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.

Value of next generation sequencing (NGS) testing in advanced cancer patients.

OBJECTIVE: The availability of targeted therapies for oncology patients is increasing. Available genomic tests to identify treatment-eligible patients include single gene tests and gene panel tests, including the whole-exome, whole-transcriptome OncoExTra test. We assessed the costs and clinical benefits of test choice. METHODS: A Microsoft Excel-based model was developed to evaluate test choice in patients with advanced/metastatic non-small cell lung cancer (NSCLC), breast, prostate, and colorectal cancer. Treatment pathways were based on NCCN guidelines and medical expert opinion. Inputs were derived from published literature. Annual economic results and lifetime clinical results with OncoExTra testing were projected per-tested-patient and compared with single gene testing and no testing. Separately, results were estimated for a US health plan without the OncoExTra test and with its use in 5% of patients. RESULTS: Compared with no genomic testing, OncoExTra test use increased costs by $4,915 per patient; however, 82%-92% of individuals across tumour types were identified as eligible for targeted therapy or a clinical trial. Compared with single gene testing, OncoExTra test use decreased costs by $9,966 per-patient-tested while increasing use of approved or investigational targeted therapies by 20%. When considering a hypothetical health plan with 1 million members, 858 patients were eligible for genomic testing. Using the OncoExTra test in 5% of those eligible, per-member per-month costs decreased by $0.003, ranging from cost-savings of $0.026 in NSCLC patients to a $0.009 increase in prostate cancer patients. Cost-savings were driven by reduced treatment costs with increased clinical trial enrolment and reduced direct and indirect medical costs associated with targeted treatments. LIMITATIONS: Limitations include the required simplifications in modelling complex conditions that may not fully reflect evolving real-world testing and treatment patterns. CONCLUSIONS: Compared to single-gene testing, results indicate that using next generation sequencing test such as OncoExTra identified more actionable alterations, leading to improved outcomes and reduced costs.

Clinical Validation of a Cell-Free DNA Fragmentome Assay for Augmentation of Lung Cancer Early Detection.

Lung cancer screening via annual low-dose computed tomography has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by a low-dose computed tomography. Changes in genome-wide cell-free DNA fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer. We applied machine learning to fragmentome features to identify individuals who were more or less likely to have lung cancer. We trained the classifier using 576 cases and controls from study samples and validated it in a held-out group of 382 cases and controls. The validation demonstrated high sensitivity for lung cancer and consistency across demographic groups and comorbid conditions. Applying test performance to the screening eligible population in a 5-year model with modest utilization assumptions suggested the potential to prevent thousands of lung cancer deaths. Significance: Lung cancer screening has poor adoption. Our study describes the development and validation of a novel blood-based lung cancer screening test utilizing a highly affordable, low-coverage genome-wide sequencing platform to analyze cell-free DNA fragmentation patterns. The test could improve lung cancer screening rates leading to substantial public health benefits. See related commentary by Haber and Skates, p. 2025.

Health and economic impact of HPV 16/18 vaccination and cervical cancer screening in Eastern Africa.

Eastern Africa has the world's highest cervical cancer incidence and mortality rates. We used epidemiologic data from Kenya, Mozambique, Tanzania, Uganda, and Zimbabwe to develop models of HPV-related infection and disease. For each country, we assessed HPV vaccination of girls before age 12 followed by screening with HPV DNA testing once, twice, or three times per lifetime (at ages 35, 40, 45). For women over age 30, we assessed only screening (with HPV DNA testing up to three times per lifetime or VIA at age 35). Assuming no waning immunity, mean reduction in lifetime cancer risk associated with vaccination ranged from 36 to 45%, and vaccination followed by screening once per lifetime at age 35 with HPV DNA testing ranged from 43 to 51%. For both younger and older women, the most effective screening strategy was HPV DNA testing three times per lifetime. Provided the cost per vaccinated girl was less than I$10 (I$2 per dose), vaccination had an incremental cost-effectiveness ratio [I$ (international dollars)/year of life saved (YLS)] less than the country-specific per capita GDP, a commonly cited heuristic for "very cost-effective" interventions. If the cost per vaccinated girl was between I$10 (I$2 per dose) and I$25 (I$5 per dose), vaccination followed by HPV DNA testing would save the most lives and would be considered good value for public health dollars. These results should be used to catalyze design and evaluation of HPV vaccine delivery and screening programs, and contribute to a dialogue on financing HPV vaccination in poor countries.

Real-world impact of disease on functioning and activity: what is missed when using general instruments to estimate quality-adjusted life years.

OBJECTIVE: Economic evaluations conducted to inform healthcare resource allocation often rely on quality-adjusted life years (QALYs) to measure therapeutic benefit. However, QALYs, with underlying health utilities estimated using the EQ-5D or SF-36, may fail to capture the impact of disease for all patients. How well-being and heath utility differ across several common conditions was explored. METHODS: This study examined eight diseases: arthritis, asthma, cancer, depression, diabetes, heart disease, lung disease and stroke. Health utilities for each disease were obtained from published literature. Other measures of disease burden, including physical functioning, cognitive functioning and physical activity, were estimated from the National Health and Nutrition Examination Survey (NHANES). Group rankings by these measures were compared to rankings by health utility. RESULTS: Health utilities were lowest for patients with depression (0.44), and highest for those with cancer (0.81). Physical functioning was most limited (higher score) among those with stroke (28.2) and had the least impact for cancer (24.4). Physical activity was most impacted by heart disease (27.3) and least impacted by depression (40.7). Cognitive functioning was lowest in stroke (41.6) and highest in asthma (52.0). CONCLUSION: Differences in rankings of disease severity by metric indicate that the results of cost-utility analyses might be biased against treatments for certain diseases. As patient preferences for clinical outcomes vary, the full burden of disease should be considered in evaluations. Restricting access to treatments based on an incomplete estimate of burden could lead to misallocation of resources and a withholding of therapies that patients find valuable.

Protecting the gains: What changes are needed to prevent a reversal of the downward cardiovascular disease mortality trend?

AIMS: Cardiovascular disease (CVD) mortality has decreased over 60% over the past 50 years in the United States; however, emerging data indicate CVD incidence may be rising because of shifting demographics, increasing risk factor prevalence, and competing needs for limited resources. We projected CVD mortality from 2015 to 2040 given varying informed assumptions regarding changes in risk factor prevalence, uptake of current therapeutic options, and future innovations. METHODS: A microsimulation model was used to project US CVD mortality trends. National Health and Nutrition Examination Survey data were used to estimate population-level trends in CVD risk factors. Risk factors were used to generate Framingham Risk Scores for cohorts of 1 000 000 individuals from the general population to determine each individuals' CVD risk. Annual cardiovascular incidence, prevalence, and mortality were projected for scenarios differing by uptake of current therapies, anticipated pharmaceutical innovations with variable efficacy, risk factor prevalence, and changes in health disparities. RESULTS: When incorporating a demographic shift, continued changes in risk factors, current treatment utilization, and no major innovations, we predicted the CVD mortality rate would increase 41% by 2040. If innovations providing incremental benefits equal to those associated with the introduction of statins are identified and widely utilized, CVD mortality could remain constant through 2040. With more efficacious innovations, CVD mortality could be further reduced. CONCLUSIONS: Given demographic and risk prevalence changes, increasing access and adherence to current preventative therapeutics could slow the expected mortality increase, but new therapies may be needed to maintain the downward trend in CVD deaths.

Costs associated with unplanned readmissions among patients with heart failure with and without hyponatremia.

PURPOSE: Costs associated with unplanned readmissions among patients with heart failure with and without hyponatremia were studied. METHODS: This study estimated the costs of patients hospitalized for heart failure (HF) discharged with or without corrected sodium. A model was developed to monetize the 30-day readmission risk based on hyponatremia correction. Costs of discharging patient with corrected versus uncorrected hyponatremia were estimated using readmission rates from a previously published study and hospitalization costs from the Healthcare Costs and Utilization Cost Project and the Premier Healthcare Database. RESULTS: Discharging patients with HF and hyponatremia increased costs from $488-$569 per discharge compared to patients with corrected hyponatremia. This range reflected differences in readmission rates and sources of hospitalization costs. Sensitivity analyses showed hospitalization costs and readmission rates had the largest impact on model results. CONCLUSION: A retrospective study supports the value of upfront monitoring and correction of low serum sodium levels before discharge among patients with HF and hyponatremia by presenting an economic argument in addition to the clinical rational for reducing risk of readmission.

Healthcare Policy Changes in Osteoporosis Can Improve Outcomes and Reduce Costs in the United States.

In the United States, osteoporosis affects over 10 million adults, has high societal costs ($22 billion in 2008), and is currently being underdiagnosed and undertreated. Given an aging population, this burden is expected to rise. We projected the fracture burden in US women by modeling the expected demographic shift as well as potential policy changes. With the anticipated population aging and growth, annual fractures are projected to increase from 1.9 million to 3.2 million (68%), from 2018 to 2040, with related costs rising from $57 billion to over $95 billion. Policy-driven expansion of case finding and treatment of at-risk women could lower this burden, preventing 6.1 million fractures over the next 22 years while reducing payer costs by $29 billion and societal costs by $55 billion. Increasing use of osteoporosis-related interventions can reduce fractures and result in substantial cost-savings, a rare and fortunate combination given the current landscape in healthcare policy. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Utilization and budget impact of tolvaptan in the inpatient setting among patients with heart failure and hyponatremia.

OBJECTIVE: Assess characteristics of patients with heart failure (HF) and hyponatremia (HN) using tolvaptan, a selective vasopressin V2-receptor antagonist, for sodium correction, and estimate the budget impact of tolvaptan use in a hospital. METHODS: The Premier hospital database was analyzed to assess the utilization of tolvaptan, characteristics of users and non-users, and hospitalization costs among patients with HF and HN. Using these findings, a model was developed to estimate tolvaptan costs in proportion to total medical costs of managing patients with HF and HN, and the budget impact of tolvaptan use. Results were regenerated using data from the Healthcare Cost and Utilization Project (HCUP) database, and robustness was assessed in sensitivity analyses. RESULTS: Tolvaptan was used in 4.96% of inpatient visits among patients with HF and HN, more commonly among sicker patients as reflected in high utilization during intensive care stays (30.46%). Additionally, utilization increased by length of stay, which can serve as a proxy for disease severity. The model estimated that tolvaptan costs accounted for 0.3% of total hospitalization-related costs for patients with HF and HN, and the budget impact was $52.42 per visit. CONCLUSIONS: Results demonstrate that tolvaptan is used infrequently among patients with HF and HN, and is utilized among sicker patients. Tolvaptan accounted for 0.3% of total spending on management of inpatient visits with HF and HN, and had a marginal impact on hospital budget when compared with fluid restriction for HN correction. Availability of tolvaptan can provide an additional therapeutic option for sodium correction.

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.

Budget impact of somatostatin analogs as treatment for metastatic gastroenteropancreatic neuroendocrine tumors in US hospitals.

OBJECTIVE: With the introduction of new therapies, hospitals have to plan spending limited resources in a cost-effective manner. To assist in identifying the optimal treatment for patients with locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors, budget impact modeling was used to estimate the financial implications of adoption and diffusion of somatostatin analogs (SSAs). PATIENTS AND METHODS: A hypothetical cohort of 500 gastroenteropancreatic neuroendocrine tumor patients was assessed in an economic model, with the proportion with metastatic disease treated with an SSA estimated using published data. Drug acquisition, preparation, and administration costs were based on national pricing databases and published literature. Octreotide dosing was based on published estimates of real-world data, whereas for lanreotide, real-world dosing was unavailable and we therefore used the highest indicated dosing. Alternative scenarios reflecting the proportion of patients receiving lanreotide or octreotide were considered to estimate the incremental budget impact to the hospital. RESULTS: In the base case, 313 of the initial 500 gastroenteropancreatic neuroendocrine tumor patients were treated with an SSA. The model-predicted per-patient cost was US$83,473 for lanreotide and US$89,673 for octreotide. With a hypothetical increase in lanreotide utilization from 5% to 30% of this population, the annual model-projected hospital costs decreased by US$488,615. When varying the inputs in one-way sensitivity analyses, the results were most sensitive to changes in dosing assumptions. CONCLUSION: Results suggest that factors beyond drug acquisition cost can influence the budget impact to a hospital. When considering preparation and administration time, and real-world dosing, use of lanreotide has the potential to reduce health care expenditures associated with metastatic gastroenteropancreatic neuroendocrine tumor treatments.

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.

Cost-effectiveness of treatments for high-risk myelodysplastic syndromes after failure of first-line hypomethylating agent therapy.

PURPOSE: To evaluate optimal salvage therapy in high-risk myelodysplastic syndromes patients who have failed a first-line hypomethylating agent (HMA) therapy, given that treatment choice is challenging. METHODS: Using published literature and expert opinion, we developed a Markov model to evaluate the cost-effectiveness of current treatments for patients who failed first-line HMA therapy. The model predicted costs, life years, quality-adjusted life years and incremental cost-effectiveness ratios. Sensitivity analyses were conducted to assess the impact of uncertainty in model inputs. RESULTS: Supportive care was the least expensive option ($65,704/patient) with the shortest survival (0.48 years). Low- and high-intensity chemotherapies and hematopoietic cell transplantation increased survival and costs with incremental cost-effectiveness ratios of $108,808, 306,103 and 318,163/life year, respectively. Switching HMA was more costly and less efficacious than another treatment option, namely low-intensity chemotherapy. CONCLUSIONS: Subsequent treatments in myelodysplastic syndrome patients who failed first-line HMA significantly increase costs, while only providing marginal clinical benefit and substantially increasing treatment-related morbidities. Additional treatment options would benefit resource allocation, clinical decision-making and patient outcomes.

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.

Trade-offs in cervical cancer prevention: balancing benefits and risks.

BACKGROUND: New screening and vaccination technologies will provide women with more options for cervical cancer prevention. Because the risk of cervical cancer diminishes with effective routine screening, women may wish to consider additional attributes, such as the likelihood of false-positive results and diagnostic procedures for mild abnormalities likely to resolve without intervention in their screening choices. METHODS: We used an empirically calibrated simulation model of cervical cancer in the United States to assess the benefits and potential risks associated with prevention strategies differing by primary screening test, triage test for abnormal results (cytologic testing, human papillomavirus [HPV] DNA test), and screening frequency. Outcomes included colposcopy referrals, cervical intraepithelial neoplasia (CIN) types 1 and 2 or 3, lifetime cancer risk, and quality-adjusted life expectancy. RESULTS: Across strategies, colposcopy referrals and diagnostic workups varied 3-fold, although diagnostic rates of CIN 2 or 3 were similar and 95% of positive screening test results were for mild abnormalities likely to resolve on their own. For a representative group of a thousand 20-year-old women undergoing triennial screening for 10 years, we expect 1038 colposcopy referrals (7 CIN 2 or 3 diagnoses) from combined cytologic and HPV DNA testing and fewer than 200 referrals (6-7 CIN 2 or 3 diagnoses) for strategies that use triage testing. Similarly, for a thousand 40-year-old women, combined cytologic and HPV DNA testing led to 489 referrals (9 CIN 2 or 3), whereas alternative strategies resulted in fewer than 150 referrals (7-8 CIN 2 or 3). Using cytologic testing followed by triage testing in younger women minimizes both diagnostic workups and positive HPV test results, whereas in older women diagnostic workups are minimized with HPV DNA testing followed by cytologic triage testing. CONCLUSIONS: Clinically relevant information highlighting trade-offs among cervical cancer prevention strategies allows for inclusion of personal preferences into women's decision making about screening and provides additional dimensions to the construction of clinical guidelines.