Slide 1

Report
Effient® (prasugrel)
for the reduction of atherothrombotic events
in ACS in patients with UA, NSTEMI and
STEMI managed with PCI
Therapeutic Review
Prepared for Pitt Street Health
Kimberly Garrison
Jaewoo Lee
Aleksandra Stojkoska
Brittany Thompson
Outline
• Acute Coronary Syndrome
–
–
–
–
Epidemiology
Demographics and Cost
Diagnosis
Treatment
• Thienopyridine Pharmacokinetics/Pharmacodynamics
• CYP2C19 Interactions
– Non-responders
– Proton Pump Inhibitor use
•
•
•
•
•
JUMBO-TIMI 26
TRITON-TIMI 38
PRINCIPLE-TIMI 44
Economic Considerations
Recommendation
Acute Coronary Syndrome
Epidemiology
• Leading cause of death in The United States
– 25% of deaths
• 445,687 people died from coronary heart
disease in 2005
• 17,600,000 people alive with coronary heart
disease
• 316.4 billion dollars in costs in 2010
CDC: Heart Disease Facts. [Internet]. Atlanta: Center for Disease Control and Prevention. America's Heart Disease
Burden; 2010 Dec 21 [Cited 2011 Jan 15]; Available from: http://www.cdc.gov/heartdisease/facts.htm
Acute Coronary Syndrome
Pitt Street Health Demographics
Plan Enrollment:
2,650,000
Patients Patients
<65
65-74
Patients
Incidence years
years
≥75 years
Total
Diagnosis with ACS
0.51%
5,755
3,033
4,688
13,476
Undergoing a PCI
30.8%
2,283
973
897
4,153
Cost per day associated with ACS events
Repeat PCI
$20,060
Stroke
$12,143
Angina
$4,794
MI
$15,086
CABG
$46,002
Other Vascular Intervention
$18,280
Other Cardiac Conditions
$9,683
Effient® (prasugrel) Dossier. Eli Lilly and Daiichi-Sankyo. Prepared using AMCP format for formulary submissions, version 2.1.
Acute Coronary Syndrome
Diagnosis
Alpert et al. J Am Coll Cardiol 36 (3): 959–69
Acute Coronary Syndrome
Treatment
• Upon hospital arrival:
– MONA
• Morphine, oxygen, nitroglycerine, aspirin
– Beta blockers
• Only if an increase in heart rate is present
• Upon discharge:
–
–
–
–
–
Statin
Beta-blocker
Aspirin
Ace Inhibitor/ARB
Thienopyridine
Blais D. Acute coronary syndromes. Presentation given at: The Ohio State University chapter of
Academy of Managed Care Pharmacy. General body meeting. 2010 Nov 9th; Columbus,OH.
Platelet Inhibitors
Thienopyridines
Clopidogrel
Prasugrel
Ticagolor
Loading Dose
300-600 mg
60mg
180mg
Maintenance Dose
75 mg daily
10 mg daily
90 mg twice
daily
Route
Oral
Oral
Oral
Binding to P2Y12
Irreversible
Irreversible
Reversible
Prodrug
Yes
Yes
No
Hepatic
Metabolism
CYP C219
CYP 3A, 2B6,2C19
None
Platelet Inhibition
40%
~70%
95%
Onset
2 hours
30- 60 minutes
2 hours
DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically.
Platelet Inhibitors
Mechanism of Action
Schomig a. N Engl J Med. 361:1108-
CYP2C19 Interactions
Therapeutic Non-response
Bonello et al. J Am Coll Cardiol. 2010;56:919-33
CYP2C19 Interactions
Therapeutic Non-response
Primary Outcome
Composite of death from cardiovascular causes,
nonfatal myocardial infarction, or stroke
Pare et al. N Engl J Med. 2010 Oct 28;363(18):1704-14
CYP2C19 Interactions
Proton Pump Inhibitors
•Clopidogrel is converted to its active metabolite
via CYP enzymes, particulary CYP2C19
•PPI’s, shown as omeprazole, are inactivated via
the same CYP450 enzymes that activate
clopidogrel
•Concomitant use of clopidogrel with PPI’s
theoretically reduces clopidogrel effectiveness
which leads to worse outcomes
Madanick et al. Cleve Clin J Med. 2011 Jan;78(1):39-49.
CYP2C19 Interactions
Proton Pump Inhibitors
Long-term follow-up and rate of primary endpoint
(right); Proportion of non-responsders 6h (A) and 15
days (B) after clopidogrel or prasugrel stratified by the
use of a PPI in PRINCIPLE-TIMI 44 (left)
O’Donoghue et al. Lancet. 2009 Sep 1; 374:989-97.
JUMBO-TIMI 26
Study Design
Phase 2, multicenter, randomized, parallel-group, ITT,
double-blind, active comparator-controlled trial
Wiviott et al. Circulation. 2005 Jun 20;111:3366-73.
JUMBO-TIMI 26
Outcomes
A
D
B
C
E
F
Wiviott et al. Circulation. 2005 Jun 20;111:3366-73.
TRITON-TIMI 38
Study Design
N=
10,074
N=
3,534
Wibiott et al. Amer Heart Jour. 2006 Oct;152(4):627-35.
TRITON-TIMI 38
Efficacy Outcomes
Efficacy Endpoints:
• Primary:
• Death from CV causes,
non-fatal MI or non-fatal
stroke
• Secondary:
• Stent thrombosis,
rehospitalization
Antman et al. JACC;51(21):2028-33
TRITON-TIMI 38
Safety Outcomes and Net Clinical Benefit
• Safety Outcomes
Stent thrombosis,
rehospitalization, and TIMI
major non-CABG bleed
•Study Strengths:
Sample size adequate for 90%
power, length of study,
randomized, double-blinded
•Study Limitations
Funding from Eli Lilly, did not use
highest possible dose of
clopidogrel, mostly white males
Antman et al. JACC;51(21):2028-33
TRITON-TIMI 38
Special Populations - Diabetics
Wiviott et al. Circulation. 2008 Aug 31;118:1626-36.
TRITON-TIMI 38
Special Populations – Stent Placements
• The graph to the left shows both early (030 days) and late (30 days on) thrombosis
• At 0-30 days, stent thrombosis was
reduced by 59% for prasugrel vs.
clopidogrel (p<0.0001)
• At 30 days on, stent thrombosis was
reduced by 40% for prasugrel vs.
clopidogrel (p=0.03)
• The table to the right shows the effect of
prasugrel versus clopiogrel in key
subgroups
• The most significant treatment subgroup
favoring prasugrel was in patients with a
previous MI (p=0.047)
Wiviott et al. Lancet. 2008 Apr 19;371:1353-63.
PRINCIPLE-TIMI 44
Study Design
Wiviott et al. Circulation. 2007 Dec 3;116:2923-32.
PRINCIPLE-TIMI 44
Loading Dose Phase
• Primary efficacy endpoint significantly greater after prasugrel
vs. clopidogrel (p<0.0001)
• Patients treated with prasugrel had more rapid onset of
inhibition observed at 30 minutes
Wiviott et al. Circulation. 2007 Dec 3;116:2923-32.
PRINCIPLE-TIMI 44
Maintenance Dose Phase
• Primary efficacy endpoint significantly greater for prasugrel vs.
clopidogrel (p<0.0001)
• Patients treated with prasugrel were observed to have more
consistent levels of inhibition and few hyporesponsive episodes
Wiviott et al. Circulation. 2007 Dec 3;116:2923-32.
Economic Considerations
Budget Impact Model
• Model was designed to estimate the total annual costs for
treating a population with either prasugrel or clopidogrel
– Patients with no history of transient ischemic attack that are to
undergo treatment with a thienopyridine
• Patients took the thienopyridine for up to 15 months after PCI
• Model assumes a 100% compliance rate of clopidogrel and
prasugrel
• Lacks consideration of other thienopyridine agents
– Does not take into account other medications required to prevent an
additional ACS event from occurring
• Model results included a favorable incremental cost
effectiveness ratio (ICER) over clopidogrel
• Overall cost-benefit analysis conducted found treatment with
prasugrel to decrease overall costs due to lower rate of
rehospitalization involving PCI
– Prasugrel is the economically dominant treatment strategy
Effient® (prasugrel) Dossier. Eli Lilly and Daiichi-Sankyo. Prepared using AMCP format for formulary submissions, version 2.1.
Economic Considerations
Cost of Thienopyridine per year
Prasugrel
Clopidogrel
Year 1
$307,638
$4,954,940
Year 2
$1,154,511
$9,977,162
Year 3
$2,115,008
$7,055,834
Year 4
$2,402,058
$3,029,085
Year 5
$1,951,077
$3,192,024
At year 2 generic clopidogrel is introduced to the market
Number of eligible for treatment with a thienopyridine: 3093
Percent of patients taking prasugrel / Percent of patients taking clopidogrel:
Year 1: 5 /95
Year 2: 10/90
Year 3: 12/88
Year 4: 13/87
Year 5: 15/85
. The Congress of the United States: Congressional Budget Office. July 1998: 1-70.
Hong SH et al.JMCP. 2005;11(9):746-754.
Economic Considerations
Cost-Benefit Analysis
Prasugrel
Year 1
Year 2
Year 3
Year 4
Total
Cost/year
$270,523
$1,099,534
$1,918,375
$2,074,988
Year 5
$657,125
PMPM
$0.09
$0.26
$0.37
$0.32
$0.20
PTMPM
$1,583
$1,508
$1,436
$1,368
$1,303
Year 1
$5,285,669
Year 2
$9,829,033
Year 3
$9,449,897
Year 4
$4,290,514
Year 5
$3,793,547
PMPM
$1.99
$3.71
$3.57
$1.62
$1.43
PTMPM
$1,658
$1,579
$1,620
$1,678
$1,360
Clopidogrel
Total
Cost/year
Effient® (prasugrel) Dossier. Eli Lilly and Daiichi-Sankyo. Prepared using AMCP format for formulary submissions, version 2.1.
Economic Considerations
Cost-Benefit Analysis
Direct Medical
Savings
PMPM
PTMPM
Year 1
$5,015,147
$1.89
$1,621
Year 2
$9,037,202
$3.41
$1,461
Year 3
$8,312,709
$3.14
$1,344
Year 4
$3,271,909
$1.23
$1,074
Year 5
$3,136,422
$1.18
$1,035
Effient® (prasugrel) Dossier. Eli Lilly and Daiichi-Sankyo. Prepared using AMCP format for formulary submissions, version 2.1.
Recommendation
for Pitt Street Health Formulary
• Movement of prasugrel from non-preferred
brand to preferred brand
– Requires a prior authorization
Approved dose
Age Restrictions
Ineligible for treatment
Recommended follow-up
Recommended length of
therapy
Prasugrel 10 milligrams daily
Not approved for patients >75
yoa
Patients <60kg, prior TIA or
CVA or CABG scheduled in
next 7 days
Two weeks, 1 month, then
every 3 months thereafter
Left to the discretion of the
health-care team
Recommendation
Flow-chart for Decision Making
ACS patient
UA
STEMI
First event?
NSTEMI
N
Diabetic or
previous stent?
TIMI
N
Y
5+
0-2
3-4
Intermediate
High
Low
Intermediate
Y
•High Risk:
•Intermediate Risk:
•Low Risk:
TIMI
0-4
5+
High
Intermediate
prasugrel
prasugrel or clopidogrel
clopidogrel
High
Recommendation
Role of Health-Care Practitioners
• Physician/Cardiologist
– Identifying patients as high, intermediate or low risk
– Prescribing the appropriate dose of chosen thienopyridine
– Monitoring of safety/efficacy of agent chosen
• Clinical Pharmacist
– Assisting the physician in identifying high, intermediate or low
risk patients and determining the appropriate dose
– Follow up with patient to assess safety/efficacy
– Appropriately educating patient on proper use of thienopyridine
• Community Pharmacist
– Dispensing correct product from pharmacy
– Medication therapy management and drug-utilization review of
all medications the patient is currently taken
Effient® (prasugrel)
for the reduction of atherothrombotic events
in ACS in patients with UA, NSTEMI and
STEMI managed with PCI
Therapeutic Review
Prepared for Pitt Street Health
Kimberly Garrison
Jaewoo Lee
Aleksandra Stojkoska
Brittany Thompson

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