Breathing Practices for Stress and Anxiety Reduction: Conceptual Framework of Implementation Guidelines Based on a Systematic Review of the Published Literature.

Anxiety and stress plague populations worldwide. Voluntary regulated breathing practices offer a tool to address this epidemic. We examined peer-reviewed published literature to understand effective approaches to and implementation of these practices. PubMed and ScienceDirect were searched to identify clinical trials evaluating isolated breathing-based interventions with psychometric stress/anxiety outcomes. Two independent reviewers conducted all screening and data extraction. Of 2904 unique articles, 731 abstracts, and 181 full texts screened, 58 met the inclusion criteria. Fifty-four of the studies' 72 interventions were effective. Components of effective and ineffective interventions were evaluated to develop a conceptual framework of factors associated with stress/anxiety reduction effectiveness. Effective breath practices avoided fast-only breath paces and sessions <5 min, while including human-guided training, multiple sessions, and long-term practice. Population, other breath paces, session duration ≥5 min, and group versus individual or at-home practices were not associated with effectiveness. Analysis of interventions that did not fit this framework revealed that extensive standing, interruptions, involuntary diaphragmatic obstruction, and inadequate training for highly technical practices may render otherwise promising interventions ineffective. Following this evidence-based framework can help maximize the stress/anxiety reduction benefits of breathing practices. Future research is warranted to further refine this easily accessible intervention for stress/anxiety relief.

Slow-Breathing Curriculum for Stress Reduction in High School Students: Lessons Learned From a Feasibility Pilot.

Purpose: Nearly one in three US adolescents meet the criteria for anxiety, an issue that has worsened with the COVID-19 pandemic. We developed a video-based slow diaphragmatic breathing stress-reduction curriculum for high school students and evaluated its feasibility, tolerability, and preliminary effectiveness. Methods: This cluster-randomized feasibility pilot compared 5-min slow diaphragmatic breathing for 5 weeks with treatment-as-usual control among four 12th-grade public high school classes. Students individually participated after school during COVID-19-related hybrid teaching, with slow diaphragmatic breathing three times/week and breath science education once/week. Feasibility was based on completion of breathing exercises, breath science education, and preliminary effectiveness assessments, and ease/tolerability was based on qualitative assessments. Preliminary effectiveness was measured with the State-Trait Anxiety Inventory (STAI) and a timed-exhale carbon dioxide tolerance test (CO2TT) of physiological stress response. Descriptive statistics and repeated analysis of variance were performed to quantify and compare outcomes between time periods. Human subjects research approval was granted through Western IRB-Copernicus Group (WCG IRB) [ClinicalTrials.gov, Identifier: NCT05266833.]. Results: Forty-three students consented to participate. Breath practice compliance ranged from 29 to 83% across classes and weeks, and decreased on average over the 5 weeks. Compliance with the breath science videos ranged from 43 to 86%, and that with the weekly STAI-State and CO2TT measures varied from 36 to 86%. Compliance with ease/tolerability assessments ranged from 0 to 60%. Preliminary effectiveness assessments' compliance varied across classes from 83 to 89% during baseline, and 29 to 72% at follow-up. The curriculum was rated as somewhat-to-definitely useful/beneficial, and definitely-to-very easy/tolerable. Students reported enjoying the diaphragmatic breathing, CO2TT, and breath science education; some found the extended exhales challenging and the curriculum and assessments time-consuming. Preliminary effectiveness analyses indicated no significant changes in STAI or CO2TT from baseline to followup or from before to after breathing exercises (p > 0.05 for all). Conclusions: Implementation of this 5-week slow breathing curriculum was feasible and tolerable to this cohort. Compliance, tolerability, and effectiveness may be improved with in-class participation. Future research on simple and accessible slow-breathing exercises is warranted to address today's adolescent stress-management crisis. Trial Registration: ClinicalTrials.gov, Identifier: NCT05266833.

Costs associated with treatment of insomnia in Alzheimer's disease caregivers: a comparison of mindfulness meditation and cognitive behavioral therapy for insomnia.

BACKGROUND: Among the over 5 million informal caregivers for patients with Alzheimer's disease (AD) in the United States (US), over 60% experience insomnia. Research on insomnia treatment efficacy in AD caregivers is limited. An ongoing randomized non-inferiority clinical trial, the Caregiver Sleep Research study, is evaluating whether mindfulness meditation is non-inferior to cognitive behavioral therapy for insomnia (CBT-I) in the treatment of insomnia in AD caregivers. The present report examines estimated intervention costs in this ongoing trial. METHODS: Micro-costing was used to itemize and abstract costs of the two interventions: a mindfulness-based intervention known as mindful awareness practices for insomnia (MAP-I); and CBT-I. This approach involves collecting detailed data on resources utilized and the unit costs of those resources, thereby revealing actual resource use and economic costs for each treatment arm. Personnel time, patient time, and supplies were inventoried, and unit costs were applied. Caregiver time costs, including travel, were based on US Labor Bureau home-health aide national mean hourly wages; instructor/staff costs were based on hourly wages. Per-participant and program costs were calculated assuming individual- and group-delivery to reflect real-world implementation. Sensitivity analyses evaluated robustness of estimates. RESULTS: From the societal perspective, per-participant MAP-I costs were $1884 for individual and $1377 for group delivery; for CBT-I, these costs were $3978 and $1981, respectively. Compared with CBT-I, MAP-I provided cost savings of $2094 (53%) and $604 (30%) per treated caregiver for individual and group delivery, respectively. From the US healthcare system perspective, MAP-I vs. CBT-I participant savings were $1872 (65%) for individual and $382 (44%) for group interventions, respectively. For MAP-I and CBT-I, instructor in-class time was the highest cost component. Results were most sensitive to combined instructor time costs. CONCLUSIONS: Treatment of insomnia with MAP-I, compared to CBT-I, yields substantial cost savings for society and the healthcare system. With this potential for cost savings, results of the ongoing non-inferiority trial have critical implications for insomnia treatment dissemination and its benefits to AD caregivers and other community populations with insomnia.

The economic burden of caregiving in epilepsy: An estimate based on a survey of US caregivers.

OBJECTIVE: The burden of caregiving for persons with epilepsy (PWEs) has not been examined previously in the United States. We assessed the clinical impact and direct and indirect economic costs for caregivers of PWEs. METHODS: An internet survey of 500 caregivers of PWEs was conducted from May to July 2015 using a combination of validated instruments and questions designed specifically for this survey. Caregivers were stratified by PWE age (adult/child) and disease severity (low: 0 vs high: 1 + seizures in the prior month). Annual self-reported direct and indirect costs were reported per caregiver and extrapolated to all US caregivers. The economic burden of caregiving for PWEs was defined as the difference between costs for caregivers and the general population. RESULTS: Caregivers reported that PWEs averaged 11.4 seizures in the prior month. Eighty percent of respondents were female and the average age was 44.3. Since becoming a caregiver, many reported anxiety (52.8%), depression (41.0%), and insomnia (30.8%). Annual mean direct medical costs for caregivers of children with low vs high seizure frequency were $4344 and $10 162, respectively. Costs for caregivers of adult PWEs were $4936 and $8518. Mean indirect costs associated with caregiving for a child with low vs high seizure frequency were $20 529 and $40 137; those for caregivers of an adult were $13 981 and $28 410. The cost estimates are higher vs the general US population; annual per-person healthcare utilization costs were $2740 and productivity loss costs were $5015. When extrapolating to the US population of PWE caregivers, annual costs exceeded $62 billion vs $14 billion for the general population, resulting in a caregiver burden of nearly $48 billion. SIGNIFICANCE: The clinical and economic burden of caregivers for PWE were substantial, and greatest for those caring for children with frequent seizures. The impact on caregivers should be considered when estimating the value of interventions that control epilepsy.

Cost-Effectiveness of Cetuximab as First-line Treatment for Metastatic Colorectal Cancer in the United States.

PURPOSE: We conducted a cost-effectiveness analysis incorporating recent phase III clinical trial (FIRE-3) data to evaluate clinical and economic tradeoffs associated with first-line treatments of KRAS wild-type (WT) metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: A cost-effectiveness model was developed using FIRE-3 data to project survival and lifetime costs of FOLFIRI plus either cetuximab or bevacizumab. Hypothetical KRAS-WT mCRC patients initiated first-line treatment and could experience adverse events, disease progression warranting second-line treatment, or clinical response and hepatic metastasectomy. Model inputs were derived from FIRE-3 and published literature. Incremental cost-effectiveness ratios (ICERs) were reported as US$ per life year (LY) and quality-adjusted life year (QALY). Scenario analyses considered patients with extended RAS mutations and CALGB/SWOG 80405 data; 1-way and probabilistic sensitivity analyses were conducted. RESULTS: Compared with bevacizumab, KRAS-WT patients receiving first-line cetuximab gained 5.7 months of life at a cost of $46,266, for an ICER of $97,223/LY ($122,610/QALY). For extended RAS-WT patients, the ICER was $77,339/LY ($99,584/QALY). Cetuximab treatment was cost-effective 80.3% of the time, given a willingness-to-pay threshold of $150,000/LY. Results were sensitive to changes in survival, treatment duration, and product costs. CONCLUSIONS: Our analysis of FIRE-3 data suggests that first-line treatment with cetuximab and FOLFIRI in KRAS (and extended RAS) WT mCRC patients may improve health outcomes and use financial resources more efficiently than bevacizumab and FOLFIRI. This information, in combination with other studies investigating comparative effectiveness of first-line options, can be useful to clinicians, payers, and policymakers in making treatment and resource allocation decisions for mCRC patients.

Real-world cardiovascular disease burden in patients with atherosclerotic cardiovascular disease: a comprehensive systematic literature review.

OBJECTIVE: Based on randomized controlled trials (RCTs), non-fatal myocardial infarction (MI) rates range between 9 and 15 events per 1000 person-years, ischemic stroke between 4 and 6 per 1000 person-years, CHD death rates between 5 and 7 events per 1000 person-years, and any major vascular event between 28 and 53 per 1000 person-years in patients with atherosclerotic cardiovascular disease (ASCVD). We reviewed global literature on the topic to determine whether the real-world burden of secondary major adverse cardiovascular events (MACEs) is higher among ASCVD patients. METHODS: We searched PubMed and Embase using MeSH/keywords including cardiovascular disease, secondary prevention and observational studies. Studies published in the last 5 years, in English, with ≥50 subjects with elevated low-density lipoprotein cholesterol (LDL-C) or on statins, and reporting secondary MACEs were included. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of each included study. RESULTS: Of 4663 identified articles, 14 studies that reported MACE incidence rates per 1000 person-years were included in the review (NOS grades ranged from 8 to 9; 2 were prospective and 12 were retrospective studies). Reported incidence rates per 1000 person-years had a range (median) of 12.01-39.9 (26.8) for MI, 13.8-57.2 (41.5) for ischemic stroke, 1.0-94.5 (21.1) for CV-related mortality and 9.7-486 (52.6) for all-cause mortality. Rates were 25.8-211 (81.1) for composite of MACEs. Multiple event rates had a range (median) of 60-391 (183) events per 1000 person-years. CONCLUSIONS: Our review indicates that MACE rates observed in real-world studies are substantially higher than those reported in RCTs, suggesting that the secondary MACE burden and potential benefits of effective CVD management in ASCVD patients may be underestimated if real-world data are not taken into consideration.

A systematic literature review of methods of incorporating mortality in cost-effectiveness analyses of lipid-lowering therapies.

AIMS: Cost effectiveness analysis (CEA) is a useful tool for estimating the value of an intervention in relation to alternatives. In cardiovascular disease (CVD), CEA is especially important, given the high economic and clinical burden. One key driver of value is CVD mortality prevention. However, data used to inform CEA parameters can be limited, given the difficulty in demonstrating statistically significant mortality benefit in randomized clinical trials (RCTs), due in part to the frequency of fatal events and limited trial durations. This systematic review identifies and summarizes whether published CVD-related CEAs have incorporated mortality benefits, and the methodology among those that did. MATERIALS AND METHODS: A systematic literature review was conducted of CEAs of lipid-lowering therapies published between 2000-2017. Health technology assessments (HTA) and full-length manuscripts were included, and sources of mortality data and methods of applying mortality benefits were extracted. Results were summarized as proportions of articles to articulate common practices in CEAs of CVD. RESULTS: This review identified 100 studies for inclusion, comprising 93 full-length manuscripts and seven HTA reviews. Among these, 99% assumed a mortality benefit in the model. However, 87 of these studies that incorporated mortality differences did so despite the trials used to inform model parameters not demonstrating statistically significant differences in mortality. None of the 12 studies that used statistically significant findings from an individual RCT were based on active control studies. In a sub-group analysis considering the 60 CEAs that incorporated a direct mortality benefit, 48 (80%) did not have RCT evidence for statistically significant benefit in CVD mortality. LIMITATIONS AND CONCLUSIONS: The finding that few CEA models included mortality inputs from individual RCTs of lipid-lowering therapy may be surprising, as one might expect that treatment efficacy should be based on robust clinical evidence. However, regulatory requirements in CVD-related RCTs often lead to insufficient sample sizes and observation periods for detecting a difference in CVD mortality, which results in the use of intermediate outcomes, composite end-points, or meta-analysis to extrapolate long-term mortality benefit in a lifetime CEA.

Measuring the Value of New Drugs: Validity and Reliability of 4 Value Assessment Frameworks in the Oncology Setting.

BACKGROUND: Several organizations have developed frameworks to systematically assess the value of new drugs. OBJECTIVE: To evaluate the convergent validity and interrater reliability of 4 value frameworks to understand the extent to which these tools can facilitate value-based treatment decisions in oncology. METHODS: Eight panelists used the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), Institute for Clinical and Economic Review (ICER), and National Comprehensive Cancer Network (NCCN) frameworks to conduct value assessments of 15 drugs for advanced lung and breast cancers and castration-refractory prostate cancer. Panelists received instructions and published clinical data required to complete the assessments, assigning each drug a numeric or letter score. Kendall's Coefficient of Concordance for Ranks (Kendall's W) was used to measure convergent validity by cancer type among the 4 frameworks. Intraclass correlation coefficients (ICCs) were used to measure interrater reliability for each framework across cancers. Panelists were surveyed on their experiences. RESULTS: Kendall's W across all 4 frameworks for breast, lung, and prostate cancer drugs was 0.560 (P= 0.010), 0.562 (P = 0.010), and 0.920 (P < 0.001), respectively. Pairwise, Kendall's W for breast cancer drugs was highest for ESMO-ICER and ICER-NCCN (W = 0.950, P = 0.019 for both pairs) and lowest for ASCO-NCCN (W = 0.300, P = 0.748). For lung cancer drugs, W was highest pairwise for ESMO-ICER (W = 0.974, P = 0.007) and lowest for ASCO-NCCN (W = 0.218, P = 0.839); for prostate cancer drugs, pairwise W was highest for ICER-NCCN (W = 1.000, P < 0.001) and lowest for ESMO-ICER and ESMO-NCCN (W = 0.900, P = 0.052 for both pairs). When ranking drugs on distinct framework subdomains, Kendall's W among breast cancer drugs was highest for certainty (ICER, NCCN: W = 0.908, P = 0.046) and lowest for clinical benefit (ASCO, ESMO, NCCN: W = 0.345, P = 0.436). Among lung cancer drugs, W was highest for toxicity (ASCO, ESMO, NCCN: W = 0. 944, P < 0.001) and lowest for certainty (ICER, NCCN: W = 0.230, P = 0.827); and among prostate cancer drugs, it was highest for quality of life (ASCO, ESMO: W = 0.986, P = 0.003) and lowest for toxicity (ASCO, ESMO, NCCN: W = 0.200, P = 0.711). ICC (95% CI) for ASCO, ESMO, ICER, and NCCN were 0.800 (0.660-0.913), 0.818 (0.686-0.921), 0.652 (0.466-0.834), and 0.153 (0.045-0.371), respectively. When scores were rescaled to 0-100, NCCN provided the narrowest band of scores. When asked about their experiences using the ASCO, ESMO, ICER, and NCCN frameworks, panelists generally agreed that the frameworks were logically organized and reasonably easy to use, with NCCN rated somewhat easier. CONCLUSIONS: Convergent validity among the ASCO, ESMO, ICER, and NCCN frameworks was fair to excellent, increasing with clinical benefit subdomain concordance and simplicity of drug trial data. Interrater reliability, highest for ASCO and ESMO, improved with clarity of instructions and specificity of score definitions. Continued use, analyses, and refinements of these frameworks will bring us closer to the ultimate goal of using value-based treatment decisions to improve patient care and outcomes. DISCLOSURES: This work was funded by Eisai Inc. Copher and Knoth are employees of Eisai Inc. Bentley, Lee, Zambrano, and Broder are employees of Partnership for Health Analytic Research, a health services research company paid by Eisai Inc. to conduct this research. For this study, Cohen, Huynh, and Neville report fees from Partnership for Health Analytic Research. Outside of this study, Cohen receives grants and direct consulting fees from various companies that manufacture and market pharmaceuticals. Mei reports a grant from Eisai Inc. during this study. The other authors have no disclosures to report. Study concept and design were contributed by Bentley and Broder, with assistance from Elkin and Cohen. Bentley took the lead in data collection, along with Elkin, Huynh, Mukherjea, Neville, Mei, Popescu, Lee, and Zambrano. Data interpretation was performed by Bentley and Broder, along with Elkin, Cohen, Copher, and Knoth. The manuscript was written primarily by Bentley, along with Elkin and Broder, and revised by Bentley, Broder, Elkin, Cohen, Copher, and Knoth. Select components of this work's methods were presented at ISPOR 19th Annual European Congress held in Vienna, Austria, October 29-November 2, 2016, and Society for Medical Decision Making 38th Annual North American Meeting held in Vancouver, Canada, October 23-26, 2016.

The Incidence and Health Care Resource Burden of the Myelodysplastic Syndromes in Patients in Whom First-Line Hypomethylating Agents Fail.

BACKGROUND: Although hypomethylating agents (HMAs) are effective and approved therapies for patients with myelodysplastic syndromes (MDS), many patients do not benefit from treatment, and nearly all ultimately stop responding to HMAs. The incidence and cost burden of HMA failure are unknown yet needed to appreciate the magnitude and significance of such failure. METHODS: We analyzed a de-identified dataset of over 5 million individuals with private health insurance in the U.S. to estimate MDS incidence, prevalence, and treatments. Based on MDS provider interviews, a conceptual model of MDS patient management was constructed to create a new, claims-relevant and drug development-relevant definition of HMA treatment failure. This algorithm was used to define resource encumbrance of MDS patients in whom HMA treatment failed. RESULTS: We estimated an MDS incidence rate of ∼70 cases per 100,000 enrollees per year and a prevalence of 155 cases per 100,000 enrollees. The proportion of MDS patients receiving HMA treatment was low (∼3%), and treatment was typically initiated within 1 year of the first MDS claim. Notably, HMA-treated individuals were older and had more comorbidities than the overall MDS cohort. Total health care costs of managing MDS patients after HMA failure were high (∼$77,000 during the first 6 months) and were driven primarily by non-pharmacy costs. CONCLUSION: This study quantifies for the first time the burden of significant unmet need in caring for MDS patients following HMA treatment failure. The Oncologist 2017;22:379-385Implications for Practice: U.S.-based treatment patterns among MDS patients demonstrate the significant clinical, financial, and health care burden associated with HMA failure and call for active therapies for this patient population.

Validity and Reliability of Value Assessment Frameworks for New Cancer Drugs.

BACKGROUND: Several organizations have developed frameworks to systematically assess the value of new drugs. These organizations include the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the Institute for Clinical and Economic Review (ICER), and the National Comprehensive Cancer Network (NCCN). OBJECTIVES: To understand the extent to which these four tools can facilitate value-based treatment decisions in oncology. METHODS: In this pilot study, eight panelists conducted value assessments of five advanced lung cancer drugs using the ASCO, ESMO, and ICER frameworks. The panelists received instructions and published clinical data required to complete the assessments. Published NCCN framework scores were abstracted. The Kendall's W coefficient was used to measure convergent validity among the four frameworks. Intraclass correlation coefficients were used to measure inter-rater reliability among the ASCO, ESMO, and ICER frameworks. Sensitivity analyses were conducted. RESULTS: Drugs were ranked similarly by the four frameworks, with Kendall's W of 0.703 (P = 0.006) across all the four frameworks. Pairwise, Kendall's W was the highest for ESMO-ICER (W = 0.974; P = 0.007) and ASCO-NCCN (W = 0.944; P = 0.022) and the lowest for ICER-NCCN (W = 0.647; P = 0.315) and ESMO-NCCN (W = 0.611; P = 0.360). Intraclass correlation coefficients (confidence interval [CI]) for the ASCO, ESMO, and ICER frameworks were 0.786 (95% CI 0.517-0.970), 0.804 (95% CI 0.545-0.973), and 0.281 (95% CI 0.055-0.799), respectively. When scores were rescaled to 0 to 100, the ICER framework provided the narrowest band of scores. CONCLUSIONS: The ASCO, ESMO, ICER, and NCCN frameworks demonstrated convergent validity, despite differences in conceptual approaches used. The ASCO inter-rater reliability was high, although potentially at the cost of user burden. The ICER inter-rater reliability was poor, possibly because of its failure to distinguish differential value among the sample of drugs tested. Refinements of all frameworks should continue on the basis of further testing and stakeholder feedback.

Tolerability of central nervous system symptoms among HIV-1 infected efavirenz users: analysis of patient electronic medical record data.

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor indicated for treatment of HIV-1 infection. Despite concern over EFV tolerability in clinical trials and practice, particularly related to central nervous system (CNS) adverse events, some observational studies have shown high rates of EFV continuation at one year and low rates of CNS-related EFV substitution. The objective of this study was to further examine the real-world rate of CNS-related EFV discontinuation in antiretroviral therapy naïve HIV-1 patients. This retrospective cohort study used a nationally representative electronic medical records database to identify HIV-1 patients ≥12 years old, treated with a 1st-line EFV-based regimen (single or combination antiretroviral tablet) from 1 January 2009 to 30 June 2013. Patients without prior record of EFV use during 6-month baseline (i.e., antiretroviral therapy naïve) were followed 12 months post-medication initiation. CNS-related EFV discontinuation was defined as evidence of a switch to a replacement antiretroviral coupled with record of a CNS symptom within 30 days prior, absent lab evidence of virologic failure. We identified 1742 1st-line EFV patients. Mean age was 48 years, 22.7% were female, and 8.1% had a prior report of CNS symptoms. The first year, overall discontinuation rate among new users of EFV was 16.2%. Ten percent of patients (n = 174) reported a CNS symptom and 1.1% (n = 19) discontinued EFV due to CNS symptoms: insomnia (n = 12), headache (n = 5), impaired concentration (n = 1), and somnolence (n = 1). The frequency of CNS symptoms was similar for patients who discontinued EFV compared to those who did not (10.3 vs. 9.9%; P = .86). Our study found that EFV discontinuation due to CNS symptoms was low, consistent with prior reports.

Cost-effectiveness of bronchial thermoplasty in commercially-insured patients with poorly controlled, severe, persistent asthma.

OBJECTIVES: We examined the cost-effectiveness of treating poorly controlled, severe, persistent asthma patients with bronchial thermoplasty (BT), a novel technology that uses thermal energy to reduce airway smooth muscle mass, with 5-year outcome data demonstrating a durable reduction in asthma exacerbations. STUDY DESIGN: We conducted a model-based cost-effectiveness analysis assessing 5-year healthcare utilization, patient quality of life and adverse events. METHODS: We utilized Markov modeling to estimate the costs and quality-of-life impact of BT compared with high-dose combination therapy among poorly controlled, severe, persistent asthma patients: those requiring high-dose combination therapy and having experienced an asthma exacerbation-related ER visit in the past year. RESULTS: The cost-effectiveness of BT was US$5495 per quality-adjusted life year; and approximately 22% of sensitivity analysis iterations estimated BT to reduce costs and increase quality of life. CONCLUSIONS: BT is a cost-effective treatment option for patients with poorly controlled, severe, persistent asthma.

Cost effectiveness of a 92-gene assay for the diagnosis of metastatic cancer.

OBJECTIVES: To estimate the clinical and economic trade-offs involved in using a molecular assay (92-gene assay, CancerTYPE ID) to aid in identifying the primary site of difficult-to-diagnose metastatic cancers and to explore whether the 92-gene assay can be used to standardize the diagnostic process and costs for clinicians, patients, and payers. METHODS: Four decision-analytic models were developed to project the lifetime clinical and economic impact of incorporating the 92-gene assay compared with standard care alone. For each model, total and incremental costs, life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and the proportion of patients treated correctly versus incorrectly were projected from the payer perspective. Model inputs were based on published literature, analyses of SEER (Surveillance Epidemiology and End RESULTS) data, publicly available data, and interviews with clinical experts. RESULTS: In all four models, the 92-gene assay increased the proportion of patients treated correctly, decreased the proportion of patients treated with empiric therapy, and increased quality-adjusted survival. In the primary model, the ICER was $50,273/QALY; thus, the 92-gene assay is therefore cost effective when considering a societal willingness-to-pay threshold of $100,000/QALY. These findings were robust across sensitivity analyses. CONCLUSIONS: Use of the 92-gene assay for diagnosing metastatic tumors of uncertain origin is associated with reduced misdiagnoses, increased survival, and improved quality of life. Incorporating the assay into current practice is a cost-effective approach to standardizing diagnostic methods while improving patient care. Limitations of this analysis are the lack of data availability and resulting modeling simplifications, although sensitivity analyses showed these to not be key drivers of results.

Cost-effectiveness of aripiprazole once-monthly compared with paliperidone palmitate once-monthly injectable for the treatment of schizophrenia in the United States.

OBJECTIVE: To develop a decision-analytic model to estimate the cost-effectiveness of initiating maintenance treatment with aripiprazole once-monthly (AOM) vs paliperidone long-acting injectable (PLAI) once-monthly among patients with schizophrenia in the US. METHODS: A decision-analytic model was developed to evaluate a hypothetical cohort of patients initiating maintenance treatment with AOM or PLAI. Rates of relapse, adverse events (AEs), and direct medical costs were estimated for 1 year. Patients either remained on initial treatment or discontinued treatment due to lack of efficacy, AEs, or other reasons, including non-adherence. Data from placebo-controlled pivotal trials and product prescribing information (PI) were used to estimate treatment efficacy and AEs. Analyses were performed assuming dosing of clinical trials, real-world practice, PIs, and highest therapeutic dose available, because of variation in practice settings. The main outcome of interest was incremental cost per schizophrenia hospitalization averted with AOM vs PLAI. RESULTS: Based on placebo-controlled pivotal trials' dosing, AOM improved clinical outcomes by reducing schizophrenia relapses vs PLAI (0.181 vs 0.277 per person per year [pppy]) at an additional cost of US$1276 pppy, resulting in an incremental cost-effectiveness ratio (ICER) of US$13,280/relapse averted. When PI dosing was assumed, this ICER increased to US$19,968/relapse averted. When real-world dosing and highest available dosing were assumed, AOM was associated with fewer relapses and lower overall treatment costs vs PLAI. CONCLUSIONS: AOM consistently provided favorable clinical benefits. Under various dosing scenarios, AOM results indicated fewer relapses at lower overall costs or a reasonable cost-effectiveness threshold (i.e., less than the cost of a hospitalization relapse) vs PLAI. Given the heterogeneous nature of schizophrenia and variability in treatment response, health plans may consider open access for treatments like AOM. Since model inputs were based on data from separate placebo-controlled trials, generalization of results to the real-world setting is limited.

Implications of the impact of prevalence on test thresholds and outcomes: lessons from tuberculosis.

BACKGROUND: With today's rapid advances in technology and understanding of disease, more screening and diagnostic tests have become available in a variety of sociodemographic and clinical settings. This analysis quantifies the impact of varying prevalence rates on test performance for given sensitivity and specificity values. METHODS: Using a worked example of latent tuberculosis infection, we compared true-positive (TP) and false-positive (FP) results when varying prevalence and test sensitivity and specificity. We used estimates from published literature to estimate two tests' sensitivity (81%, QuantiFERON®-TB Gold In-Tube; 88%, T-SPOT®.TB) and specificity (99%; 88%), and we used World Health Organization data to estimate disease prevalence in five countries. RESULTS: Varying sensitivity impacted outcomes most in high-prevalence settings; change in specificity had greater impact in low-prevalence settings. In switching from QuantiFERON-TB to T-SPOT.TB (higher sensitivity, lower specificity), trade-offs between increasing case identification (TPs) and decreasing unnecessary treatments (FPs) varied dramatically with prevalence. Lower-prevalence settings paid a greater "price" of more FPs for each TP gained, with 37.7 FPs per TP in the United States (5% prevalence) versus 2.5 in the Ivory Coast (55% prevalence). CONCLUSIONS: Prevalence affects test performance for given sensitivity and specificity values. To optimize test performance, disease prevalence should be incorporated in testing decisions, and sensitivity and specificity should be set locally, not globally. In lower-prevalence settings, using highly specific assays may optimize outcomes.

Using administrative claims data to estimate virologic failure rates among human immunodeficiency virus-infected patients with antiretroviral regimen switches.

OBJECTIVE: To develop and validate a claims signature model that estimates proportions of HIV-infected patients in administrative claims databases who switched combination antiretroviral therapy (cART) regimens because of virologic failure. METHODS: The authors used an HIV-specific registry (development data set) to develop logistic regression models to estimate odds of virologic failure among patients who switched cART regimens. Models were validated in a sample of administrative claims with laboratory values (validation data set). The final model was applied to an application data set as a worked example. RESULTS: There were 1691, 1073, and 3954 eligible patients with cART switches in the development, validation, and application data sets, respectively. In the development data set, virologic failure before a switch was observed 21.8% of the time. Failure more likely caused the regimen switch among patients who were treatment experienced, had been receiving their baseline regimen for > 180 days, had ≥ 2 or more physician visits within 90 days, had > 1 HIV RNA or CD4 cell count test within 30 days, had any resistance test within 180 days, or had a change in regimen type. The final model had good discriminatory ability (C = 0.885) and fit (Hosmer-Lemeshow P = 0.8692). Failure was estimated to occur in 18.9% (v. 18.6% observed) of switches in the validation data set and 13.8% in the application data set. CONCLUSIONS: This claims signature model allows payers to use claims data to estimate virologic failure rates in their patient populations, thereby better understanding plan costs of failure.

Cost-effectiveness of 21-gene assay in node-positive, early-stage breast cancer.

OBJECTIVE: To assess impact on health outcomes and healthcare expenditures of adopting a 21-gene assay for women with early-stage, minimally node-positive, estrogen receptor-positive (N (1-3)/ER) HER2-negative breast cancer. STUDY DESIGN: We adapted a deterministic decision-analytic model to estimate costs and quality-of-life outcomes associated with chemotherapy, adverse events, supportive care, recurrence, and second primary cancers for usual care compared with care determined by the 21-gene assay recurrence score, where 71% and 54% of women, respectively, were treated with adjuvant chemotherapy. Model input data were based on national statistics, published literature, physician surveys, and Medicare Part B prices. METHODS: Annual numbers of events were multiplied by quality-adjusted life-years (QALYs) lost and costs to estimate net health and economic impacts of each strategy. Analyses were from a managed care payer perspective for the US population. RESULTS: Patients receiving the assay were predicted to gain 0.127 QALY and save $4359 annually from avoiding chemotherapy, adverse events, supportive care, and secondary primary tumors. For a 2-million member plan, net gains were 4.44 QALYs/year and savings were $13,476/year. Cost savings were greater for the Medicare population. Although overall results were sensitive only to reduced impact of testing and chemotherapy costs, they were still highly cost-effective (incremental cost-effectiveness ratio <$20,000/QALY). CONCLUSIONS: Use of a 21-gene assay in patients with early-stage N (1-3)/ER HER2-negative breast cancer may improve health outcomes and add no incremental cost, thereby providing valuable insight for health plans, the Centers for Medicare and Medicaid Services, and clinicians regarding coverage policies and treatment decisions.

Race and gender associations between obesity and nine health-related quality-of-life measures.

PURPOSE: To assess how health-related quality of life (HRQoL) varies by body mass index (BMI) category among gender and racial subgroups using nine HRQoL measures. METHODS: Among 3,710 US adults, we evaluated self-reported height, weight, and HRQoL that was measured by six indexes (EQ-5D; HUI2; HUI3; SF-6D; QWB-SA; HALex) and three summary measures (theta; PCS; MCS). Mean HRQoL was estimated by weighted regression for normal, overweight, and obese subgroups (BMI: 18.5-24.9 kg/m(2); 25-29.9; and 30-50). RESULTS: HRQoL was significantly lower (P < 0.0001) with increasing BMI category except for MCS. Obese individuals were 5.3 units lower on PCS (1-100 scale) and 0.05-0.11 lower on the HRQoL indexes (0-1 scale) than those with normal weight. MCS scores were significantly lower for obese than normal-weight among women (P = 0.04) but not men (P = 0.11). Overweight blacks had higher HRQoL than blacks in other BMI categories (P = 0.033). CONCLUSIONS: Six commonly used HRQoL indexes and two of three health status summary measures indicated lower HRQoL with obesity and overweight than with normal BMI, but the degree of decrement varied by index. The association appeared driven primarily by physical health, although mental health also played a role among women. Counter to hypotheses, blacks may have highest HRQoL when overweight.

Cost effectiveness of atazanavir-ritonavir versus lopinavir-ritonavir in treatment-naïve human immunodeficiency virus-infected patients in the United States.

OBJECTIVE: To evaluate lifetime cost effectiveness of atazanavir-ritonavir (ATV + r) versus lopinavir-ritonavir (LPV/r), both with tenofovir-emtricitabine, in US HIV-infected patients initiating first-line antiretroviral therapy. METHODS: A Markov microsimulation model was developed to calculate quality-adjusted life-years (QALYs) based on CD4 and HIV RNA levels, coronary heart disease (CHD), AIDS, opportunistic infections (OIs), diarrhea, and hyperbilirubinemia. A million-member cohort of HIV-1-infected, treatment-naïve adults progressed at 3-month intervals through eight health states. Baseline characteristics, virologic suppression, cholesterol changes, and diarrhea and hyperbilirubinemia rates were based on 96-week CASTLE trial results. HIV mortality, OI rates, adherence, costs, utilities, and CHD risk were from literature and experts. LIMITATIONS: The incremental cost-effectiveness ratio (ICER) may be overestimated because the ATV + r treatment effect was based on an intention-to-treat analysis. The QALY weights used for diarrhea, hyperbilirubinemia, and CHD events are uncertain; however, the ICER remained < $50,000/QALY when these values were varied in sensitivity analyses. RESULTS: ATV + r patients received first-line therapy longer than LPV/r patients (97.3 vs. 70.7 months), had longer quality-adjusted survival (11.02 vs. 10.76 years), similar overall survival (18.52 vs. 18.51 years), and higher costs ($275,986 vs. 269,160). ATV+r [corrected] patients had lower rates of AIDS (19.08 vs. 20.05 cases/1000 patient-years), OIs (0.44 vs.0.52), diarrhea (1.27 vs. 6.26), and CHD events(5.44 vs. 5.51), but higher hyperbilirubinemia rates (6.99 vs. 0.25. ATV + r added 0.26 QALYs at a cost of $6826, for $26,421/QALY. CONCLUSIONS: By more effectively reducing viral load with less gastrointestinal toxicity and a better lipid profile, ATV + r lowered rates of AIDS and CHD, increased quality-adjusted survival, and was cost effective (< $50,000/QALY) compared with LPV/r.

Bias associated with failing to incorporate dependence on event history in Markov models.

PURPOSE: When using state-transition Markov models to simulate risk of recurrent events over time, incorporating dependence on higher numbers of prior episodes can increase model complexity, yet failing to capture this event history may bias model outcomes. This analysis assessed the tradeoffs between model bias and complexity when evaluating risks of recurrent events in Markov models. METHODS: The authors developed a generic episode/relapse Markov cohort model, defining bias as the percentage change in events prevented with 2 hypothetical interventions (prevention and treatment) when incorporating 0 to 9 prior episodes in relapse risk versus a model with 10 such episodes. Magnitude and sign of bias were evaluated as a function of event and recovery risks, disease-specific mortality, and risk function. RESULTS: Bias was positive in the base case for a prevention strategy, indicating that failing to fully incorporate dependence on event history overestimated the prevention's predicted impact. For treatment, the bias was negative, indicating an underestimated benefit. Bias approached zero as the number of tracked prior episodes increased, and the average bias over 10 tracked episodes was greater with the exponential compared with linear functions of relapse risk and with treatment compared with prevention strategies. With linear and exponential risk functions, absolute bias reached 33% and 78%, respectively, in prevention and 52% and 85% in treatment. CONCLUSION: Failing to incorporate dependence on prior event history in subsequent relapse risk in Markov models can greatly affect model outcomes, overestimating the impact of prevention and treatment strategies by up to 85% and underestimating the impact in some treatment models by up to 20%. When at least 4 prior episodes are incorporated, bias does not exceed 26% in prevention or 11% in treatment.