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Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USACenter for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USACurrently at the Center for Applied Genomics & Precision Medicine, Duke University School of Medicine, Durham, NC, USA
Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USACenter for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USAMcAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USACenter for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USADepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
To evaluate the cost-effectiveness of multigene testing (CYP2C19, SLCO1B1, CYP2C9, VKORC1) compared with single-gene testing (CYP2C19) and standard of care (no genotyping) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) from Medicare’s perspective.
Methods
A hybrid decision tree/Markov model was developed to simulate patients post-PCI for ACS requiring antiplatelet therapy (CYP2C19 to guide antiplatelet selection), statin therapy (SLCO1B1 to guide statin selection), and anticoagulant therapy in those that develop atrial fibrillation (CYP2C9/VKORC1 to guide warfarin dose) over 12 months, 24 months, and lifetime. The primary outcome was cost (2016 US dollar) per quality-adjusted life years (QALYs) gained. Costs and QALYs were discounted at 3% per year. Probabilistic sensitivity analysis (PSA) varied input parameters (event probabilities, prescription costs, event costs, health-state utilities) to estimate changes in the cost per QALY gained.
Results
Base-case–discounted results indicated that the cost per QALY gained was $59 876, $33 512, and $3780 at 12 months, 24 months, and lifetime, respectively, for multigene testing compared with standard of care. Single-gene testing was dominated by multigene testing at all time horizons. PSA-discounted results indicated that, at the $50 000/QALY gained willingness-to-pay threshold, multigene testing had the highest probability of cost-effectiveness in the majority of simulations at 24 months (61%) and over the lifetime (81%).
Conclusions
On the basis of projected simulations, multigene testing for Medicare patients post-PCI for ACS has a higher probability of being cost-effective over 24 months and the lifetime compared with single-gene testing and standard of care and could help optimize medication prescribing to improve patient outcomes.
Approximately 7% of the 1200 FDA-approved medications have pharmacogenetic guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC), which involves genetic information for 17 genes.
Integrating pharmacogenetic information in the drug-prescribing process can help optimize medication selection to achieve better patient outcomes through better drug efficacy and avoiding unwanted side effects.
Clinical incorporation of pharmacogenetic testing is typically completed for the immediate drug being prescribed. For patients receiving a percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS), single-gene testing for CYP2C19 has been implemented at multiple centers to guide selection of antiplatelet therapy. CPIC guidelines recommend use of prasugrel or ticagrelor for patients with CYP2C19 variants (*2 to *8) to reduce their increased risk for cardiovascular events on clopidogrel, the most commonly prescribed antiplatelet therapy.
Multigene testing, a strategy that tests for multiple pharmacogenetic genes, provides information for multiple drugs and has been proposed as an alternative to single-gene testing.
In addition, the availability of comprehensive pharmacogenetic results allows clinicians to incorporate genetic information into future prescribing decisions immediately.
Patients undergoing a PCI for ACS could potentially benefit from multigene testing rather than CYP2C19 testing alone. These patients often have comorbidities that necessitate frequent use of additional drugs that have associated CPIC guidelines
; for example, a long-term statin therapy post-ACS as secondary prevention is recommended, and lower simvastatin doses or alternative statin use for patients with SLCO1B1 variants (rs4149056 C allele) avoids an increased risk of myopathy.
Additionally, patients with ACS are at higher risk to develop atrial fibrillation during their lifetime compared with the general population, and CPIC guidelines for CYP2C9 and VKORC1 can help optimize warfarin dosing to help prevent thromboembolic and bleeding events. Specifically, reduced warfarin doses should be used for patients with various CYP2C9 (*2, *3) and VKORC1 (rs9923231 A allele) variant combinations because of an increased risk of bleeding at standard warfarin dosing.
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.
Approximately 40% of patients have CYP2C9/VKORC1 variant combinations and could benefit from pharmacogenetic testing to determine optimal warfarin dosing.
Although there are advantages to multigene testing over single-gene testing, the benefits of having comprehensive genetic information available for future drug prescribing in patients post-PCI for ACS have not been investigated to inform insurance reimbursement decisions.
Pharmacogenetic health economic evaluations in patients post-PCI with ACS are limited to evaluating single-gene CYP2C19 testing in antiplatelet therapy selection.
To this end, the objective of this study was to conduct a cost-effectiveness analysis to investigate the cost and potential health benefits associated with providing a multigene test for Medicare patients post-PCI for ACS. The gene-drug pairs included in the multigene testing strategy were limited to major cardiovascular therapeutic agents these patients are at a higher risk of being prescribed, including CYP2C19 for antiplatelet therapy selection, SLCO1B1 for statin selection, and CYP2C9/VKORC1 for warfarin dosing.
Methods
Model Structure
A hybrid decision tree/Markov model (Fig. 1) was developed in Microsoft Excel, version 14.7.7 (Redmond, WA), to evaluate the cost-effectiveness of 3 genotyping strategies for Medicare patients post-PCI for ACS from the perspective of Medicare: (1) standard of care (no genotyping), (2) single-gene testing (CYP2C19 for antiplatelet therapy selection), and (3) multigene testing (CYP2C19 for antiplatelet therapy selection, SLCO1B1 for statin selection, and CYP2C9/VKORC1 for warfarin dosing). Three time horizons were investigated: 12 months, 24 months, and lifetime. Patients entered one of the 3 interventions and remained on an antiplatelet therapy for 12 months. Cardiovascular outcomes associated with antiplatelet therapy were reported at 12 months and included no event, stroke, myocardial infarction (MI), major bleed, cardiovascular-related death, and non-cardiovascular-related death. A long-term statin was prescribed at the time of the PCI, and events associated with statin therapy were considered only for statin initiators. Statin-related outcomes at 1 month included myalgia and myopathy, which affected long-term adherence to statin therapy and associated cardiovascular outcomes.
Cardiovascular outcomes based on statin adherence were reported at 24 months, which included no event, stroke, MI, cardiovascular-related death, and non-cardiovascular-related death. Development of new-onset atrial fibrillation was assessed at 12 months in the decision tree and then every 12 months during the lifetime of the patient population using a Markov node starting at 24 months. Three-month outcomes after atrial fibrillation diagnosis and initiation of warfarin included no event, major bleed, thromboembolic event, and all-cause mortality.
Figure 1Structure of the hybrid decision tree/Markov model. Part A of the model is the decision tree component where 300 000 patients with ACS with PCI enter and are assigned to each of the 3 interventions: standard of care, single-gene testing, and multigene testing. Patients are first prescribed antiplatelet and statin therapies. Adverse outcomes related to statin therapy are assessed at 1 month. At 12 months antiplatelet-therapy-associated outcomes and the development of atrial fibrillation are assessed, and individuals prescribed warfarin are followed for 3-month post–atrial-fibrillation-associated outcomes. Then, the cohort is assessed for statin-therapy-associated long-term outcomes at 24 months. At 24 months, the cohort also enters part B of the model, the Markov component, where the development of atrial fibrillation is assessed each year until the end of life and individuals prescribed warfarin are followed for 3-month post–atrial-fibrillation-associated outcomes. The brackets in the figure indicate that the proceeding chance node branches to the right apply to each of the encompassing branches to the left of the bracket.
A closed cohort of 300 000 Medicare beneficiaries 65 years old post-PCI for ACS was simulated in the model and assigned to each intervention strategy. Institutional review board approval was not required for this study.
Sensitivity analyses were defined by the distribution values listed in this column. Some distributions had infinite tails; therefore, the 1st and 99th percentiles of ranges were used as minimum and maximum values that were tested in the one-way sensitivity analyses.
Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis.
Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis.
Cardiovascular genetic risk testing for targeting statin therapy in the primary prevention of atherosclerotic cardiovascular disease: a cost-effectiveness analysis.
Cost-effectiveness of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation at high risk of bleeding and normal kidney function.
Cost-effectiveness of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation at high risk of bleeding and normal kidney function.
∗ Minimum and maximum values represent the 1st and 99th percentiles of the distribution range that were used in the one-way sensitivity analyses.
† Sensitivity analyses were defined by the distribution values listed in this column. Some distributions had infinite tails; therefore, the 1st and 99th percentiles of ranges were used as minimum and maximum values that were tested in the one-way sensitivity analyses.
Antiplatelet therapy selection and associated events
Patients were assigned to antiplatelet therapies based on recent (2013) national rates of prescription use in individuals aged 65 years and older (75% clopidogrel, 10% prasugrel, 15% ticagrelor).
Cardiovascular event probabilities associated with antiplatelet therapies were approximated using the TRITON-TIMI 38 and PLATO trials, 2 major international randomized controlled trials (RCTs) investigating cardiovascular outcomes in patients post-PCI for ACS randomized to clopidogrel and prasugrel or ticagrelor.
Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.
The event probabilities for patients on clopidogrel were further delineated by CYP2C19 variant carrier status using 2 meta-analyses that investigated cardiovascular outcomes based on CYP2C19 variant carrier status in patients receiving clopidogrel for coronary artery disease and with some undergoing a PCI.
Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis.
For the 2 genotype-guided strategies, patients with CYP2C19 variants originally prescribed clopidogrel were switched to prasugrel. Patients could develop only one cardiovascular outcome associated with antiplatelet therapy over the first 12 months.
Statin therapy selection and associated events
The 45.7% of Medicare patients post-MI with no prior statin therapy were considered statin initiators in the simulated cohort with 13% prescribed simvastatin and 87% prescribed other statins.
Statin-associated muscle symptoms include myopathy and myalgia and were assessed 1 month after initiating statin therapy. Adherence to statin therapy and its associated long-term cardiovascular protection is affected by myopathy and myalgia. It is estimated that among simvastatin users, 60% of myopathies are caused by SLCO1B1 variants and 40% are caused by other factors. This breakdown in the cause of myopathies was applied to myopathies (11 to 26 cases per 10 000 patients per year
) to estimate cases that are caused by SLCO1B1 at-risk genotypes or other factors. Approximately 26% of statin users who experience myalgias and 40% of users who experience myopathies discontinue their statin therapy long-term.
Long-term cardiovascular event probabilities for statin adherence and nonadherence were approximated using 24-month follow-up data from the Phase Z of the A to Z Trial, an RCT of patients post-ACS who either received an intensive or less intensive/placebo statin therapy.
Only patients with SLCO1B1 variants (~25% of the population) in the multigene testing strategy and assigned to receive simvastatin were switched to an alternative statin and were no longer at risk for myopathies/myalgias caused by SLCO1B1 variants. Patients remained on their assigned statin for the entire simulation.
Warfarin use for atrial fibrillation and associated events
Clinical guidelines recommend a long-term anticoagulant for patients with atrial fibrillation to prevent thromboembolic events,
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.
Only patients receiving warfarin as an anticoagulant for the treatment of atrial fibrillation were followed in the model, and patients remained on warfarin long-term. Dose selection for warfarin can be optimized using CYP2C9/VKORC1 genetic information to achieve the target international normalized ratio (INR).
Cardiovascular event probabilities for patients on warfarin to treat atrial fibrillation were approximated using 2 meta-analyses, which included RCTs comparing cardiovascular outcomes in patients on standard warfarin dosing to pharmacogenetic-guided warfarin dosing for a variety of diagnoses.
Patients on the standard of care or single-gene testing do not have CYP2C9/VKORC1 information and received standard warfarin dosing. Patients in the multigene testing intervention group received CYP2C9/VKORC1 testing, and their warfarin dose was tailored based on genetic results.
Costs
CYP2C19 single-gene testing cost was approximated using the Centers for Medicare and Medicaid Services 2016 Clinical Diagnostic Laboratory Fee Schedule.
Medication costs were estimated by averaging 6 months of recently reported monthly costs in the GoodRx database. Event costs associated with MI, stroke, and major bleed were derived from the Centers for Medicare and Medicaid Services 2015 Inpatient Charge Data.
Cardiovascular genetic risk testing for targeting statin therapy in the primary prevention of atherosclerotic cardiovascular disease: a cost-effectiveness analysis.
Cost-effectiveness of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation at high risk of bleeding and normal kidney function.
Health utility values and ranges were obtained from recently published cost-effectiveness analyses conducted in patients with similar cardiovascular diagnoses.
Cost-effectiveness of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation at high risk of bleeding and normal kidney function.
Health utilities for antiplatelet- and statin-associated cardiovascular events were applied for 1 year and then patients returned to an event-free ACS health utility value in subsequent years. If patients developed atrial fibrillation and experienced an adverse outcome while on warfarin (ie, thromboembolic events, major bleed), the associated health utility values were assigned for 1 year and then patients returned to an event-free atrial fibrillation health state utility in subsequent years. Quality-adjusted life years (QALYs) were discounted at 3% per year.
Life expectancy estimates for the cohort were based on a study that constructed period life tables based on comorbid conditions present in a nationally representative sample of Medicare beneficiaries.
On the basis of this retrospective cohort study, the type and number of cardiovascular outcomes accumulated over time were used to estimate life expectancy for the lifetime time horizon (see Appendix Table 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2019.08.002).
The uncertainty of the parameter estimates on costs and health outcomes was investigated in one-way and probabilistic sensitivity analyses using Oracle® Crystal Ball Classroom Edition, Release 11.1.2.4 (Redwood City, CA). Event probabilities, cost, and health state utilities estimates were parameterized using beta, gamma, and beta distributions, respectively.
Input parameters were varied one at a time according to their minimum and maximum values for the one-way sensitivity analyses, and 10 000 Monte Carlo simulations were completed for the probabilistic sensitivity analyses (PSA) using the parameters listed in Table 1.
Outcomes include myopathy/myalgia, number of discontinued statin therapies, stroke, MI, major bleed, thromboembolic events, deaths, life years, and QALYs. Interventions were rank-ordered by total cost and then sequentially compared to determine the incremental cost and gain in QALYs. The primary outcome, cost per QALY gained, was summarized as incremental cost-effectiveness ratios (ICER) and graphed as ICER planes.
Tornado diagrams summarized the one-way sensitivity analyses and identified the top 10 input parameters that have the greatest impact on the ICER, and an alternate scenario using the same methodology outlined for the primary analysis was completed to explore the uncertainty of the variable that had the greatest impact on the ICER. Cost-effectiveness acceptability curves were constructed as part of the PSA to compare the probability of cost-effectiveness at various WTP thresholds ($0 to $150 000) for the cost per QALY gained.
Optimal cost-effectiveness decisions: the role of the cost-effectiveness acceptability curve (CEAC), the cost-effectiveness acceptability frontier (CEAF), and the expected value of perfection information (EVPI).
Cost-effectiveness was evaluated using $50 000 and $100 000 per QALY gained as the willingness-to-pay (WTP) thresholds, 2 commonly accepted cutoffs the United States is willing to spend on improvements in health.
Results
Base-Case Scenario
Tables 2 and 3 summarize the event outcomes and ICERs for the simulated cohort of 300 000 Medicare beneficiaries post-PCI for ACS.
Table 2Base-case results: events for genotype strategies per 300 000 Medicare beneficiaries after acute coronary syndrome with percutaneous coronary intervention for stent placement.
Numbers represent the total number of each event over the indicated time horizon.
Myalgia and myopathy
Discontinue statin long-term
Stroke
MI
Major bleed
TE
Deaths
Total life years
Average life years per person
12 months
Standard of care
4774
1287
2165
20 096
4219
NA
6645
296 678
0.989
Multigene testing
4579
1234
1527
17 181
4498
NA
5741
297 129
0.990
Single-gene testing
4774
1287
1527
17 181
4498
NA
5741
297 129
0.990
24 months
Standard of care
4774
1287
5773
39 018
4260
45
19 948
583 381
1.945
Multigene testing
4579
1234
5146
36 161
4513
14
19 085
584 716
1.949
Single-gene testing
4774
1287
5146
36 161
4540
45
19 086
584 716
1.949
Lifetime
Standard of care
4774
1287
5773
39 018
4900
737
NA
6 438 455
21.46
Multigene testing
4579
1234
5146
36 161
4738
233
NA
6 462 435
21.54
Single-gene testing
4774
1287
5146
36 161
5182
739
NA
6 461 650
21.54
Note. Standard of care resulted in the overall most number of events and lowest total life years across all time horizons when compared with single-gene testing and multigene testing. Multigene testing resulted in an overall lower number of events when compared with single-gene testing at all time horizons.
MI indicates myocardial infarction; TE, thromboembolic events; standard of care, no genotyping; single-gene testing: CYP2C19; multigene testing: CYP2C19, SLCO1B1, CYP2C9, and VKORC1.
∗ Numbers represent the total number of each event over the indicated time horizon.
Table 3Base-case league table results: incremental cost-effectiveness ratio of genotype strategies in 300 000 Medicare beneficiaries after acute coronary syndrome with percutaneous coronary intervention for stent placement.
Cost and QALY discounted at 3% per year; interventions are rank-ordered by total cost and sequentially compared.
Total cost (2016 USD)
Cost per person (2016 USD)
Total Outcome (QALY) (n)
Outcome (QALY) per person (n)
Incremental total cost (2016 USD)
Incremental total QALYs (n)
ICER (Incremental total cost [2016 USD]/ Incremental total QALY [n])
12 months
Standard of care
590 844 110
1969
254 983
0.850
—
—
—
Multigene testing
645 404 459
2151
255 894
0.853
54 560 349
911
59 876
Single-gene testing
657 885 201
2193
255 891
0.853
12 480 742
−3
Dominated
24 months
Standard of care
1 023 694 372
3412
497 265
1.658
—
—
—
Multigene testing
1 079 307 542
3598
498 925
1.663
55 613 171
1659
33 512
Single-gene testing
1 092 068 491
3640
498 919
1.663
12 760 948
−5
Dominated
Lifetime
Standard of care
1 574 907 720
5250
3 949 926
13.166
—
—
—
Multigene testing
1 630 140 791
5434
3 964 538
13.215
55 233 072
14 612
3780
Single-gene testing
1 645 260 453
5484
3 963 752
13.213
15 119 662
−786
Dominated
Note. At all 3 time horizons, single-gene testing is dominated (worse outcomes, higher costs) by multigene testing. The cost per QALY gained was $59 876, $33 512, and $3780 at 12 months, 24 months, and lifetime, respectively, for multigene testing when compared with standard of care. In comparison to standard of care, multigene testing is cost-effective at all 3 time horizons at a WTP threshold of $100 000/QALY and cost-effective only at 24 months and lifetime at a WTP threshold of $50 000/QALY gained.
QALY indicates quality-adjusted life year; ICER, incremental cost-effectiveness ratio; standard of care, no genotyping; single-gene testing, CYP2C19; multigene testing: CYP2C19, SLCO1B1, CYP2C9, and VKORC1; WTP, willingness-to-pay.
∗ Cost and QALY discounted at 3% per year; interventions are rank-ordered by total cost and sequentially compared.
Overall, multigene testing resulted in the fewest events. There were 638 strokes, 2915 MIs, and 904 deaths avoided and a gain in 451 life years at the expense of an increase in 279 major bleeds for patients on either genotyping strategies in comparison to standard of care. Multigene testing had 195 fewer myalgia/myopathy cases and 53 fewer patients who discontinued their statins long term in comparison to single-gene testing and standard of care. The number of myalgia/myopathy cases and statin discontinuations are included in longer time horizons but do not change because they are not assessed beyond this time horizon.
Comparing the interventions sequentially by increasing discounted cost resulted in an ICER ($/QALY gained) of $59 876 for multigene testing when compared with standard of care, and single-gene testing was dominated by multigene testing. Multigene testing compared with standard of care (no genotyping) was only cost-effective at the $100 000/QALY gained WTP threshold.
Twenty-four-month outcomes
Overall, multigene testing resulted in the fewest events. There were 627 strokes and 2857 MIs avoided, and 1335 more life years for patients either of the genotyping strategies when compared with standard of care. Multigene testing had the lowest number of major bleeds and thromboembolic events out of the 3 interventions. The number of strokes and that of MIs are included in longer time horizons but do not change because they are not assessed beyond this time horizon.
Comparing the interventions sequentially by increasing discounted cost resulted in an ICER ($/QALY gained) of $33 512 for multigene testing when compared with standard of care, and single-gene testing was dominated by multigene testing. At both WTP thresholds, multigene testing compared with standard of care was cost-effective.
Lifetime outcomes
Overall, multigene testing resulted in the fewest events. Development of atrial fibrillation is the only new condition assessed annually during the remaining years. Out of the 3 interventions, multigene testing had the highest number of life years and the lowest number of outcomes associated with atrial fibrillation (ie, major bleeds and thromboembolic events).
Comparing the interventions sequentially by increasing discounted cost resulted in an ICER ($/QALY gained) of $3780 for multigene testing when compared with standard of care, and single-gene testing was dominated by multigene testing. At both WTP thresholds, multigene testing compared with standard of care was cost-effective.
One-Way Sensitivity Analysis
The most impactful input parameter across all time horizons comparisons, as indicated by the tornado plots (see Appendix Figs. 1 to 3 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2019.08.002), was the cost of single-gene and multigene testing.
Probabilistic Sensitivity Analysis
Figure 2 shows the cost-effectiveness plane for the 10 000 Monte Carlo simulations estimating the discounted cost per QALY gained for multigene testing versus standard of care and single-gene versus multigene testing. For the 3 time horizons, the majority of simulations for multigene testing compared with standard of care were in the northeast quadrant, indicating that genotyping results in higher QALYs at an increasing cost. At the $100 000/QALY WTP threshold, multigene testing compared with standard of care was cost-effective in 87.4% (12 months), 98.7% (24 months), and 99.9% (lifetime) of simulations. At the $50 000/QALY gained WTP threshold, multigene testing compared with standard of care was cost-effective in 42.1% (12 months), 82.0% (24 months), and 99.8% (lifetime) of simulations. At all time horizons for single-gene testing in comparison to multigene testing, the majority of simulations (53% to 56%) were dominated. At both WTP thresholds at 12 and 24 months, single-gene testing compared with multigene testing was cost-effective in approximately 30% of simulations. Over the lifetime, single-gene testing compared with multigene testing was cost-effective at both WTP thresholds in approximately 20% of simulations. For both comparisons across all time horizons, there is more variability in the QALYs gained than in the cost, and this variability increases at longer time horizons.
Figure 2Probabilistic sensitivity analysis results: incremental cost-effectiveness plane for 10 000 Monte Carlo simulations estimating the cost per QALYs gained per person at (1) 12 months, (2) 24 months, and (3) lifetime for Medicare beneficiaries with ACS undergoing a PCI for stent placement. Cost and QALYs are discounted at 3% per year. Notes: Single-gene testing versus multigene testing: At all time horizons, 53% to 56% of simulations were dominated, 7% to 8% of simulations were dominant, 15% to 16% of simulations were in the northeast quadrant, and 21% to 24% of simulations were in the southwest quadrant. At the $100 000 and $50 000 per QALY gained WTP thresholds at 12 and 24 months, single-gene testing was cost-effective in approximately 30% of simulations (majority in southwest quadrant). Over the lifetime, single-gene testing was cost-effective at both WTP thresholds in approximately 20% of simulations (majority in northeast quadrant). Multigene versus standard of care: At the $100 000/QALY WTP threshold, multigene testing was cost-effective in 87.4% (12 months), 98.7% (24 months), and 99.9% (lifetime) of simulations. At the $50 000/QALY gained WTP threshold, multigene testing was cost-effective in 42.1% (12 months), 82.0% (24 months), and 99.9% (lifetime) of simulations.
ACS indicates acute coronary syndrome; multigene testing, CYP2C19, SLCO1B1, CYP2C9, and VKORC1; PCI, percutaneous coronary intervention; QALY, quality-adjusted life year; single-gene testing: CYP2C19; standard of care, no genotyping.
Figure 2Probabilistic sensitivity analysis results: incremental cost-effectiveness plane for 10 000 Monte Carlo simulations estimating the cost per QALYs gained per person at (1) 12 months, (2) 24 months, and (3) lifetime for Medicare beneficiaries with ACS undergoing a PCI for stent placement. Cost and QALYs are discounted at 3% per year. Notes: Single-gene testing versus multigene testing: At all time horizons, 53% to 56% of simulations were dominated, 7% to 8% of simulations were dominant, 15% to 16% of simulations were in the northeast quadrant, and 21% to 24% of simulations were in the southwest quadrant. At the $100 000 and $50 000 per QALY gained WTP thresholds at 12 and 24 months, single-gene testing was cost-effective in approximately 30% of simulations (majority in southwest quadrant). Over the lifetime, single-gene testing was cost-effective at both WTP thresholds in approximately 20% of simulations (majority in northeast quadrant). Multigene versus standard of care: At the $100 000/QALY WTP threshold, multigene testing was cost-effective in 87.4% (12 months), 98.7% (24 months), and 99.9% (lifetime) of simulations. At the $50 000/QALY gained WTP threshold, multigene testing was cost-effective in 42.1% (12 months), 82.0% (24 months), and 99.9% (lifetime) of simulations.
ACS indicates acute coronary syndrome; multigene testing, CYP2C19, SLCO1B1, CYP2C9, and VKORC1; PCI, percutaneous coronary intervention; QALY, quality-adjusted life year; single-gene testing: CYP2C19; standard of care, no genotyping.
Figure 3 uses discounted costs and QALYs and compares the probability of cost-effectiveness for each intervention at each time horizon. At all time points, the most cost-effective intervention initially starts with standard of care and then switches to multigene testing at a WTP threshold starting at $58 000 (12 months), $33 000 (24 months), and $4000 (lifetime). At a $100 000/QALY gained WTP threshold, there was a greater probability that multigene testing was cost-effective in the majority of simulations across the 12-month, 24-month, and lifetime time horizons (64%, 70%, and 80%, respectively). At the WTP threshold of $50 000/QALY gained, there was a greater probability that multigene testing was a cost-effective strategy in the majority of simulations only at the 24-month and lifetime time horizons (61% and 81%, respectively). Standard of care had the highest probability of cost-effectiveness (52%) at the12-month time horizon under the $50 000/QALY gained WTP threshold. Single-gene testing was not a preferred strategy in most simulations at any time point across any of the WTP thresholds.
Figure 3Probabilistic sensitivity analysis: cost-effectiveness acceptability curves comparing the probability of cost-effectiveness per QALY gained at various WTP thresholds for standard of care, single-gene testing, and multigene testing at (1) 12 months, (2) 24 months, and (3) lifetime for Medicare beneficiaries with ACS undergoing a PCI for stent placement. Cost and QALYs are discounted at 3% per year. Dashed lines in graph indicate the $50 000 and $100 000 WTP thresholds. Multigene testing had the highest probability of being the most cost-effective strategy starting at a WTP threshold of approximately $58 000 at 12 months, approximately $33 000 at 24 months, and approximately $4000 over the lifetime. Multigene testing remained the strategy with the highest probability of being cost-effective at increasing WTP thresholds across all time horizons.
ACS indicates acute coronary syndrome; multigene testing, CYP2C19, SLCO1B1, CYP2C9, and VKORC1; PCI, percutaneous coronary intervention; QALY, quality-adjusted life year; single-gene testing, CYP2C19; standard of care, no genotyping; WTP, willingness-to-pay.
Figure 3Probabilistic sensitivity analysis: cost-effectiveness acceptability curves comparing the probability of cost-effectiveness per QALY gained at various WTP thresholds for standard of care, single-gene testing, and multigene testing at (1) 12 months, (2) 24 months, and (3) lifetime for Medicare beneficiaries with ACS undergoing a PCI for stent placement. Cost and QALYs are discounted at 3% per year. Dashed lines in graph indicate the $50 000 and $100 000 WTP thresholds. Multigene testing had the highest probability of being the most cost-effective strategy starting at a WTP threshold of approximately $58 000 at 12 months, approximately $33 000 at 24 months, and approximately $4000 over the lifetime. Multigene testing remained the strategy with the highest probability of being cost-effective at increasing WTP thresholds across all time horizons.
ACS indicates acute coronary syndrome; multigene testing, CYP2C19, SLCO1B1, CYP2C9, and VKORC1; PCI, percutaneous coronary intervention; QALY, quality-adjusted life year; single-gene testing, CYP2C19; standard of care, no genotyping; WTP, willingness-to-pay.
The ICER was most sensitive to genotyping costs across all time horizons, and given the likelihood that genetic costs will decrease in the future, an alternate scenario changing only the cost of single-gene testing to match multigene testing was completed (see Supplemental Results in Supplemental Materials found at https://doi.org/10.1016/j.jval.2019.08.002). Results of the alternate scenario were similar to the primary scenario with the exception that simulations indicated that multigene testing did not have a higher chance of being cost-effective until the lifetime time horizon when compared with single-gene testing.
Discussion
Approximately 300 000 US Medicare beneficiaries undergo a PCI for ACS annually. In this analysis, the projected health and cost benefits of providing multigene testing (CYP2C19 to guide antiplatelet therapy selection, SLCO1B1 to guide statin selection, and CYP2C9/VKORC1 to guide warfarin dosing) for Medicare beneficiaries aged 65 years post-PCI for ACS were simulated and compared with single-gene testing (CYP2C19) and standard of care (no genotyping). Pharmacogenetic cost-effectiveness analyses have traditionally focused on a single gene-drug pair.
Therefore, this analysis provides novel insight into the potential benefits multigene testing may afford this high-risk patient population in the short- (12 months) and long-term (24 months and lifetime).
The base-case scenario indicates that multigene testing is associated with the highest number of events avoided and the highest discounted QALYs gained, although these gains are small when compared with single-gene testing and standard of care over all time horizons. Single-gene testing was dominated by multigene testing at all time horizons. At a WTP threshold of $100 000/QALY gained, multigene testing compared with standard of care was cost-effective at 12 months, 24 months, and over the lifetime; however, at a WTP threshold of $50 000/QALY gained, cost-effectiveness was indicated only at 24 months and over the lifetime. The PSA cost-effectiveness acceptability curves indicate that, at a $100 000/QALY gained WTP threshold, there was a greater probability that multigene testing was cost-effective in the majority of simulations across the 12-month, 24-month, and lifetime time horizons (64%, 70%, and 80%, respectively). At the WTP threshold of $50 000/QALY gained, multigene testing had a greater probability of being cost-effective in the majority of simulations only at the 24-month and lifetime time horizons (61% and 81%, respectively). Taken together, the base-case scenario and PSA indicate that the probability of multigene testing being cost-effective at both WTP thresholds increases at longer time horizons. This finding was confirmed even when accounting for variation in genetic testing cost, the input parameter that affected the ICER most per one-way sensitivity analyses. Longer time horizons allow the discounted cost and health benefits of multigene testing to accrue beyond what is offered with just single-gene testing of CYP2C19, although these gains are slight given the low proportion of patients prescribed simvastatin and warfarin.
The results of the single-gene testing of CYP2C19 in this analysis are in line with the results of a recently published review of cost-effectiveness analyses evaluating CYP2C19 testing to guide antiplatelet therapy selection for ACS patients, which found genotype-guided selection of antiplatelet therapies to be a cost-effective strategy when compared with universal use of antiplatelet therapies.
There are no published cost-effectiveness analyses investigating the role of SLCO1B1 genotyping to guide statin therapy selection. The cost-effectiveness of CYP2C9/VKORC1 genotyping for warfarin dosing in patients with atrial fibrillation is limited to specific subpopulations; for instance, one study concluded cost-effectiveness of CYP2C9/VKORC1 genotyping for warfarin dosing among patients with atrial fibrillation only if a high hemorrhage risk was present,
The results of these cost-effectiveness analyses suggest that cost-effectiveness depends on the gene-drug pair being considered and can be limited to specific subpopulations. In this analysis, the cost-effectiveness of multigene testing was largely driven by CYP2C19 genotype-guided antiplatelet therapy selection, and provided an avenue for the incremental benefits of SLCO1B1, CYP2C9, and VKORC1 testing to be used in the drug-prescribing process for patients post-PCI for ACS. The prescribing patterns of antiplatelet therapies may differ from this simulation in the future, and as the main driver of cost-effectiveness, the benefits of the genetic testing interventions are likely to be lower if prescribing rates of clopidogrel decrease.
Although there are 84 drugs in various therapeutic areas with actionable pharmacogenetic guidance,
this analysis was limited to 3 major cardiovascular medications that have associated pharmacogenetic guidance and are likely to be prescribed to patients post-PCI for ACS. The benefits of multigene testing are likely underestimated in this analysis because these patients will likely require additional drugs with CPIC guidance beyond cardiovascular medications, such as antidepressants.
Future cost-effectiveness analyses investigating additional relevant gene-drug pairs beyond the cardiovascular therapeutic area are needed to understand the comprehensive benefits multigene testing can provide this population.
Additional limitations must be considered when interpreting the results given the simplifications that were made to project future cost and health consequences for this cohort. First, because there are limited data on the health state utilities for multiple comorbidities, health utilities for single comorbidities were used in the model. This may underestimate the actual health states of patients in this cohort who experienced multiple comorbidities and, as a result, underestimate the number of QALYs gained in the genotyping interventions where events were avoided. In addition, because this population starts out with reduced QALYs because of comorbidities, gains in QALYs are not as pronounced as they would be if healthier populations were simulated. To estimate the event probabilities from studies, a fixed event rate was assumed over time for the entire cohort because patient-level time-to-event data are not available to estimate the change in event risk over time more accurately. Additionally, generalizations beyond US Medicare beneficiaries post-PCI for ACS are limited, and findings are not tailored to reflect subgroups within this patient population. A major assumption in this analysis was successful interoperability in the healthcare system that ensured pharmacogenetic results remained accessible for patients over time to guide future treatment decisions. Lastly, it was assumed that genetic information was used 100% of the time to guide drug-prescribing decisions, which may overestimate use in clinical practice.
Despite these limitations, this analysis offers valuable insight into the potential benefits that multigene testing could provide for Medicare beneficiaries post-PCI for ACS. The added SLCO1B1 and CYP2C9/VKORC1 information was relevant in achieving better cardiovascular outcomes and indicates that information gained from multigene testing is beneficial for this population. The findings from this analysis highlight the importance of infrastructure within the healthcare system to store these results in the EHR and allow pharmacogenetic test results to follow patients across time. A mechanism to alert future clinicians that pharmacogenetic testing has been completed in their patients to ensure that the information is accessible is needed for successful implementation and has been a key component of pharmacogenetic studies at major medical centers that have already implemented multigene testing.
Preemptive genotyping for personalized medicine: design of the right drug, right dose, right time-using genomic data to individualize treatment protocol.
On the basis of projected simulations, the results suggest that multigene testing (CYP2C19, SLCO1B1, CYP2C9, VKORC1) is a potentially cost-effective strategy that may help optimize medication selection for Medicare beneficiaries post-PCI for ACS. This was the case when multigene testing was compared with standard of care (no genotyping) and single-gene testing (CYP2C19) at 12 months, 24 months, and over the lifetime if the WTP threshold is $100 000/QALY gained, and over 24 months and the lifetime if the WTP threshold is $50 000/QALY gained.
Acknowledgments
The project described was supported by an American Heart Association grant (18PRE33960079) to O.M. Dong and a UNC Eshelman Institute for Innovation grant (R1020 RX03612214) to T. Wiltshire.
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Preemptive genotyping for personalized medicine: design of the right drug, right dose, right time-using genomic data to individualize treatment protocol.
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