Cost-effectiveness analysis of CYP3A5 genotype-guided tacrolimus dosing in solid organ transplantation using real-world data.

The objective of this study was to estimate the cost-effectiveness of CYP3A5 genotype-guided tacrolimus dosing in kidney, liver, heart, and lung transplant recipients relative to standard of care (SOC) tacrolimus dosing, from a US healthcare payer perspective. We developed decision-tree models to compare economic and clinical outcomes between CYP3A5 genotype-guided and SOC tacrolimus therapy in the first six months post-transplant. We derived inputs for CYP3A5 phenotype frequencies and physician use of genotype test results to inform clinical care from literature; tacrolimus exposure [high vs low tacrolimus time in therapeutic range using the Rosendaal algorithm (TAC TTR-Rosendaal)] and outcomes (incidences of acute tacrolimus nephrotoxicity, acute cellular rejection, and death) from real-world data; and costs from the Medicare Fee Schedule and literature. We calculated cost per avoided event and performed sensitivity analyses to evaluate the robustness of the results to changes in inputs. Incremental costs per avoided event for CYP3A5 genotype-guided vs SOC tacrolimus dosing were $176,667 for kidney recipients, $364,000 for liver recipients, $12,982 for heart recipients, and $93,333 for lung recipients. The likelihood of CYP3A5 genotype-guided tacrolimus dosing leading to cost-savings was 19.8% in kidney, 32.3% in liver, 51.8% in heart, and 54.1% in lung transplant recipients. Physician use of genotype results to guide clinical care and the proportion of patients with a high TAC TTR-Rosendaal were key parameters driving the cost-effectiveness of CYP3A5 genotype-guided tacrolimus therapy. Relative to SOC, CYP3A5 genotype-guided tacrolimus dosing resulted in a slightly greater benefit at a higher cost. Further economic evaluations examining intermediary outcomes (e.g., dose modifications) are needed, particularly in populations with higher frequencies of CYP3A5 expressers.

Pharmacogenetic testing among patients with depression in a US managed care population.

Actionable drug-gene pairs relevant to depression treatment include CYP2D6 and CYP2C19 with specific antidepressants. While clinical use of pharmacogenetic testing is growing, little is known about pharmacogenetic testing for depression treatment in managed care. We determined the incidence of single-gene CYP2D6 and CYP2C19 testing following a new depression episode among US managed care patients, and described characteristics and antidepressant use of patients receiving tests. We used paid medical and pharmacy claims for patients from commercial health plans in the US. For adult patients with a new depression episode from January 1, 2013 to June 30, 2018, we identified covered claims for single-gene CYP2D6 and CYP2C19 pharmacogenetic tests and antidepressant fills. Fewer than 1% (n = 1795) of the depressed cohort (n = 438,534) received a single-gene CYP2D6 or CYP2C19 test through their insurance within 365 days of their earliest depression episode. The percentage of patients who received a test nearly tripled from 0.2% in 2013 to 0.5% in 2014 before plateauing at 0.4% from 2014 to 2017. Among the patients who received a single-gene CYP2D6 or CYP2C19 test and filled an antidepressant within 365 days of their depression diagnosis, up to 30% may have had their initial antidepressant informed by the test result. Our findings describe the use of antidepressants before and after pharmacogenetic testing, which is clinically relevant as pharmacogenomic testing becomes more common in clinical practice. Our study also emphasizes the need for procedure and billing codes that capture multiple-gene panel tests to be more widely implemented in administrative databases.

Economic Impact of Coverage Expansion for Non-invasive Prenatal Testing Through a Performance-Based Risk-Sharing Agreement.

BACKGROUND: Harvard Pilgrim Health Care expanded coverage for non-invasive prenatal testing (NIPT) to include all pregnant, single-gestation women aged < 35 years, through a performance-based risk-sharing (PBRS) agreement with Illumina to offset costs from coverage expansion. NIPT analyzes cell-free DNA fragments from a maternal blood sample to screen for fetal aneuploidies and is considered a more accurate screening method than conventional serum biochemical screening and nuchal translucency ultrasound-based approaches. OBJECTIVE: This study assessed the impact of NIPT coverage expansion on prenatal screening strategies and payer expenditures. METHODS: This was a real-world comparison of utilization and expenditures of prenatal screening and diagnostic testing in pregnant women aged < 35 years pre- (1 March 2016-28 February 2018) and post- (1 March 2018-30 September 2019) coverage expansion. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were estimated to compare changes in utilization of conventional and NIPT-based prenatal screening methods. Change in per member per month (PMPM) expenditures in $US year 2020 were assessed post-coverage expansion using a budget impact model. RESULTS: A total of 5041 and 4109 distinct pregnancies were identified in pre- and post-coverage expansion periods, respectively. Mean ± standard deviation maternal age was consistent between pre- and post-coverage expansion periods (30.35 ± 3.35 and 30.33 ± 3.28, respectively). Screening orders for conventional methods decreased, with an adjusted IRR in the post-expansion period of 0.87 (95% CI 0.85-0.90) times the rate in the pre-expansion period; orders for NIPT increased, with an adjusted IRR in the post-expansion period of 1.41 (95% CI 1.32-1.51) times the rate in the pre-expansion period. Invasive diagnostic testing was low at baseline (1.0%) and did not change post-coverage expansion. The change in PMPM is estimated at $US0.026 post-coverage expansion. CONCLUSION: The PBRS agreement to expand NIPT coverage for women aged < 35 years was associated with an increase in NIPT utilization, decreases in conventional screening methods, and a modest increase in PMPM expenditures.

The landscape of pharmacogenetic testing in a US managed care population.

PURPOSE: Little is known about how many insured patients receive pharmacogenetic testing. We describe trends of single-gene pharmacogenetic testing in a US managed care population, and demographic and clinical characteristics of patients who received a test. METHODS: We leveraged a random sample of nearly 11 million patients from a data set of paid medical and pharmacy claims to identify patients with at least one claim indicating receipt of at least one of these single-gene pharmacogenetic tests: CYP2C19, CYP2D6, CYP2C9, VKORC1, UGT1A1, and HLA class 1 typing. RESULTS: From 1 January 2013 to 30 September 2017, 5712 patients received at least one pharmacogenetic test (55% female; mean age = 43 years). The median number of tests per patient was 3 (mean = 2.7, max = 12); 54% were processed through Managed Medicare/Medicaid, while 45% were processed through commercial insurance. The total number of pharmacogenetic tests received more than doubled from 2013 (n = 1955) to 2015 (n = 4192), then decreased slightly in 2016 (n = 3946). The most common test was CYP2C19 (n = 4719), and "long-term (current) use of other medications" was the most common diagnosis. CONCLUSION: Pharmacogenetic testing through patients' insurance was low, but more than doubled from 2013 to 2016. This study highlights the need to better understand utilization patterns and insurance coverage for pharmacogenetic tests.

A Quasi-Experimental Analysis of Lethal Means Assessment and Risk for Subsequent Suicide Attempts and Deaths.

BACKGROUND: Counseling on access to lethal means is highly recommended for patients with suicide risk, but there are no formal evaluations of its impact in real-world settings. OBJECTIVE: Evaluate whether lethal means assessment reduces the likelihood of suicide attempt and death outcomes. DESIGN: Quasi-experimental design using an instrumental variable to overcome confounding due to unmeasured patient characteristics that could influence provider decisions to deliver lethal means assessment. SETTING: Kaiser Permanente Colorado, an integrated health system serving over 600,000 members, with comprehensive capture of all electronic health records, medical claims, and death information. PARTICIPANTS: Adult patients who endorsed suicide ideation on the Patient Health Questionnaire-9 (PHQ-9) depression screener administered in behavioral health and primary care settings from 2010 to 2016. INTERVENTIONS: Provider documentation of lethal means assessment in the text of clinical notes, collected using a validated Natural Language Processing program. MEASUREMENTS: Main outcome was ICD-9 or ICD-10 codes for self-inflicted injury or suicide death within 180 days of index PHQ-9 event. RESULTS: We found 33% of patients with suicide ideation reported on the PHQ-9 received lethal means assessment in the 30 days following identification. Lethal means assessment reduced the risk of a suicide attempt or death within 180 days from 3.3 to 0.83% (p = .034, 95% CI = .069-.9). LIMITATIONS: Unmeasured suicide prevention practices that co-occur with lethal means assessment may contribute to the effects observed. CONCLUSIONS: Clinicians should expand the use of counseling on access to lethal means, along with co-occurring suicide prevention practices, to all patients who report suicide ideation.

Stakeholder perspectives of the clinical utility of pharmacogenomic testing in solid organ transplantation.

Aims: To assess stakeholder perspectives regarding the clinical utility of pharmacogenomic (PGx) testing following kidney, liver, and heart transplantation. Methods: We conducted individual semi-structured interviews and focus groups with kidney, liver, and heart transplantation patients and providers. We analyzed the qualitative data to identify salient themes. Results: The study enrolled 36 patients and 24 providers. Patients lacked an understanding about PGx, but expressed interest in PGx testing. Providers expressed willingness to use PGx testing, but reported barriers to implementation, such as lack of knowledge, lack of evidence demonstrating clinical utility, and patient healthcare burden. Conclusion: Patient and provider educational efforts, including foundational knowledge, clinical evidence, and applications to patient care beyond just immunosuppression, may be useful to facilitate the use of PGx testing in transplant medicine.

Monitoring suicidal patients in primary care using electronic health records.

INTRODUCTION: Patients at risk for suicide often come into contact with primary care providers, many of whom use electronic health records (EHRs) for charting. It is not known, however, how often suicide ideation or attempts are documented in EHRs. METHODS: We used retrospective analyses of de-identified EHR data from a distributed health network of primary care organizations to estimate the frequency of using diagnostic codes to record suicidal ideation and attempts. Data came from 3 sources: a clinician notes field processed using natural language processing; a suicidal ideation item on a patient-reported depression severity instrument (9-item Patient Health Questionnaire [PHQ-9]); and diagnostic codes from the EHR. RESULTS: Only 3% of patients with an indication of suicidal ideation in the notes field had a corresponding International Classification of Diseases, 9th Revision (ICD-9), code (κ = 0.036). Agreement between an indication of suicidal ideation from item 9 of the PHQ-9 and an ICD-9 code was slightly higher (κ = 0.068). Suicide attempt indicated in the notes field was more likely to be recorded using an ICD-9 code (19%; κ = 0.18). CONCLUSIONS: Few cases of suicidal ideation and attempt were documented in patients' EHRs using diagnostic codes. Increased documentation of suicidal ideation and behaviors in patients' EHRs may improve their monitoring in the health care system.

Dynamic medication adherence modeling in primary prevention of cardiovascular disease: a Markov microsimulation methods application.

BACKGROUND: Real-world patients' medication adherence is lower than that of clinical trial patients. Hence, the effectiveness of medications in routine practice may differ. OBJECTIVES: The study objective was to compare the outcomes of an adherence-naive versus a dynamic adherence modeling framework using the case of statins for the primary prevention of cardiovascular (CV) disease. METHODS: Statin adherence was categorized into three state-transition groups on the basis of an epidemiological cohort study. Yearly adherence transitions were incorporated into a Markov microsimulation using TreeAge software. Tracker variables were used to store adherence transitions, which were used to adjust probabilities of CV events over the patient's lifetime. Microsimulation loops "random walks" estimated the average accrued quality-adjusted life-years (QALYs) and CV events. For each 1,000-patient microsimulations, 10,000 outer loops were performed to reflect second-order uncertainty. RESULTS: The adherence-naive model estimated 0.14 CV events avoided per person, whereas the dynamic adherence model estimated 0.08 CV events avoided per person. Using the adherence-naive model, we found that statin therapy resulted in 0.40 QALYs gained over the lifetime horizon on average per person while the dynamic adherence model estimated 0.22 incremental QALYs gained. Subgroup analysis revealed that maintaining high adherence in year 2 resulted in 0.23 incremental QALYs gained as compared with 0.16 incremental QALYs gained when adherence dropped to the lowest level. CONCLUSIONS: A dynamic adherence Markov microsimulation model reveals risk reduction and effectiveness that are lower than with an adherence-naive model, and reflective of real-world practice. Such a model may highlight the value of improving or maintaining good adherence.

Association between glycated hemoglobin and health utility for Type 1 diabetes.

OBJECTIVES: Cost-effectiveness models for diabetes link glycated hemoglobin (HbA1c) to diabetes-related complications. Independent of diabetes-related complications, there is little known on the association between HbA1c and health utility scores. This link can alter the cost effectiveness of interventions designed to improve HbA1c. The cross-sectional relationship between HbA1c and health utility scores in adult type 1 diabetes patients was estimated after adjusting for diabetes-related complications. METHODS: The EuroQoL-5 dimension (EQ-5D) questionnaire and an ad hoc survey requesting demographic information and adherence to glucose monitoring therapies was administered to adult type 1 diabetes patients during a clinic visit and combined with clinical medical record data. Health utility scores were derived using the US time-tradeoff valuation of the EQ-5D. Linear regression was used to estimate the relationship between HbA1c and utility, adjusting for treatments, demographics, and diabetes-related complications. RESULTS: Among 176 patients, mean (standard deviation [SD]) age was 38 (12.2) years, duration of disease was 22 (12.1) years, and number of chronic conditions other than type 1 diabetes was 2.7 (2.0). Unadjusted mean (SD) utility was 0.94 (0.09) for those with HbA1c levels <7 % (n = 54), 0.89 (0.15) for those with HbA1c ≥ 7 % (n = 122), and 0.91 (0.14) for all patients. After adjustment, a 1 % absolute increase in HbA1c was associated with a disutility of -0.03 (95 % confidence interval [CI] -0.049, -0.006). CONCLUSIONS: Findings suggest that, after adjusting for diabetes-related complications, higher HbA1c levels are associated with a significant health disutility. Pending additional data from longitudinal studies, these findings could be used in cost-effectiveness evaluations of type 1 diabetes interventions that impact HbA1c.

Comparative safety of selective serotonin reuptake inhibitors among pediatric users with respect to adverse cardiac events.

PURPOSE: This study aims to perform a comparative safety study assessing the risk of ventricular arrhythmia, cardiac arrest, or sudden death among pediatric selective serotonin reuptake inhibitor (SSRI) users. METHODS: Using US claims data from 1997 to 2009, new pediatric (age < 18 years) users of SSRI monotherapy were identified. Adverse cardiac outcomes occurring within 12 months of SSRI initiation were identified using a previously validated International Classification of Disease, ninth edition algorithm. Cox proportional hazard analysis was used to estimate the risk for each SSRI, using fluoxetine as the referent group, adjusting for the propensity to receive an individual SSRI, demographics, and exposure covariates. RESULTS: Over the study period, 113,714 subjects met the inclusion criteria and contributed 40,639 person-years of SSRI exposure time. Sertraline (33%) and fluoxetine (29%) were the most commonly prescribed SSRIs. Forty events occurred within 12 months of SSRI initiation. The crude incidence rate was highest for escitalopram (19.5/10,000 person-years) and lowest for fluoxetine (4.2/10,000 person-years). The median time to event ranged from 45 to 86 days. The adjusted risk of adverse event, relative to fluoxetine, was highest for citalopram Hazard Ratio (HR) = 3.53, 95% confidence interval [CI] = 1.09­11.46) and escitalopram (HR = 3.30, 95%CI = 1.08­10.14) and lowest for paroxetine (HR = 1.34, 95%CI = 0.30­5.99) and sertraline (HR = 2.14, 95%CI = 0.75­6.16). CONCLUSIONS: The incidence of adverse cardiac events among pediatric SSRI users was low. However, the risk of an adverse outcome was higher for citalopram and escitalopram users as compared with fluoxetine users. Future studies should focus on confirming these findings and identifying modifying risk factors to optimize medication selection for this population.

Rates of 5 common antidepressant side effects among new adult and adolescent cases of depression: a retrospective US claims study.

BACKGROUND: Antidepressants are the first-line treatment for depression, yet medication-related side effects may be associated with antidepressant discontinuation before reaching a period of exposure believed to result in effectiveness. There is a gap in knowledge of the prevalence of side effects across commonly prescribed antidepressants and the effect of the type of antidepressant on the likelihood of side effects in real-world clinical practice. OBJECTIVE: The aim of this study was to estimate and compare the prevalence of headaches, nausea or vomiting, agitation, sedation, and sexual dysfunction among patients diagnosed with depression who initiated monotherapy across different classes of antidepressants and to estimate the effect of the type of antidepressant on the likelihood of each of the 5 side effects. METHODS: A retrospective cohort of patients aged ≥13 who were newly diagnosed with depression and began antidepressant monotherapy was created using LifeLink managed care claims from 1998 to 2008. Antidepressant groups included selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), bupropion, phenylpiperazine, and tetracyclic antidepressants. Prevalence of headache, nausea or vomiting, agitation, sedation, and sexual dysfunction were compared across antidepressant groups. Propensity-adjusted Cox proportional hazards regression was used to estimate the likelihood of each of the 5 side effects for each antidepressant group compared with SSRIs, adjusted for demographic, clinical, and treatment characteristics. RESULTS: The study cohort included 40,017 patients (3617 adolescents, aged 13-18 years, and 36,400 adults, aged ≥19 years; mean age = 45 years; 67% female) with a new episode of depression who were initiated on antidepressant monotherapy within 30 days of diagnosis (SSRI [66%], bupropion [14%], SNRI [12%], other [8%]). The most common side effects were headache (up to 17/1000 person-months of therapy in adults and adolescents) and nausea (up to 7.2/1000 in adults, 9.3/1000 in adolescents). Relative to adults receiving SSRIs, adults receiving SNRIs had a higher risk of nausea (hazard ratio [HR] = 1.26; 95%CI,1.05-1.51). Adults (HR = 0.78; 95% CI, 0.62-0.96) and adolescents (HR = 0.43; 95% CI, 0.21-0.87) taking bupropion were less likely to experience headaches compared with adults and adolescents, respectively, taking an SSRI. Adolescents receiving a tetracyclic were more likely to experience headaches than adolescents receiving an SSRI (HR = 3.16; 95%CI, 1.13-8.84). CONCLUSIONS: Prevalence and risk of the 5 side effects varied across types of antidepressants for both adults and adolescents. Results from this study were consistent with prior clinical trials, suggesting that variation in side effect profiles exists in a more generalized managed care population.