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A Cost-Effectiveness Analysis of Multi-Gene Pharmacogenetic Testing in Acute Coronary Syndrome Patients Following Percutaneous
Coronary Intervention Olivia Dong, MPH
Wiltshire Lab, Eshelman School of Pharmacy
University of North Carolina at Chapel Hill, USA
ISPOR 21th Annual European Congress
November 13, 2018
PGx is the study of genetic differences in drug metabolic pathways that can affect individual responses to drugs (therapeutic effect and/or adverse effects).
Pharmacogenetics (PGx) Can Help Optimize
Drug Prescribing
2
Many Drugs Have PGx Guidelines
133 FDA-approved drugs have PGx information.
This includes information for 37 genes (germline
mutations).
36 drugs have CPIC guidelines.
This includes information for 14 genes (germline
mutations).
• These drugs cover various therapeutic areas: oncology, psychiatry, cardiology, infectious disease, etc.
• Only 7% of US hospitals offer PGx testing.
Johnson and Weitzel, Clin Pharmacol Ther., 2016
When patients are prescribed a drug with actionable
PGx guidance, should multi-gene or single gene PGx
testing be done?
Multi-Gene Testing
Provides genetic information to help optimize the
prescribing of an immediate drug PLUS additional
genetic information for drugs that may be prescribed
in the future.
Provides genetic information to help optimize
the prescribing of an immediate drug.
Single-Gene Testing
3
ObjectiveTo determine the cost-effectiveness of multi-gene PGx testing (CYP2C19, SLCO1B1, CYP2C9, VKORC1) for acute coronary syndrome patients (ACS) undergoing percutaneous coronary intervention (PCI) compared to single-gene PGx testing (CYP2C19) and standard of care (no genotyping) from the perspective of Medicare.
Medication Gene(s) At-risk
genotype
Outcome Recommended action for
at-risk genotype carriers
Clopidogrel CYP2C19 *2-*8 Increased risk
for adverse
cardiovascular
events
Alternative antiplatelet is
recommended (prasugrel
or ticagrelor)1
Simvastatin SLCO1B1 rs4149056
TC or CC
Increased
myopathy risk
Prescribe lower dose or
consider alternative statin2
Warfarin CYP2C9
&
VKORC1
Various
combinations
Increased risk
for bleeding
A lower dose of warfarin is
recommended3
CVD medications with CPIC guideline recommendations
1Scott et al., Clin Pharmacol Ther., 2013 ; 2Ramsey et al., Clin Pharmacol Ther., 2014 ; 3Johnson et al., Clin Pharmacol Ther., 2017
The health benefits of multi-gene PGx testing have not been investigated in ACS patients undergoing PCI before.
Novelty
Multi-gene
Testing+
Medicare patients with
ACS undergoing PCI
health
benefits?=
4
CVD Patient Population
• ~300,000 PCI with stent placement are completed each year in Medicare patients with acute coronary syndrome (ACS).1
1Kim et al., Am J Cardiol., 20142Levine et al., J. Am. Coll. Cardiol., 20163Levine et al., Circulation, 20114Brilakis et al., JAMA, 20135Stone et al., J. Am. Coll. Cardiol, 2014
• A long-term statin is indicated as a secondary prevention measure.5
• Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor is indicated for at least 12 months following a percutaneous coronary intervention (PCI) for ACS events.2-4
• A proportion of these patients may develop atrial fibrillation and require anticoagulation.
Basic Structure of the Model
Standard of Care
(no genetic testing)
Multi-Gene Testing
(CYP2C19, SLCO1B1,
CYP2C9, VKORC1)
Cost
QALYs
Cost
QALYs
Single-Gene Testing
(CYP2C19)
Cost
QALYs300,000 65-year
old Medicare
beneficiaries with
ACS undergoing
PCI
• Primary Outcome: Cost per quality-adjusted life years (QALY) gained
• Costs include genotyping, outcome events, and prescription costs
• QALYs reflect specific health outcomes that were tracked in the model
Outcomes:
Simulated model
cohort assigned to
each intervention:
Interventions:
• A hybrid decision tree/Markov model evaluated the lifetime costs and health benefits for the 3 intervention strategies.
5
Timeline of Major Outcomes Tracked in Model
300,000 65-year
old Medicare
beneficiaries with
ACS undergoing
a PCI receive an
antiplatelet and
statin therapy
Evaluation for
atrial
fibrillation
(only those
prescribed
warfarin are
followed)
End
of
LifeWarfarin therapy
associated
outcomes: major
bleed,
thromboembolic
events, all-cause
mortality
15
months
CYP2C9,
VKORC1• Atrial fibrillation
development evaluated
every 12 months
• Warfarin associated
outcomes evaluated every
15 months
Antiplatelet therapy
associated outcomes:
stroke, myocardial
infarction, major bleed,
cardiovascular-related
death,
non-cardiovascular
related death
CYP2C19
24
months
Statin therapy associated
cardiovascular outcomes:
stroke, myocardial infarction,
cardiovascular-related
death,
non-cardiovascular-related
death
SLCO1B1
Start12
months
Methods
• Model inputs were estimated from published studies and Medicare fee schedules. All costs were inflated to 2018 US dollars. Cost and QALYs were discounted at 3% per year.
• Base-case scenario reflects current national prescribing patterns for antiplatelet and stain therapy and warfarin.
• Probabilistic sensitivity analysis with 10,000 Monte Carlo simulations was completed using Oracle® Crystal Ball Classroom Edition, Release 11.1.2.4.
• Parameters that were varied included: disease incidence, event cost, prescription cost, outcome events, and health state utilities.
6
Base-Case Scenario Analysis Results (Lifetime)
Intervention Cost
per
person
QALY
per
person
Incremental
cost ($)
Incremental
QALYs (n)
ICER
($/QALY)
Standard of Care $5,956 13.166 - - -
Multi-gene testing $6,148 13.215 $192 0.049 $3,918
Single-gene testing Dominated
Costs are reported in 2018 US$, cost and QALYs were discounted at 3% per year.
Interventions are rank-ordered by cost and sequentially compared.
Incremental cost-effectiveness ratio (ICER) of genotype strategies in 300,000 Medicare beneficiaries after ACS with PCI.
Multi-gene testing was the most cost-effective intervention at a willingness-to-pay threshold of $50,000/QALY.
Cost-effectiveness acceptability curve (CEAC) comparing the probability of cost-
effectiveness at various willingness-to-pay thresholds for the cost per QALY gained
for standard of care, single-gene testing, and multi-gene testing.
Probabilistic Sensitivity Analysis (Lifetime)
Costs are reported in 2018 US$, cost and QALYs were discounted at 3% per year.
Multi-gene testing was the preferred intervention starting at a willingness-to-pay threshold of ~$12,500.
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Willingness-to-Pay Threshold (2018 $US)
Multi-gene Testing Standard of Care Single-gene Testing
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LimitationsOnly 4 genes and 3 CVD medications were included in the multi-gene PGx testing strategy when more genes are often included in these tests.
The results likely underestimate the true benefits of multi-gene PGx tests that impact numerous additional non-CVD medications.
Generalizability is limited to U.S. Medicare patients.
Assumed genetic information would be followed 100% according to FDA and CPIC guidelines.
Assumed genetic information would be available at the time of drug prescribing and would follow Medicare patients over their lifetime.
• In the long-term, multi-gene PGx testing (CYP2C19, SLCO1B1, VKORC1, CYP2C9) was the most cost-effective intervention to help optimize medication selection for Medicare beneficiaries who are undergoing a PCI for ACS when compared to single-gene PGx testing (CYP2C19) and standard of care (no genotyping).
• Future research is needed to evaluate additional gene-drug pairs that may also be relevant for this population to obtain a more comprehensive understanding of the impact multi-gene PGx testing provides for this patient population.
Conclusions
8
When patients are prescribed a drug with actionable
PGx guidance, should multi-gene or single gene PGx
testing be done?
Multi-Gene Testing
Provides genetic information to help optimize the
prescribing of an immediate drug PLUS additional
genetic information for drugs that may be prescribed
in the future.
Provides genetic information to help optimize
the prescribing of an immediate drug.
Single-Gene Testing
This cost-effectiveness analysis suggests that multi-gene testing is the preferred
strategy in patients with ACS undergoing PCI.
Acknowledgements
Tim Wiltshire, PhD
Craig Lee, PharmD, PhD
Stephanie Wheeler, PhD, MPH
Stacie Dusetzina, PhD
Deepak Voora, MD
Gracelyn Cruden, MA
Funding sources:
• American Heart Association Predoctoral Fellowship (18PRE33960079)
• UNC Eshelman Institute for Innovation grant R1020
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Drug Prescribing Breakdown for Cohort*Drug CPIC
Guidelines
Proportion of
Cohort1,2,3
Antiplatelet Therapy (for ACS with PCI)
Clopidogrel CYP2C19 75%
Prasugrel -- 10%
Ticagrelor -- 15%
Statin Therapy (for ACS with PCI)
Simvastatin SLCO1B1 13%
Other statin
(atorvastatin, fluvastatin,
lovastatin, pitavastatin,
pravastatin, rosuvastatin)
-- 87%
Anticoagulant Therapy (for atrial fibrillation)
Warfarin CYP2C9/VKO
RC1
30%
Other anticoagulants/None -- 70%
*The drug prescribing breakdowns are based on current national prescribing patterns in Medicare patients.
1Kim et al., J Manag Care Spec Pharm, 2017; 2Rosenson et al., J Am Coll Cardiol., 2017; 3Hernandez et al., Stroke, 2017
12 months of
antiplatelet therapy
Long-term statin
therapy
Long-term
anticoagulant
therapy
11
End of
Life
Antiplatelet therapy associated outcomes
Drugs included: clopidogrel, prasugrel, ticagrelor
Health Outcomes References
• Stroke
• Myocardial infarction
• Major bleed
• Cardiovascular-related
death
• Non-cardiovascular death
• PLATO study (ticagrelor vs clopidgorel)
• TRITON-TIMI 38 study (prasugrel vs
clopidogrel)
• Two meta-analyses for clopidogrel outcomes
based on CYP2C19 carrier status (Jin et al
2011, and Hulot et al 2010)
Input Parameters: Antiplatelet therapy Associated Outcomes
15
months
24
months12
monthsStart
End of
Life
Warfarin dosing associated outcomes
Health Outcomes References
• Major bleed
• Thromboembolic
event
• Death
• Two meta-analyses comparing outcomes for standard
warfarin dosing to pharmacogenetic-guided dosing for
warfarin (Shi et al 2015, Li et al 2015)
Input Parameters: Warfarin Dosing Associated Outcomes
15
months
24
months12
monthsStart
12
Input Parameters: Statin therapy Associated Outcomes
End of
Life
Statins included: simvastatin vs other statins
(atorvastatin, pravastatin, rosuvastatin, lovasatin)
Health Outcomes References
• Adherence to statin
(based on
myalgia/myopathy)
• Stroke
• Myocardial infarction
• Cardiovascular-related
death
• Non-cardiovascular death
• A retrospective cohort study that estimated
statin adherence based on myopathy events
and proportion attributed to SLCO1B1 (Zhang
et al 2017; Search Collaborative Group 2008)
• Phase Z of the A to Z Trial: a large RCT of high
intensity vs low intensity/placebo statin therapy
(de Lemos et al 2004)
15
months
24
months12
monthsStart
Base-Case Scenario Analysis Results (12 and 24 months)
Intervention ICER
($/QALY)
12 months
Single-gene testing vs. standard of care $74,079
Multi-gene testing vs. standard of care $60,221
Multi-gene testing vs. single gene testing Dominant
24 months
Single-gene testing vs. standard of care $41,517
Multi-gene testing vs. standard of care $33,799
Multi-gene testing vs. single gene testing Dominant
Costs are reported in 2018 US$, cost and QALYs were discounted at 3% per year.
Incremental cost-effectiveness ratio (ICER) of genotype strategies in 300,000 Medicare beneficiaries after ACS with PCI.
13
Cost-effectiveness acceptability curve (CEAC) comparing the probability of cost-
effectiveness at various willingness-to-pay thresholds for the cost per QALY gained
for standard of care, single-gene testing, and multi-gene testing.
Probabilistic Sensitivity Analysis (12 months)
Costs are reported in 2018 US$, cost and QALYs were discounted at 3% per year.
Multi-gene testing was the preferred intervention starting at a willingness-to-pay threshold of ~$65,000.
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Willingness-to-Pay Threshold (2018 $US)
Multi-gene Testing Standard of Care Single-gene Testing
Cost-effectiveness acceptability curve (CEAC) comparing the probability of cost-
effectiveness at various willingness-to-pay thresholds for the cost per QALY gained
for standard of care, single-gene testing, and multi-gene testing.
Probabilistic Sensitivity Analysis (24 months)
Costs are reported in 2018 US$, cost and QALYs were discounted at 3% per year.
Multi-gene testing was the preferred intervention starting at a willingness-to-pay threshold of ~$125,000.
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Willingness-to-Pay Threshold (2018 $US)
Multi-gene Testing Standard of Care Single-gene Testing
