Prasugrel
2.4%
2.1%
Clopidogrel
0
0 30 60 90
N = 3534
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180
270
360
450
Days
Montalescot G et al Lancet 2009, in press
TRITON – STEMI
TRITON-TIMI 38: STEMI cohort
Mortality at 30 Days
[% Patients]
3
2
1
2.6
2.4
1.6
p=0.0445
1.4
p=0.0469
0
All Cause Death
Clopidogrel
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Cardiovascular Death
Prasugrel
Montalescot G et al. Lancet 2009;373:723_731
NICE
NICE TA 182
Issued October 2009
Review September 2010
Guidance
1.1 Prasugrel in combination with aspirin is
recommended as an option for preventing
atherothrombotic events in people with acute
coronary syndromes having percutaneous
coronary intervention, only when:
•
stent thrombosis has occurred during
clopidogrel treatment
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http://guidance.nice.org.uk/TA182/Guidance/pdf/English
TRITON – Stent Thrombosis
TRITON-TIMI 38: Stent thrombosis rates
at end of study
prasugrel
clopidogrel
Stent Thrombosis* (%)
4
3
52% RRR
64% RRR
48% RRR
(1.2% ARR)
(1.5% ARR)
(1.1% ARR)
P<0.0001
P<0.0001
2.35
2
1
P=0.0009
2.41
2.31
1.27
1.13
0.84
0
N=6,422 N=6,422
n=2,865 n=2,878
n=3,237 n=3,224
All Stents
Drug-eluting Stents
Bare-metal Stents
*Stent thrombosis defined as Academic Research Consortium definite plus probable
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ARC = Academic Research Consortium
ARR = Absolute Risk Reduction
HR = Hazard Ratio
NNT = Number Needed to Treat
PCI = Percutaneous Coronary Intervention
RRR = Relative Risk Reduction
Wiviott SD et al. Lancet 2008;371:1353-1363
TRITON – Stent Thrombosis
TRITON-TIMI 38: Intensive antiplatelet therapy with
prasugrel resulted in fewer ischaemic outcomes
including stent thrombosis than with clopidogrel
Early Stent Thrombosis
Pras n=6,422; clop n=6,422
Late Stent Thrombosis
pras n=6,271; clop n=6,250
% of Subjects
2.5
2
clopidogrel + aspirin
clopidogrel + aspirin
prasugrel + aspirin
prasugrel + aspirin
1.56%
1.5
HR 0.60 (0.37-0.97)
P=0.03
RRR 40%
HR 0.41 (0.29-0.59)
P<0.0001
RRR 59%
1
0.5
0.82%
0.64%
0.49%
0
0
5
10
15
20
ARC = Academic Research Consortium
HR = Hazard ratio
RRR = Relative risk reduction
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25
30 30
90
150
210
270
330
390
450
Days
Wiviott SD et al. Lancet 2008;371:1353-1363
NICE
NICE TA 182
Issued October 2009
Review September 2010
Guidance
1.1 Prasugrel in combination with aspirin is
recommended as an option for preventing
atherothrombotic events in people with acute
coronary syndromes having percutaneous
coronary intervention, only when:
•
the patient has diabetes mellitus.
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http://guidance.nice.org.uk/TA182/Guidance/pdf/English
TRITON – Diabetes
TRITON-TIMI 38: Diabetic Subgroup
Analysis (n=3,146)
18
CV Death, MI, Stroke
clopidogrel + aspirin
16
17.0
prasugrel + aspirin
14
12.2
12
HR 0.70
P<0.001
NNT=21
10
End Point (%)
8
6
Non-CABG
TIMI Major Bleeds
4
2.6
2.5
2
0
0
30
60
90
CABG = Coronary Artery Bypass Graft surgery
CV = Cardiovascular
HR = Hazard Ratio
MI = Myocardial Infarction
NNT = Number Needed to Treat
TIMI = Thrombolysis In Myocardial Infarction
180
270
360
450
Days
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Adapted from Antman EM et al. AHA Scientific
Sessions; 2007, Nov 4-7; Orlando, FL
NICE
NICE TA 182
Issued October 2009
Review September 2010
Guidance
1.1 Prasugrel in combination with aspirin is recommended as an option
for preventing atherothrombotic events in people with acute
coronary syndromes having percutaneous coronary intervention,
only when:
•
immediate primary percutaneous coronary intervention for STsegment-elevation myocardial infarction is necessary or
•
stent thrombosis has occurred during clopidogrel treatment or
•
the patient has diabetes mellitus.
1.2 People currently receiving prasugrel for treatment of acute coronary
syndromes whose circumstances do not meet the criteria in 1.1
should have the option to continue therapy until they and their
clinicians consider it appropriate to stop.
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http://guidance.nice.org.uk/TA182/Guidance/pdf/English
Conclusions
Conclusions
• Prasugrel is a more potent antiplatelet than
clopidogrel
• This translates into fewer ischemic events in ACS
patients undergoing PCI in TRITON
• A significant increase in bleeding events in
Prasugrel treated patients was observed in this trial
• A post-hoc analysis was performed to define the
population deriving net clinical benefit with
prasugrel
• SMC and NICE have found EFIENT to be costeffective in a subset of ACS patients undergoing PCI
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Thank You !
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Adverse Event Reporting
Adverse events should be reported. Reporting forms
and information can be found at
www.yellowcard.gov.uk
Adverse events should also be reported to Eli Lilly
and Company Limited (Tel No 0870 240 1125)
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Prescribing Information (1/5)
EFIENT*▼ (PRASUGREL) ABBREVIATED PRESCRIBING INFORMATION
Presentation
Film-coated tablet; 5mg or 10mg prasugrel hydrochloride.
Uses
Efient, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in
patients with acute coronary syndrome (ie, unstable angina, non-ST segment elevation myocardial infarction
[UA/NSTEMI], or ST segment elevation myocardial infarction [STEMI]) undergoing primary or delayed percutaneous
coronary intervention (PCI).
Dosage and Administration Adults: Initiate with a single 60mg loading dose and then continue at 10mg daily. Patients
should also take ASA daily (75mg to 325mg). In patients with ACS who are managed with PCI, premature
discontinuation of any antiplatelet agent, including Efient, could result in an increased risk of thrombosis,
myocardial infarction, or death due to the patient’s underlying disease. Treatment of up to 12 months is
recommended unless the discontinuation is clinically indicated.
Patients ≥75 years old: Use in patients ≥75 years of age is generally not recommended. If, after a careful individual
benefit/risk evaluation by the prescribing physician, treatment is deemed necessary, then following a 60mg loading
dose a reduced maintenance dose of 5mg should be prescribed. Patients ≥75 years of age have greater sensitivity
to bleeding and higher exposure to the active metabolite of prasugrel. The evidence for the 5mg dose is based only
on pharmacodynamic/pharmacokinetic analyses and no clinical data currently exist on the safety of this dose in the
age group ≥75 years.
Patients weighing <60kg: Give as a single 60mg loading dose and then continue at 5mg once daily. The 10mg
maintenance dose is not recommended.
Renal impairment: No dose adjustment is necessary for patients with renal impairment, including patients with end
stage renal disease.
Hepatic impairment: No dose adjustment is necessary in subjects with mild to moderate hepatic impairment (Child-Pugh
class A and B).
Children and adolescents: Not recommended.
Method of administration: For oral use. May be administered with or without food. Administration of the 60mg loading
dose in the fasted state may provide most rapid onset of action. Do not crush or break the tablet.
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Prescribing Information (2/5)
Contra-indications
Hypersensitivity to the active substance or to any of the excipients. Active pathological bleeding. History of stroke or transient
ischaemic attack (TIA). Severe hepatic impairment (Child-Pugh class C).
Warnings and Special Precautions
Bleeding risk: Increased risk of bleeding; anaemia; thrombocytopaenia; a history of pathological intracranial findings. Use in patients
at increased risk of bleeding should only be considered when the benefits in terms of prevention of ischaemic events are
deemed to outweigh the risk of serious bleedings. This concern applies especially to patients:
• ≥75 years of age.
• with a propensity to bleed.
• with body weight <60kg. In these patients the 10mg maintenance dose is not recommended. A 5mg maintenance dose should
be used.
• with concomitant administration of medicinal products that may increase the risk of bleeding, including oral
anticoagulants, clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), and fibrinolytics.
For patients with active bleeding for whom reversal of the pharmacological effects of Efient is required, platelet
transfusion may be appropriate.
Use in patients ≥75 years of age is generally not recommended and should only be undertaken with caution after a careful individual
benefit/risk evaluation.
Therapeutic experience with prasugrel is limited in patients with renal impairment (including ESRD) and in patients with moderate
hepatic impairment. These patients may have an increased bleeding risk. Therefore, prasugrel should be used with caution in
these patients.
Use with caution in Asian patients as therapeutic experience is limited.
Patients should be told that it might take longer than usual to stop bleeding and that they should report any unusual bleeding (site or
duration) to their physician.
Surgery: If a patient is to undergo elective surgery, and an antiplatelet effect is not desired, Efient should be discontinued at least 7
days prior to surgery. Increased frequency (3-fold) and severity of bleeding may occur in patients undergoing CABG surgery
within 7 days of discontinuation of prasugrel.
Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucosegalactose
malabsorption should not take Efient.
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Prescribing Information (3/5)
Interactions
Warfarin: Warfarin (or other coumarin derivatives) and prasugrel should be co-administered with caution.
Non-steroidal anti-inflammatory drugs (NSAIDs): Chronic NSAIDs (including COX-2 inhibitors) and Efient should be co-administered
with caution.
Effects of Other Medicinal Products on Efient
Acetylsalicylic acid: To be administered concomitantly with ASA. Although a pharmacodynamic interaction with ASA leading to an
increased risk of bleeding is possible, the demonstration of the efficacy and safety of prasugrel comes from patients
concomitantly treated with ASA.
Effects of Efient on Other Medicinal Products
Medicinal products metabolised by CYP2B6: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel decreased
exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%. This effect is likely to be of clinical
concern only when prasugrel is co-administered with medicinal products for which CYP2B6 is the only metabolic pathway and
have a narrow therapeutic window (eg, cyclophosphamide, efavirenz).
Pregnancy and Lactation
Should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.
Driving, etc
Prasugrel is expected to have no or negligible influence on the ability to drive and use machines.
Undesirable Effects
Safety in patients with acute coronary syndrome undergoing PCI was evaluated in one clopidogrel-controlled study (TRITON). Drug
discontinuation due to adverse events was 7.2% for prasugrel and 6.3% for clopidogrel. Of these, bleeding was the most
common adverse reaction for both drugs leading to study drug discontinuation (2.5% for prasugrel and 1.4% for clopidogrel).
Bleeding
Non-Coronary Artery Bypass Graft (CABG) related bleeding: In TRITON the incidence of non-CABG-related TIMI major bleeding,
including life-threatening and fatal, as well as TIMI minor bleeding, was statistically significantly higher in subjects treated with
prasugrel compared to clopidogrel in the UA/NSTEMI and all ACS populations. No significant difference was seen in the STEMI
population. The most common site of spontaneous bleeding was the gastro-intestinal tract; the most frequent site of provoked
bleeding was the arterial puncture site.
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Prescribing Information (4/5)
CABG-related bleeding: In the Phase 3 clinical trial, 437 patients underwent CABG during the course of the study. Of those patients,
the rate of CABG-related TIMI major or minor bleeding was 14.1% for the prasugrel group and 4.5% in the clopidogrel group.
The higher risk for bleeding events in subjects treated with prasugrel persisted up to 7 days from the most recent dose of study
drug. For patients who received their thienopyridine within 3 days prior to CABG, the frequencies of TIMI major or minor
bleeding were 26.7% (12 of 45 patients) in the prasugrel 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 3.3% (3 of 90 patients) in the clopidogrel group. Beyond 7 days after drug
discontinuation, the observed rates of CABG-related bleeding were similar between treatment groups.
Adverse Reactions
The following is based on data from clinical trials:
Common (≥1-<10%): Anaemia, haematoma, epistaxis, gastro-intestinal haemorrhage, rash, ecchymosis, haematuria, vessel puncture
site haematoma, puncture site haemorrhage, contusion.
Uncommon (≥1/1000-<1/100): Eye haemorrhage, retroperitoneal haemorrhage.
For full details of these and other side-effects, please see the Summary of Product Characteristics, which is available at
http://emc.medicines.org.uk/.
Legal Category POM
Marketing Authorisation Numbers
EU/1/08/503/001, EU/1/08/503/002, EU/1/08/503/003, EU/1/08/503/004, EU/1/08/503/005, EU/1/08/503/006, EU/1/08/503/007,
EU/1/08/503/008, EU/1/08/503/009, EU/1/08/503/010, EU/1/08/503/011, EU/1/08/503/012, EU/1/08/503/013, EU/1/08/503/014
Basic NHS Cost £ 47.56 per pack of 28 tablets
Date of Preparation or Last Review June 2009
Full Prescribing Information is Available From
Eli Lilly and Company Limited, Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL, Telephone: Basingstoke (01256) 315
999
*EFIENT (prasugrel) is a trademark of Eli Lilly and Company.
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Prescribing Information (5/5)
• Adverse events should be reported. Reporting forms
and information can be found at
www.yellowcard.gov.uk
• Adverse events should also be reported to Eli Lilly
and Company Limited
• (Tel No 0870 240 1125)
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