Financial analysis of cyp2c19 genotyping in patients receiving dual antiplatelet therapy following acute coronary syndrome and percutaneous coronary intervention
Financial Analysis of CYP2C19 Genotyping in Patients Receiving Dual Antiplatelet Therapy Fol owing Acute Coronary Syndrome and Percutaneous Coronary Intervention Samuel G. Johnson, PharmD, FCCP, BCPS; Don Gruntowicz, PharmD, BCPS, CGP;Theresa Chua, PharmD Candidate; and Robert J. Morlock, PhD
What is already known about this subject
BACKGROUND: Dual antiplatelet therapy is an established standard of care for patients with acute coronary syndrome (ACS) to reduce thrombotic risk. • Despite demonstrated clinical utility for CYP2C19 genotyping in Reduced CYP2C19 activity impairs clopidogrel bio-activation and increases patients with acute coronary syndrome (ACS) undergoing per- risk of adverse clinical outcomes. Patients with poor and intermediate cutaneous coronary intervention, broad implementation of such CYP2C19 metabolizers treated with clopidogrel incur higher cardiovascular pharmacogenetic testing, particularly outside of academic medi- event rates, including myocardial infarction, stroke, and stent thrombosis, cal centers, has not occurred.
fol owing ACS than patients with normal CYP2C19 function. Tests are avail- • Lack of uniform reimbursement for pharmacogenetic testing is a able to identify the CYP2C19 genotype and can be used to support individu- barrier to widespread use. While several published studies sug- alization of antiplatelet therapy. gest the cost-effectiveness of CYP2C19 genotyping for individual- OBJECTIVE: To estimate the financial impact of CYP2C19 genotyping in a izing antiplatelet therapy, many health systems struggle to assess theoretical cohort of 1,000 patients with ACS, who received percutaneous and develop business cases that support implementation.
coronary intervention and coronary stent implantation and were treated with clopidogrel, prasugrel, or ticagrelor in a managed care setting. What this study adds
METHODS: Differences in overall and average cost per patient were esti- • Important financial benefits may be realized by using a geno- mated based on the rate of CYP2C19 genotyping in a theoretical cohort type-guided approach to reserve prasugrel or ticagrelor use for of 1,000 patients. Sensitivity analysis was carried out for varying costs, CYP2C19 poor and intermediate metabolizers. adherence, and the percentage of patients treated according to genotyp- • Financial benefit and clinical utility of CYP2C19 genotyping sup- ing results. All clinical event costs were reported in terms of 2012 U.S. port clinical implementation across different health care delivery dollars. The budget impact analysis used published event rates from primary literature to estimate costs of events analysis for 3 different sce-narios: Scenario A, no CYP2C19 genotyping; Scenario B, 50% of patients received CYP2C19 genotyping with appropriate treatment based on geno-type; and Scenario C, 100% of patients received CYP2C19 genotyping with appropriate treatment based on genotype.
The field of pharmacogenomics encompasses a growing knowledge base linking genetic variation to drug dis-position and response. Yet, despite the fact that the U.S. RESULTS: According to this model, there was no change in the market Food and Drug Administration (FDA) began incorporating share for the 3 antiplatelet agents in Scenario A. Initial market share for clopidogrel, prasugrel, and ticagrelor was 93%, 5%, and 2%, respectively; genetic information into drug labels in 2007, clinical imple- however, use of CYP2C19 genotyping is expected to shift market share from mentation outside of academic medical centers remains largely clopidogrel to either prasugrel or ticagrelor. In Scenario B, where 50% of absent.1,2 While completion of the Human Genome Project the patients received genotyping, clopidogrel market share was reduced to raised expectations that predicting response to drug therapy is 83%, while prasugrel increased to 12.1% and ticagrelor increased to 4.9%. now possible for many patients, debate continues on whether In Scenario C, where al patients received genotyping, clopidogrel market pharmacogenomic testing should be routinely used. Realistic share was reduced to 73%, prasugrel increased to 19.3%, and ticagrelor application of genomic technologies to clinical practice requires increased to 7.7%. Total estimated cost differences when all possible several steps, including (a) discovery and validation of pharma- patients were genotyped included annual savings of roughly $444,852.
cogenomic markers in well-designed studies; (b) replication of CONCLUSIONS: Important financial benefits may be realized through use of drug-gene associations and demonstration of utility in at-risk genotype-guided antiplatelet therapy to reserve prasugrel or ticagrelor use patients; and (c) assessment of the clinical and financial impact for patients with reduced CYP2C19 activity to avoid costs associated with of pharmacogenomic testing. adverse cardiac events.
Although clopidogrel is the most frequently prescribed J Manag Care Spec Pharm. 2015;21(7):552-57 antiplatelet agent, mounting evidence suggests that alterna- Copyright 2015, Academy of Managed Care Pharmacy. All rights reserved.
tive agents could be prescribed for certain patients, such as 552 Journal of Managed Care & Specialty Pharmacy JMCP July 2015 Vol. 21, No. 7 www.amcp.org
Financial Analysis of CYP2C19 Genotyping in Patients Receiving Dual Antiplatelet
Therapy Following Acute Coronary Syndrome and Percutaneous Coronary Intervention
CYP2C19 poor metabolizers.1,3-6 Although polymorphisms genotype-guided therapy was the most cost-effective strategy in several genes coding for drug metabolizing enzymes or provided the cost of genotyping did not exceed $358 based on transport proteins for clopidogrel (e.g., PON1, ABCB1, CYP1A2, a willingness-to-pay threshold of $50,000 per quality-adjusted CYP2B6, CYP2C9, CYP3A4/5, and CYP2C19) have been life-year.8 Additional cost-effectiveness analyses support that associated with interindividual variability in clopidogrel CYP2C19 genotype-guided therapy has economic benefits response, available data for the impact of CYP2C19 genetic resulting from savings because of prevention of avoidable variation in patients with cardiovascular disease receiving adverse cardiac events.8,10,11 Although cost-effectiveness of clopidogrel arguably remains compelling and actionable infor- CYP2C19 genotype-guided antiplatelet therapy has been inves- mation for clinicians.6 Furthermore, in March 2010, the FDA tigated, an opportunity to predict economic impact within released a black box warning, stating that the "effectiveness of managed care organizations remains. The objective of this clopidogrel depends on activation to an active metabolite by the investigation was to model the financial impact of CYP2C19 cytochrome P450 (CYP) system, principally CYP2C19. Tests are genotyping in ACS patients undergoing PCI and treated with available to identify a patient's CYP2C19 genotype and can be clopidogrel, prasugrel, or ticagrelor in addition to aspirin used as an aid in determining therapeutic strategy."7 within such an environment. Since 2010, 2 meta-analyses reviewed available studies for major adverse cardiovascular events in patients who received ■■ Methods
clopidogrel for all cardiovascular indications (e.g., medical and Model Overview
invasive management of coronary artery disease) stratified A budget impact analysis was conducted over a 1-year time
according to CYP2C19 genotype.3,5 Findings suggested that horizon using overall and average cost per patient modeling
clopidogrel use in CYP2C19 poor metabolizers (e.g., homozy-
based on the rate of CYP2C19 genotyping in a theoretical gous for CYP2C19*2) and CYP2C19 intermediate metabolizers 1,000 patient cohort. This model assumed all patients suffered (e.g., heterozygous for CYP2C19*2) was associated with sig- ACS and underwent PCI with coronary stent implantation and nificantly increased risk for adverse cardiac events, particu- received dual antiplatelet therapy for 1 year following PCI and larly stent thrombosis.3,5 Despite the demonstrated association reflects methodology used in other published analyses.10,11 This between the CYP2C19 genotype and improved clinical out- analysis was intentionally modeled from the payer perspec- comes from antiplatelet therapy use, lingering barriers limit tive to practically demonstrate the magnitude of the financial widespread use, including health care provider knowledge impact from CYP2C19 genotype-guided antiplatelet therapy. gaps, genotyping costs, and lack of uniform reimbursement for pharmacogenomic testing.8 Model Structure and Input Data
Lack of uniform coverage and reimbursement for pharma- This model identified patients likely to be hyporesponsive to cogenetic testing is another significant barrier to clinical imple- clopidogrel and the possible cost difference if the CYP2C19 mentation along with cost-effectiveness of genotyping. While genotype was obtained prior to initiation of dual antiplatelet several large organizations (e.g., the Personalized Medicine therapy. Approximately 27% of patients had predicted pheno-Coalition) continue to advocate for this testing, it is uncer- types of intermediate (e.g., CYP2C19 *1/*2) or poor metabo- tain whether the current payer systems are ideally prepared lizer status (e.g., CYP2C19 *2/*2), while 73% were predicted to assess clinical utility for pharmacogenomic applications or to be ultrarapid (e.g., CYP2C19 *17/*17 or *1/*17) or exten-next-generation sequencing.9 sive metabolizers (e.g., CYP2C19 *1/*1) based on published Several published studies have evaluated the cost-effective- estimates.12 The analysis adjudicated patients with 1 loss-of- ness of CYP2C19 genotyping for individualized antiplatelet function allele and 1 gain-of-function allele into ultrarapid or therapy; however, opportunities to demonstrate favorable eco- extensive metabolizers because no change in treatment is rec- nomic impact in different types of health systems exist.8,10,11 ommended based on the presence of a gain-of-function allele A recent investigation by Kazi et al. (2014) evaluated the (i.e., CYP2C19 *17). cost-effectiveness of CYP2C19 genotype-guided antiplatelet Based on market share rates from a large administrative therapy for patients with acute coronary syndrome (ACS) claims database, the model assumed that market shares for using a Markov model to evaluate 5 possible scenarios: (1) clopidogrel, prasugrel, and ticagrelor were 93%, 5%, and 2%, using empiric clopidogrel, (2) using empiric prasugrel, (3) respectively. Additionally, the model assumed rate and cost for using empiric ticagrelor, (4) switching from clopidogrel to cardiovascular events based on published literature estimates. prasugrel based on CYP2C19 genotype, and (5) switching Specifically, patients receiving clopidogrel have the highest from clopidogrel to ticagrelor based upon CYP2C19 genotype.8 probability of nonfatal myocardial infarction (MI) overall but Based on a cohort of 100,000 patients with ACS who under- the lowest probability of cardiovascular death (CVD). Poor went percutaneous coronary intervention (PCI) and received at metabolizers for CYP2C19 had a predicted 3-fold increase in least 1 drug-eluting stent, the results suggested that CYP2C19 nonfatal stroke.4 Patients receiving prasugrel have a decreased www.amcp.org Vol. 21, No. 7 July 2015 JMCP Journal of Managed Care & Specialty Pharmacy 553
Financial Analysis of CYP2C19 Genotyping in Patients Receiving Dual Antiplatelet
Therapy Following Acute Coronary Syndrome and Percutaneous Coronary Intervention
Total Estimated Annual Costs Budget Impact for 3 Clinical Scenarios of Clinical Outcomes and Scenario A ($)a
Scenario B ($)b
Scenario C ($)c
Estimated Costs ($)a
Nonfatal bleeding Nonfatal bleeding aNo patients received CYP2C19 genotyping. b50% of patients received CYP2C19 genotyping. c100% of patients received CYP2C19 genotyping. CVD = cardiovascular death; MI = myocardial infarction. aEstimated costs are based on 2012 costs for events,12 2013 Average Wholesale Price (AWP), and market-based CYP2C19 genotyping cost estimate. Annual Cost Difference Between CVD = cardiovascular death; MI = myocardial infarction. Scenarios A, B, and C Cost Difference Between Cost Difference Between
Scenarios A and B ($)
Scenarios A and C ($)
probability of nonfatal stroke and nonfatal MI; however, they Total costs have an increased probability of CVD and nonfatal bleeding. Cost per patient Poor and intermediate CYP2C19 metabolizers taking pra- sugrel have a lower probability of nonfatal MI and nonfatal Nonfatal bleeding bleeding.13 Ticagrelor has the lowest rates of nonfatal MI but the CVD = cardiovascular death; MI = myocardial infarction. highest probability of CVD and death from bleeding. Patients on ticagrelor have the same probability of events regardless of CYP2C19 metabolism.14 The probability for each outcome iden- share of each antiplatelet agent. Scenario B assumed that tified was used from previous trials that compared antiplatelet 50% of patients received CYP2C19 genotype-guided anti- platelet therapy based on previous published estimates of Costs of adverse events, including nonfatal MI, stroke (tran- genotype frequency. Scenario C assumed all patients received sient ischemic attack and cerebral vascular accident), bleeds, CYP2C19 genotype-guided antiplatelet therapy. Patients who and CVD were estimated using mean national Medicare reim- had CYP2C19 intermediate/poor metabolizing phenotypes and bursement rates for the corresponding diagnosis-related group were allocated to clopidogrel were reassigned to either prasu- code (Table 1).15 Costs from nonfatal bleeding events were grel or ticagrelor, maintaining the starting market share ratio. estimated using Medicare reimbursement for inpatient treat-
ment of gastrointestinal hemorrhage.16 All costs were varied in ■■ Results
sensitivity analyses and inflated to 2012 U.S. dollars. Costs for In Scenario A (assumes no patients received CYP2C19 geno-
antiplatelet drugs were described in terms of estimated 2012 typing), there is no change in market share for the 3 differ-
wholesale drug costs available to a large managed care organi-
ent antiplatelet agents. In Scenario B (where 50% of patients zation. The model assumed 80% adherence to antiplatelet med- received CYP2C19 genotyping), clopidogrel market share fell to ications for patients based on previous data.17 The predicted 83%; prasugrel market share increased to 12.1%; and ticagrelor cost of CYP2C19 genotyping was set at $315 based on average market share increased to 4.9%. In Scenario C (all patients cost.8 Total cost for each therapy option was calculated by mul- received CYP2C19 genotyping), clopidogrel market share fell to tiplying the number of patients, the number of adverse events, 73%; prasugrel increased to 19.3%; and ticagrelor increased to and cost of the adverse events. This was calculated separately 7.7%. The cost and event differences between Scenario A and for ultrarapid/extensive metabolizer patients and intermediate/ Scenario B are shown in Table 3. The total cost difference favors poor metabolizer patients. The results, the cost of the specific Scenario B with annual cost savings of $222,426. Table 3 also therapy, and the cost of genotyping were added together for a compares costs and event differences between Scenario A and total cost per therapy option. The costs included in the analysis Scenario C. When all possible patients are genotyped, these were not discounted or adjusted for current market price.
numbers double, saving $444,852 annually. This budget impact analysis explored 3 scenarios (Table 2). A sensitivity analysis was conducted to test the robustness Scenario A assumed that none of the patients were genotyped of this model and suggested that varying all costs, adherence to and were allocated to treatment based on current market therapy, and CYP2C19 genotyping rates reduced overall costs, 554 Journal of Managed Care & Specialty Pharmacy JMCP July 2015 Vol. 21, No. 7 www.amcp.org
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Therapy Following Acute Coronary Syndrome and Percutaneous Coronary Intervention
decreased mortality, and increased nonfatal bleeding. Overall, genotype-based versus standard regimens or a decision model-adverse events and associated costs had the largest impact on based study (i.e., one that uses a simulated patient cohort).21 the results rather than medication or CYP2C19 genotyping costs. Regardless of the specific approach used, the economic impact and cost-effectiveness of pharmacogenetic screening may be affected by different variables. To illustrate this point, 2 The well-characterized drug-gene interaction between clopi- studies utilized modeling techniques with simulated patient dogrel and CYP2C19 represents a clinically significant phar- cohorts to evaluate potential clinical and economic outcomes macogenetic application. Published Clinical Pharmacogenetics for genotype-guided warfarin dosing. While the relatively high Implementation Consortium guidelines provide evidence- cost of a CYP2C9 and VKORC1 bundled test ($326 to $570) based recommendations for antiplatelet drug selection based resulted in only modest improvements (quality-adjusted life-upon CYP2C19 genotype, supporting health systems engaged years, survival rates, and total adverse rates), investigators also in clinical implementation of pharmacogenetic testing.6 Despite suggested that improvements in the cost-effectiveness can be evidence demonstrating clinical utility for CYP2C19 genotyp- achieved through further cost reduction of the genotyping test ing in patients with ACS undergoing PCI, routine clinical use and utilizing a genotype-guided warfarin dosing algorithm in of CYP2C19 genotyping lags behind. One lingering barrier is outliers (patients with out-of-range international normalized the relative lack of evidence for economic viability of genotyp- ratios and/or those who are at high risk for hemorrhage).22,23 ing, particularly across health systems other than academic Other variables, such as different population prevalence of a medical centers, despite published examples demonstrating specific variant and cost of alternative treatment approaches, feasibility of clinical pharmacogenomics implementation. would also impact the economic impact analysis. Ultimately, In the point-of-care genetic testing for personalization of clinical utility and cost-effectiveness cannot solely determine antiplatelet treatment study, patients who were undergoing the relative value of pharmacogenetic testing in optimizing PCI were randomized to receive CYP2C19 genotype-guided drug therapy for individual patients. Rather, they should be antiplatelet therapy using a point-of-care device able to rapidly used to supplement the best practices currently in place to return results. Importantly, this study demonstrated that it achieve optimal drug therapy.
was feasible to use a targeted genotyping approach within the Tailoring antiplatelet therapy regimens according to cardiac catheterization laboratory to individualize therapy.18 CYP2C19 genotype can reduce costs associated with prevent- Another small study conducted in a community pharmacy set- able adverse outcomes, particularly stent thrombosis related ting by Ferreri et al. (2014) demonstrated the feasibility of pro- to low or absent CYP2C19 activity. Stent thrombosis is a rare viding CYP2C19 genotyping for patients prescribed clopidogrel but serious complication typically resulting in high cost inter-along with patient counseling by a pharmacist.19 ventions and increased case fatality risk.24 At the health care Despite this demonstrated feasibility, only a handful of provider level, this increased risk, when ignored, can result in institutions have successfully implemented and documented adverse consequences for patients and health care delivery sys-clinical implementation of pharmacogenomic testing, using tems. For example, in March 2014, the Hawaii attorney general a preemptive genotyping approach where data for multiple filed suit against makers of branded clopidogrel for a "failure pharmacogenes are acquired at the same time and electroni- to adequately market that clopidogrel has diminished effective- cally stored for future use.20 This approach enables decreased ness for East Asians or Pacific Islanders."25
individual genotype costs and development of advanced clini-
cal decision support tools for use by frontline pharmacists and Limitations
other clinicians (similar to, but more advanced than, drug Foremost among the analysis limitations is that published cost
allergy or drug-drug interaction information). In this para-
estimates were used to determine budget impact of CYP2C19 digm, medication order entry automatically triggers a search genotyping for clopidogrel. We did not compare published cost for relevant drug-gene interactions for the patient; if clinically estimates with real-world health system costs. Second, our actionable variants are identified, the system guides the clini- analysis relies on published clinical trial outcomes data from cian toward appropriate individualized therapy. A particularly randomized clinical trials, which may not be representative appealing feature of this preemptive approach is that testing of patient populations at various health systems. Third, our can be multiplexed, assaying hundreds to thousands of genetic analysis does not compare budget impact according to type variants at a time. This genetic information can be reused as of coronary stent implanted (i.e., bare metal vs. drug-eluting other drugs are prescribed over a lifetime and as the knowledge or next-generation drug-eluting), which may influence the base of drug-gene interactions grows. results.26 Fourth, our analysis does not consider preemp- Additional approaches for demonstrating cost-effectiveness tive pharmacogenetic testing but, rather, assumes targeted of genotype-guided therapy range from a clinical trial compar- CYP2C19 genotyping based upon indication for clopidogrel ing per-patient costs for specific clinical outcomes between (i.e., ACS and PCI). Fifth, the simplifying assumptions that www.amcp.org Vol. 21, No. 7 July 2015 JMCP Journal of Managed Care & Specialty Pharmacy 555
Financial Analysis of CYP2C19 Genotyping in Patients Receiving Dual Antiplatelet
Therapy Following Acute Coronary Syndrome and Percutaneous Coronary Intervention
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Therapy Following Acute Coronary Syndrome and Percutaneous Coronary Intervention
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'Heart Failure Is Killing Your Diabetes Patients,' Experts Warn at EASDShel ey Wood BARCELONA, SPAIN — Cardiologists speaking here at the European Association for the Study of Diabetes(EASD) 2013 Meeting are urging diabetologists to sit up and take notice: heart failure is kil ing their patients and isnot getting the attention it deserves. Not only is heart failure one of the most lethal—if not the most lethal—complications of diabetes, its role in diabetesis being routinely overlooked by physicians, by journals publishing diabetes research, and perhaps worst of al , byregulators tasked with tel ing companies what's important for trials of new diabetes drugs.