Pitt Street Health Plan
Pharmacy and Therapeutics
Committee:
Effient™ (prasugrel)
Tim Mizak
Shailly Shah
Elyse Weitzman
Nick Wytiaz
Effient™ (prasugrel)
Eli Lilly and Co.
Therapeutic Class: Thienopyridine
Indication:
– Reduction of thrombotic cardiovascular (CV) events in
patients with acute coronary syndrome (ACS) who
are managed with percutaneous coronary intervention
(PCI)
Place in therapy:
– 1st line alternative in ACS patients who undergo PCI
and lack significant risk factors for bleeding events
Disease Description
Acute Myocardial Ischemia
• Insufficient blood flow and O2 to heart
• Often due to coronary heart disease (CHD) from
plaque build-up in arteries (atherosclerosis)
Acute Coronary Syndrome
• Range of clinical symptoms consistent with acute
myocardial ischemia including:
– Unstable angina (UA)
– Myocardial infarction (MI)
• Non-ST segement MI (NSTEMI)
• ST segment MI (STEMI)
American Heart Association. Acute Coronary Syndrome: what is acute coronary
syndrome? http://www.americanheart.org/presenter.jhtml?identifier=3010002.
Accessed January 18, 2011
Epidemiology
• 80 million US adults had one or more
forms of CVD in 2006, resulting in over
800,000 deaths
• CVD is leading cause of death in the US
– Greater than 2nd (cancer) and 3rd
(cerebrovascular diseases) causes combined
Causes of ACS
• Narrowing of the coronary arteries
– Blood flow to the heart greatly reduced or
completely blocked
– Heart muscle damage or death
• Clots often responsible for narrowing
– Plaque build up over years
– Atherosclerosis
Alpert JS, Thygesen K, Antman E, Bassand JP. (2000). "Myocardial infarction redefined--a consensus document of The Joint European Society of
Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction". J Am Coll Cardiol 36 (3): 959–69.
Management of ACS
UA/NSTEMI
Relief of ischemia
- Medical
- Surgical: PCI
and/or
CABG
STEMI
Restore Perfusion:
- Fibrinolysis
- Primary PCI
Torpy JM, Lynn C, Glass RM. Percutaneous Coronary. JAMA.
2004;291(6):778.doi:10.1001/jama.291.6.778
Antiplatelet Therapy Guidelines for
Patients With ACS Who Undergo PCI
Guidelines
Aspirin (ASA)
Clopidogrel
Ticlopidine
UA/NSTEMI
(ACC/AHA,
2007)
• Class 1
Evidence
• 162-325mg
immediately upon
•75-325mg pre-PCI
•presentation
• If ASA intolerant,
use clopidogrel
• If unable to take ASA
• 300mg LD >6 hours pre-PCI
• 75mg daily for at least 12
months post-PCI (if DES)
• 75mg daily (preferred over
ticlopidine) if unable to take
ASA
•No
recommendation
STEMI
(ACC/AHA
2004)
• Class 1
Evidence
•162-325mg daily
for at least 1 m
after BMS, 3 mo
after SES, 6 mo
after PES
• 75mg daily added to ASA
•Use only if true
regardless of reperfusion
allergy to ASA
• 75mg daily for at least 12 mo
after DES, 1 mo after BMS
• Continue for 14 days if not
undergoing stent
Effient™: Clinical Pharmacology
• Thienopyridine
inhibitor of platelet
activation and
aggregation
• Selectively and
irreversibly binds
P2Y12 class of
adenosine phosphate
receptors
Bhatt DL. Prasugrel in clinical practice. N Eng J Med 2009;361(10):940-2.
Effient™: Prescribing Information
• Contraindications:
– Active pathological bleeding
– Prior transient ischemic attack (TIA) or stroke
• Black Box Warning: Bleeding Risk
– Patients > 75 years of age
– Patients likely to undergo urgent CABG
– Stop 7 days prior to any surgery where possible
• Additional Warnings:
– General Bleed Risk (Premature discontinuation, CABG-related)
– Thrombocytopenia purpura (TTP)
Thienopyridine Clinical Comparison
Drug
Indication
Dosing
Adverse Reaction
Warnings/
Precautions
Contraindications
EFFIENT™
(prasugrel)
• 5mg and
10mg tablets
Reduce thrombotic
CV events in ACS:
• UA or NSTEMI
managed with PCI
• STEMI managed
with PCI
• 60mg LD
• 10mg daily MD
with ASA
• Bleeding
(including life
threatening and
fatal)
• Black Box for
bleeding risk
• Active pathological
bleed
PLAVIX®
(clopidogrel)
• 75mg and
300mg tablets
Reduce
atherothrombolic
events:
• Recent MI, recent
stroke, peripheral
arterial disease
Recent
atherothrombolic
events:
75mg daily
• Bleed risk
increase
• TTP (rarely)
• Prolongs bleeding
time
•Reduced
CYP2C19 function
• Caution severe
hepatic and/or
renal impairment
• Active pathological
bleed
• Neutropenia /
thrombocytopenia
• TTP, aplastic
anemia, leukemia,
agranulocytosis,
bone-marrow
depression
• Life-threatening
hematological
adverse reactions
• Increase serum
cholesterol and
triglycerides
• Adjust dosing for
renal impairment
• Hematopoietic
disorders
(neutropenia,
thrombocytopenia,
past history of TTP
or aplastic anemia)
•Sever liver
impairment
• ACS (same as
Effient™)
TICLID®
(ticlopidine)
• 250mg
tablets
• Reduce risk of
thrombotic stroke
(only if cannot take
ASA)
• Adjunct to ASA in
coronary stent
implantation
ACS:
• 300mg LD
• 75mg MD with
ASA
Stroke: 250mg
BID with food
Stent: 250mg BID
with food and ASA
up to 30 days
post-implantation
• Bleed risk
increase
• Rash
• GI complaints
•History of TIA or
stroke
•Active pathological
bleed
Manufacturer’s Value Arguments
• Significant reduction in rate of
atherothrombotic events and stent
thrombosis compared with clopidogrel
– More rapid onset
– Higher, more consistent, inhibition of platelet
aggregation (IPA)
– Less interpatient variability
– Economically dominant due to lower costs
and greater life expectancy
Wiviott SD, Antman EM, Kenneth J, et al. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine
P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the joint utilization of medications to block
platelets optimally (JUMBO)-TIMI 26 trial. Circulation 2005; 111:3366-73/
JUMBO-TIMI 26: Study Design
PCI with stenting
(N = 900)
Stratified by use of GP Iib/IIIa inhibitor
PRASUGREL
LD 40 mg
MD 7.5 mg
N=200
PRASUGREL
LD 60 mg
MD 10 mg
N=200
PRASUGREL
LD 60 mg
MD 15 mg
N=250
CLOPIDOGREL
LD 300 mg
MD 75 mg
N=250
Maintenance Rx for 30 days
1o endpoint:
Significant (non-CABG) bleeding through 30 days
2o endpoints: MACE through 30 D, major bleeding,
component clinical endpoints
JUMBO-TIMI 26: Summary
• Similar safety profile to clopidogrel
– No significant difference in rate of bleeding
– Lower incidences of primary and secondary endpoints
• Limitations:
– Not powered for clinical efficacy outcomes
– Clopidogrel 600mg LD was not considered
– Excluded patients with planned PCI for immediate treatment of
STEMI
• Delfini Validity and Usability Grade U
– Uncertain clinical usefulness
– More testing to demonstrate causal link between study outcomes
and clinically significant outcome
TRITON-TIMI 38: Study Design
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,608
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Duration of therapy: 6-15 months
1o endpoint:
CV death, MI, Stroke
o
2 endpoint:
Stent Thrombosis
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Exclusion Criteria: Increased risk of bleeding
Anemia, Thrombocytopenia
History of pathological intracranial finding
Use of a thienopyridine within 5 days of enrollment
Wiviott SD, Antman EM et al AHJ 2006
TRITON-TIMI 38: Primary Results
Wiviott SD. N Engl J Med 2007;357:2001-15.
TRITON-TIMI 38: Subgroup Analyses
TRITON-TIMI 38: Summary
• For every 1,000 patients treated with prasugrel instead
of clopidogrel:
– 24 CV endpoints would be prevented
– 10 additional bleeding events would occur
• Limitations / Weaknesses
–
–
–
–
LD given before PCI in only 25% of patients
Timing of administration
Clopidogrel 600mg LD was not considered
Composite endpoint conclusion
• Delfini Validity and Usability Grade B
– Possibly useful within noted populations
– More studies needed
Schafer JA, Kjesbo NK, Gleason PP. Critical review of prasugrel
for formulary decision makers. JMCP. 2009;15(4):335-342.
PRINCIPLE-TIMI 44: Study Design
Loading phase
n = 201
Planned elective PCI
Baseline laboratory measures
Clopidogrel naïve
No planned GP IIb/IIIa use
Prasugrel
60 mg
Clopidogrel
600 mg
0.5 hr Post-loading-dose labs
Coronary angiography
Post-angiography labs
Maintenance phase
n = 100
Clopidogrel
150 mg × 14 days
Prasugrel
10 mg × 14 days
PCI
No PCI
6 h* labs, 18–24 hr labs
6 hr* labs, 15 day events
Day 15 clinical events,
labs,† CROSSOVER
Day 29 clinical events, labs†
Prasugrel
10 mg × 14 days
Clopidogrel
150 mg × 14 days
1º Enpoint: *Loading = 6 hr IPA (20 µM ADP); †Maintenance = Day 15 or 29 IPA (20 µM ADP)
Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in
Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial.
Circulation. 2007 Dec 18;116(25):2923-32.
PRINCIPLE-TIMI 44: Results
• IPA at six hours significantly greater in
subjects receiving prasugrel compared
with clopidogrel in LD and MD phases
– prasugrel 60 mg (74.8+13.0%) vs clopidogrel
600 mg (31.8+21.1%), p<0.0001
– prasugel 10 mg (61.3+17.8%) vs clopidogrel
150 mg (46.1+21.3%), p,0.0001
• More rapid onset of action than clopidogrel
in both phases
PRINCIPLE-TIMI 44: Limitations
• Not powered to detect clinical efficacy difference
• Higher levels of platelet inhibition may or may not
translate into clinical efficacy
• Excluded patients with NSTEMI and/or STEMI who were
to be managed with PCI
• Timing of LD administration
• Delfini Validity and Usability Grade U
– Additional valid evidence needed to demonstrate
causal link between study outcomes and a clinically
significant outcome
Summary: Economic Studies
Citation
Time
Cost Measure
(US$)
Outcome
Etemad et
al.
1 yr
Total health care
utilization for pts
with new-onset
ACS
• Total 1st yr direct costs to
MCO: $309 million
- Younger age associated
with higher cost
Shetty S et 1 yr
al.
Total cost of care
Medical and
pharmaceutical costs
significantly higher for pts
with new ACS
Sidney S
et al.
1 yr
Total mean
hospitalization
and follow-up
costs per patient
Patients not undergoing
procedure had lower
hospitalization costs, but
higher follow-up costs
Menzin et
al.
1 yr
Total 3rd party
costs for ACSrelated, ischemic
heart disease,
and all cause
Total mean hospitalization
costs were same for all
three categories. ACSrelated costs accounted for
83% of total IHD-related
expenditure
Cost-effectiveness of Prasugrel Versus
Clopidogrel in Patients with ACS and Planned
PCI: Results from TRITON-TIMI 38 Trial
Costs: - $221
Life expectancy:
+ 0.102 years
BUDGET IMPACT MODEL
• Model Design
– Estimates impact of adding prasugrel to the
formulary on either MCO or hospital costs
– Time horizon: 3 years
• Model Assumptions
– Patients having ACS+PCI with no history of
stroke or trans transient ischemic attack (TIA)
– Maximum market share of 50% after 1 year
– Complete (100%) adherence and persistence
– No switching from clopidogrel to prasugrel
PROJECTED BUDGET IMPACT
• Model parameters:
– MCO perspective; Medicare and commercial
– 2,650,00 population
– 5,151 pts undergoing PCI eligible for thienopyridine
Total Costs
Current
Projected
Absolute
Difference
Relative
Difference
Annual Costs
$124,086,590.90
$123,476,060.55
-$610,530.35
-0.49%
Per member per
month (PMPM)
$3.90
$3.80
-$0.02
-0.49%
$1,997.62
-$9.88
-0.49%
Per treated
$2,007.49
member per
month (PTMPM)
BIM: SENSITIVITY ANALYSIS
Packaging price or
Incidence rate of repeat
PCI of prasugrel
O
R
Packaging price or
Incidence rate of repeat
PCI of clopidogrel
$ Prasugrel+Clopidogrel > $ Clopidogrel
• Additional Considerations
– Generic clopidogrel
– High-dose clopidogrel
– Extrapolation of outcome measures
EFFIENT™:
SUMMARY OF EVIDENCE
• Clinical Comparison to Clopidogrel
– Quicker onset of action, higher, more
consistent IPA
– Less interpatient variability
– Fewer CV-related events
– Benefit for diabetes and STEMI patients
– Higher bleed risk
– Contraindicated if history of stroke or TIA
EFFIENT™:
SUMMARY OF EVIDENCE
• Economic Comparison to Clopidogrel
– BIM and economic studies: “economically dominant”
• Lower costs ($221 per patient)
• Greater life expectancy (0.102 years)
– Results may not be directly applicable at this time
•
•
•
•
Medicare / Medicaid
Long term outcomes / effects of prasugrel
Generic clopidogrel
High dose clopidogrel
PITT STREET HEALTH PLAN
• Three-tier structure
• 2,650,000 covered lives
Prescription Benefit : Thienopyridines
Preferred / Formulary
Non-Preferred / Non-Formulary
Ticlopidine (Ticlid®)
Prasugrel (Effient™ [Eli Lily&Co.]
[generic]
Clopidogrel (Plavix®)
[Bristol-Myers Squibb /
sanofi-aventis]
RECOMMENDATIONS TO THE
COMMITTEE: Effient™ (prasugrel)
• “Preferred/Formulary”
• Prior authorization:
1. < 75 years of age AND > 60 kg
•
•
•
•
ACS-UA/NSTEMI and STEMI with primary or delayed PCI
AND no history of TIA, stroke, or active bleeding
AND no expected urgent CABG
AND no known significant hepatic failure
2. > 75 years of age AND > 60 kg
• All previous criteria
• Diabetes OR Previous MI OR Failed clopidogrel therapy
– Initial approval: 12 months