Study Objective-To estimate the cost-effectiveness of genotype-guided selection of antiplatelet therapy compared with selecting clopidogrel or prasugrel irrespective of genotype. Design-Decision model based on event occurrence in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38.Patients-Simulated cohort of patients with acute coronary syndrome scheduled to undergo percutaneous coronary intervention (PCI), consisting of three arms: those receiving genotypeguided antiplatelet therapy with clopidogrel or prasugrel, those receiving clopidogrel regardless of genotype, and those receiving prasugrel regardless of genotype. Measurements and MainResults-All three arms of the model incorporated the probability that patients would experience a cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or non-fatal stroke), a bleeding event (major or minor bleeding), or no event while receiving antiplatelet therapy during the 15 months after the scheduled PCI. The cytochrome P450 (CYP) 2C19 genotype determined antiplatelet drug selection in the genotyping group. Costeffectiveness was expressed as the incremental cost-effectiveness ratio (ICER) for each event avoided in the genotype-guided therapy arm versus the other two arms. Genotype-guided antiplatelet therapy was dominant, or more effective and less costly, when compared with the selection of clopidogrel (ICER -$6760 [95% confidence interval (CI) -$6720 to -$6790]) or prasugrel 950]) for all patients with-out regard to genotype. Genotype-guided therapy that included generic clopidogrel was dominant to prasugrel for all patients 420]). Cost savings were not evident when genotype-guided therapy that included generic clopidogrel was compared with generic clopidogrel for all patients (ICER $2300 [95% CI $2290 to $2320]).Conclusion-Genotype-guided antiplatelet therapy selection may be more cost-effective and may provide more clinical value due to fewer adverse outcomes. Keywordsclopidogrel; prasugrel; cytochrome P450 2C19; pharmacogenomics; cost-effectiveness NIH Public Access Author ManuscriptPharmacotherapy. Author manuscript; available in PMC 2014 January 07. however, prasugrel will remain under patent for much longer and will presumably be more expensive than generic clopidogrel. The use of pharmacogenomic screening could allow for individualized antiplatelet therapy in which patients with fully functional CYP2C19 alleles could be treated with clopidogrel, whereas the more expensive agent (prasugrel) could be reserved for those with reduced-function CYP2C19 alleles. Whether this approach would be cost-effective has not been studied.Recently, a cost-effectiveness analysis based on the overall TRITON-TIMI 38 study without regard to genotype was published. 15 The study found prasugrel to be cost-effective compared with clopidogrel for patients with a planned PCI. The study found that average costs were $221/patient lower with pr...

There is a high risk of voriconazole failure in those with subtherapeutic drug concentrations, which is more common in CYP2C19 (cytochrome P450 2C19) rapid/ultrarapid metabolizers (RMs/UMs). We evaluated CYP2C19 genotype‐guided voriconazole dosing on drug concentrations and clinical outcomes in adult allogeneic hematopoietic cell transplant recipients. Poor (PMs), intermediate (IMs), and normal metabolizers (NMs) received voriconazole 200 mg twice daily; RMs/UMs received 300 mg twice daily. Steady‐state trough concentrations were obtained after 5 days, targeting 1.0–5.5 mg/L. Of 89 evaluable patients, 29% had subtherapeutic concentrations compared with 50% in historical controls (P < 0.001). Zero, 26%, 50%, and 16% of PMs, IMs, NMs, and RMs/UMs were subtherapeutic. Voriconazole success rate was 78% compared with 54% in historical controls (P < 0.001). No patients experienced an invasive fungal infection (IFI). Genotype‐guided dosing resulted in $4,700 estimated per patient savings as compared with simulated controls. CYP2C19 genotype‐guided voriconazole dosing reduced subtherapeutic drug concentrations and effectively prevented IFIs.

Comparative effectiveness research (CER), or research design to meet the needs of post-regulatory decision makers, has been brought into the spotlight with the introduction of the American Recovery and Reinvestment Act, which provided $US1.1 billion over 2 years to support CER. In the short run, the majority of this money will be invested in observational studies and building of infrastructure; however, in the long run, we will likely see an increase in the number of randomized controlled trials (RCTs), as this method is arguably the most unbiased approach for establishing causal effect between treatments and health outcomes. RCTs are an integral component of CER for generating credible evidence on the relative value of alternative interventions in order to meet the needs of post-regulatory decision makers (patients, physicians, payers and policy makers). Explanatory phase III RCTs are fit for purpose; researchers make use of guidance documents produced by the US FDA to inform the design of these clinical trials. Historically, without explicit FDA guidance, broad patient populations, including women and minorities, often were not considered in trial design. In addition, attempts to minimize cost and maximize efficiency have led to smaller sample sizes, as is clear from the increase in 'creeping phase II-ism'. To demonstrate effectiveness, RCTs must be reflective of how an intervention will be used in the healthcare market. The concept of pragmatic clinical trials has emerged to describe those trials that are designed explicitly with this need in mind. Use of pragmatic trials will be most impactful if post-regulatory decision makers are engaged in the development of recommendations for trial design features, such as indicating outcomes measures and articulating patient populations of interest, which clearly express their evidence needs.

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Among older individuals diagnosed with metastatic colon cancer (mCC) there is limited evidence available that describes the characteristics associated with advancing to second- and subsequent lines of treatment with chemotherapy/biologics. Our objective was to describe the trends and lines of treatment received among elderly mCC patients. Elderly beneficiaries diagnosed with mCC from 2003 to 2007 were identified in the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset. Beneficiaries were followed up until death or censoring. Treatment lines were classified in combinations of chemotherapies and biologics. Modified Poisson regression was used to predict receipt of lines of treatment. Analyses controlled for age, race/ethnicity, gender, marital status, state buy-in during diagnosis year, SEER-registry site, Charlson comorbidity index (CCI), poor performance indicators, surgery of primary site, and surgery of regional/distal sites. Among 7951 Medicare beneficiaries identified with mCC, 3266 initiated therapy. Of these, 1440 advanced to second-line treatment. Of these, 274 advanced to a subsequent-line treatment. Surgeries of the primary tumor site and of the regional/distal sites and marital status were the most significant variables associated with advancing through second- and subsequent-line treatments. Greater than 80 years of age, African American race, SEER-registry area, less than 6 months state buy-in assistance in mCC diagnosis year, and having poor performance indicators were inversely associated with receipt of second- or subsequent-line treatments. Among elderly individuals diagnosed with mCC, we identified demographic, clinical, and regional factors associated with receipt of second- and subsequent-line chemotherapy/biologics. Additional research is warranted to understand the role of physician versus patient preferences as well as geographic differences explaining why patients advance through lines of chemotherapy.