International Systematic Review of Utility Values Associated with Cardiovascular Disease and Reflections on Selecting Evidence for a UK Decision-Analytic Model.

PURPOSE: Evaluating interventions for cardiovascular disease (CVD) requires estimates of its effect on utility. We aimed to 1) systematically review utility estimates for CVDs published since 2013 and 2) critically appraise UK-relevant estimates and calculate corresponding baseline utility multipliers. METHODS: We searched MEDLINE and Embase (April 22, 2021) using CVD and utility terms. We screened results for primary studies reporting utility distributions for people with experience of heart failure, myocardial infarction, peripheral arterial disease, stable angina, stroke, transient ischemic attack, or unstable angina. We extracted characteristics from studies included. For UK estimates based on the EuroQoL 5-dimension (EQ-5D) measure, we assessed risk of bias and applicability to a decision-analytic model, pooled arms/time points as appropriate, and estimated baseline utility multipliers using predicted utility for age- and sex- matched populations without CVD. We sought utility sources from directly applicable studies with low risk of bias, prioritizing plausibility of severity ordering in our base-case model and highest population ascertainment in a sensitivity analysis. RESULTS: Most of the 403 studies identified used EQ-5D (n = 217) and most assessed Organisation for Economic Co-operation and Development populations (n = 262), although measures and countries varied widely. UK studies using EQ-5D (n = 29) produced very heterogeneous baseline utility multipliers for each type of CVD, precluding meta-analysis and implying different possible severity orderings. We could find sources that provided a plausible ordering of utilities while adequately representing health states. CONCLUSIONS: We cataloged international CVD utility estimates and calculated UK-relevant baseline utility multipliers. Modelers should consider unreported sources of heterogeneity, such as population differences, when selecting utility evidence from reviews. HIGHLIGHTS: Published systematic reviews have summarized estimates of utility associated with cardiovascular disease published up to 2013.We 1) reviewed utility estimates for 7 types of cardiovascular disease published since 2013, 2) critically appraised UK-relevant studies, and 3) estimated the effect of each cardiovascular disease on baseline utility.Our review 1) recommends a consistent and reliable set of baseline utility multipliers for 7 types of cardiovascular disease and 2) provides systematically identified reference information for researchers seeking utility evidence for their own context.

The cost-effectiveness of universal hepatitis B screening for reaching WHO diagnosis targets in Australia by 2030.

OBJECTIVES: To assess the impact on diagnosis targets, cost, and cost-effectiveness of universal hepatitis B screening in Australia. DESIGN: Markov model simulation of disease and care cascade progression for people with chronic hepatitis B in Australia. SETTING: Three scenarios were compared: 1. no change to current hepatitis B virus (HBV) testing practice; 2. universal screening strategy, with the aim of achieving the WHO diagnosis target by 2030 (90% of people with chronic hepatitis B diagnosed), based on opportunistic (general practitioner-initiated) screening for HBsAg; 3. universal screening strategy, and also ensuring that 50% of people with chronic hepatitis B are receiving appropriate clinical management by 2030. MAIN OUTCOME MEASURES: Projected care cascade for people with chronic hepatitis B, cumulative number of HBV-related deaths, intervention costs, and health utility (quality-adjusted life-years [QALYs] gained during 2020-2030). An incremental cost-effectiveness ratio (ICER) threshold (v scenario 1) of $50 000 per QALY gained was applied. RESULTS: Compared with scenario 1, 80 HBV-related deaths (interquartile range [IQR], 41-127 deaths) were averted during 2020-2030 in scenario 2, 315 HBV-related deaths (IQR, 211-454 deaths) in scenario 3. Scenario 2 cost $84 million (IQR, $41-106 million) more than scenario 1 during 2020-2030 (+8%), yielding an ICER of $104 921 (IQR, $49 587-107 952) per QALY gained. Scenario 3 cost $263 million (IQR, $214-316 million) more than scenario 1 during 2020-2030 (+24%), yielding an ICER of $47 341 (IQR, $32 643-58 200) per QALY gained. Scenario 3 remained cost-effective if the test positivity rate was higher than 0.35% or the additional costs per person tested did not exceed $4.02. CONCLUSIONS: Universal screening for hepatitis B will be cost-effective only if the cost of testing is kept low and people receive appropriate clinical management.

Cost-effectiveness model of renal cell carcinoma (RCC) surveillance in hereditary leiomyomatosis and renal cell carcinoma (HLRCC).

PURPOSE: To determine the cost-effectiveness of annual renal imaging surveillance (RIS) in hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is associated with a 21% risk to age 70 years of RCC. Presentations with advanced renal cell cancer (RCC) are associated with poor outcomes whereas RIS detects early-stage RCC; however, evidence for the cost-effectiveness of RIS is lacking. METHODS: We developed a decision-analytic model to compare, at different age starting points (11 years, 18 years, 40 years, 60 years), the costs and benefits of lifetime contrast-enhanced renal MRI surveillance (CERMRIS) vs no surveillance in HLRCC. Benefits were measured in life-years gained (LYG), quality-adjusted life years (QALYs) and costs in British Pounds Sterling (GBP). Net monetary benefit (NMB) was calculated using a cost-effectiveness threshold of £20 000/QALY. One-way sensitivity and probabilistic analyses were also performed. RESULTS: In the base-case 11-year age cohort, surveillance was cost-effective (Incremental_NMB=£3522 (95% CI -£2747 to £7652); Incremental_LYG=1.25 (95% CI 0.30 to 1.86); Incremental_QALYs=0.29 (95% CI 0.07 to 0.43)] at an additional mean discounted cost of £2185/patient (95% CI £430 to £4144). Surveillance was also cost-effective in other age cohorts and dominated a no surveillance strategy in the 40 year cohort [Incremental_NMB=£12 655 (95% CIs -£709 to £21 134); Incremental_LYG=1.52 (95% CI 0.30 to 2.26); Incremental_QALYs=0.58 (95% CI 0.12 to 0.87) with a cost saving of £965/patient (95% CI -£4202 to £2652). CONCLUSION: Annual CERMRI in HLRCC is cost-effective across age groups modelled.

A cost-effectiveness analysis of primary versus hospital-based specialist care for direct acting antiviral hepatitis C treatment.

BACKGROUND: Hepatitis C virus elimination may be possible by scaling up direct-acting antiviral (DAA) treatment. Due to the safety and simplicity of DAA treatment, primary care-based treatment delivery is now feasible, efficacious and may be cheaper than hospital-based specialist care. In this paper, we use Prime Study data - a randomised controlled trial comparing the uptake of DAA treatment between primary and hospital-based care settings amongst people who inject drugs (PWID) - to estimate the cost of initiating treatment for PWID diagnosed with hepatitis C in primary care compared to hospital-based care. METHODS: The total economic costs associated with delivering DAA treatment (post hepatitis C diagnosis) within the Prime study - including health provider time/training, medical tests, equipment, logistics and pharmacy costs - were collected. Appointment data were used to estimate the number/type of appointments required to initiate treatment in each case, or the stage at which loss to follow up occurred. RESULTS: Among the hepatitis C patients randomised to be treated within primary care, 43/57 (75%) commenced treatment at a mean cost of A$885 (95% CI: A$850-938) per patient initiating treatment. In hospital-based care, 18/53 hepatitis C patients (34%) commenced treatment at a mean cost of A$2078 (range: A$2052-2394) per patient initiating treatment - more than twice as high as primary care. The lower cost in the primary care arm was predominantly the result of increased retention in care compared to the hospital-based arm. CONCLUSIONS: Compared to hospital-based care, providing hepatitis C services for PWID in primary care can improve treatment uptake and approximately halve the average cost of treatment initiation. To improve treatment uptake and cure, countries should consider primary care as the main model for hepatitis C treatment scale-up.

Enhancing the hepatitis B care cascade in Australia: A cost-effectiveness model.

If Australia is to successfully eliminate hepatitis B as a public health threat, it will need to enhance the chronic hepatitis B (CHB) care cascade. This study used a Markov model to assess the impact, cost and cost-effectiveness of scaling up CHB diagnosis, linkage to care and treatment to reach national and international elimination targets for hepatitis B in Australia. Compared to continued current trends, the model calculated the difference in care cascade projection, disability-adjusted life years (DALYs), costs and the incremental cost-effectiveness ratio (ICER), of scaling up CHB diagnosis, linkage to care and treatment to reach: (a) Australia's 2022 national targets and (b) the WHO's 2030 global targets. Achieving the national and WHO targets had ICERs of A$13 435 (A$10 236-A$21 165) and A$14 482 (A$13 031-A$25 641) per DALY averted between 2016 and 2030 in Australia, respectively. However, this excluded implementation and demand generation costs. The ICER for the National Strategy and WHO Strategy remained under A$50 000 per DALY averted if Australia spent up to A$328 or A$538 million, respectively, per annum (for 2016-2030) on implementation and demand generation activities. Sensitivity analysis showed that cost-effectiveness was predominately driven by the cost of CHB treatment and influenced by disease progression rates. Hence for Australia to reach the National Hepatitis B Strategy 2022 targets and WHO Strategy 2030 targets, it requires an improvement in the CHB care cascade. We estimated it is cost-effective to spend up to A$328 million or A$538 million per year to reach the National and WHO Strategy targets, respectively.

The case for a universal hepatitis C vaccine to achieve hepatitis C elimination.

BACKGROUND: The introduction of highly effective direct-acting antiviral (DAA) therapy for hepatitis C has led to calls to eliminate it as a public health threat through treatment-as-prevention. Recent studies suggest it is possible to develop a vaccine to prevent hepatitis C. Using a mathematical model, we examined the potential impact of a hepatitis C vaccine on the feasibility and cost of achieving the global WHO elimination target of an 80% reduction in incidence by 2030 in the era of DAA treatment. METHODS: The model was calibrated to 167 countries and included two population groups (people who inject drugs (PWID) and the general community), features of the care cascade, and the coverage of health systems to deliver services. Projections were made for 2018-2030. RESULTS: The optimal incidence reduction strategy was to implement test and treat programmes among PWID, and in settings with high levels of community transmission undertake screening and treatment of the general population. With a vaccine available, the optimal strategy was to include vaccination within test and treat programmes, in addition to vaccinating adolescents in settings with high levels of community transmission. Of the 167 countries modelled, between 0 and 48 could achieve an 80% reduction in incidence without a vaccine. This increased to 15-113 countries if a 75% efficacious vaccine with a 10-year duration of protection were available. If a vaccination course cost US$200, vaccine use reduced the cost of elimination for 66 countries (40%) by an aggregate of US$7.4 (US$6.6-8.2) billion. For a US$50 per course vaccine, this increased to a US$9.8 (US$8.7-10.8) billion cost reduction across 78 countries (47%). CONCLUSIONS: These findings strongly support the case for hepatitis C vaccine development as an urgent public health need, to ensure hepatitis C elimination is achievable and at substantially reduced costs for a majority of countries.

Defining Optimal Care for Functional Gut Disorders - Multi-Disciplinary Versus Standard Care: A Randomized Controlled Trial Protocol.

BACKGROUND: Functional gastrointestinal disorders (FGIDs) are the commonest reason for gastroenterological consultation, with patients usually seen by a specialist working in isolation. There is a wealth of evidence testifying to the benefit provided by dieticians, behavioral therapists, hypnotherapists and psychotherapists in treating these conditions, yet they rarely form a part of the therapeutic team, and these treatment modalities are rarely offered as part of the therapeutic management. There has been little examination of different models of care for FGIDs. We hypothesize that multi-disciplinary integrated care is superior to standard specialist-based care in the treatment of functional gut disorders. METHODS: The "MANTRA" (Multidisciplinary Treatment for Functional Gut Disorders) study compares comprehensive multi-disciplinary outpatient care with standard hospital outpatient care. Consecutive new referrals to the gastroenterology and colorectal outpatient clinics of a single secondary and tertiary care hospital of patients with an FGID, defined by the Rome IV criteria, will be included. Patients will be prospectively randomized 2:1 to multi-disciplinary (gastroenterologist, gut-hypnotherapist, psychiatrist, behavioral therapist ('biofeedback') and dietician) or standard care (gastroenterologist or colorectal surgeon). Patients are assessed up to 12 months after completing treatment. The primary outcome is an improvement on a global assessment scale at the end of treatment. Symptoms, quality of life, psychological well-being, and healthcare costs are secondary outcome measures. DISCUSSION: There have been few studies examining how best to deliver care for functional gut disorders. The MANTRA study will define the clinical and cost benefits of two different models of care for these highly prevalent disorders. TRIAL REGISTRATION NUMBER: Clinicaltrials.govNCT03078634 Registered on Clinicaltrials.gov, completed recruitment, registered on March 13th 2017. Ethics and Dissemination: Ethical approval has been received by the St Vincent's Hospital Melbourne human research ethics committee (HREC-A 138/16). The results will be disseminated in peer-reviewed journals and presented at international conferences. Protocol version 1.2.

Estimating Joint Health Condition Utility Values.

OBJECTIVES: To predict health state utility values (HSUVs) for individuals with up to 4 conditions simultaneously. METHODS: Person-level data were taken from the General Practice Patient Survey, a national survey of adult patients registered with general practices in England. Individuals reported whether they had any 1 of 16 chronic conditions and completed the 3-level EuroQol 5-dimensional questionnaire. Four nonparametric methods (additive, multiplicative, minimum, and the adjusted decrement estimator) and 1 parametric estimator (the linear index) were used to predict HSUVs for individuals with a joint health condition (JHC). Predicted and actual utility scores were compared for precision using root mean square error and mean absolute error. Bias was assessed using mean error. RESULTS: The analysis included 929,565 individuals, of which 30.5% had at least 2 conditions. Of the nonparametric estimators, the multiplicative approach produced estimates with the lowest bias and most precision for 2 JHCs. For populations with a long-term mental health condition within the JHC, the multiplicative approach overestimated utility scores. All nonparametric methods produced biased results when estimating HSUVs for 3 or 4 JHCs. The linear index generally produced unbiased results with the highest precision. CONCLUSIONS: The multiplicative approach was the best nonparametric estimator when estimating HSUVs for 2 JHCs. None of the nonparametric approaches for estimating HSUVs can be recommended with more than 2 JHCs. The linear index was found to have good predictive properties but needs external validation before being recommended for routine use.

The economic case for precision medicine.

Introduction: The advancement of precision medicine into routine clinical practice has been highlighted as an agenda for national and international health care policy. A principle barrier to this advancement is in meeting requirements of the payer or reimbursement agency for health care. This special report aims to explain the economic case for precision medicine, by accounting for the explicit objectives defined by decision-makers responsible for the allocation of limited health care resources. Areas covered: The framework of cost-effectiveness analysis, a method of economic evaluation, is used to describe how precision medicine can, in theory, exploit identifiable patient-level heterogeneity to improve population health outcomes and the relative cost-effectiveness of health care. Four case studies are used to illustrate potential challenges when demonstrating the economic case for a precision medicine in practice. Expert commentary: The economic case for a precision medicine should be considered at an early stage during its research and development phase. Clinical and economic evidence can be generated iteratively and should be in alignment with the objectives and requirements of decision-makers. Programmes of further research, to demonstrate the economic case of a precision medicine, can be prioritized by the extent that they reduce the uncertainty expressed by decision-makers.

Cost-effectiveness analyses of genetic and genomic diagnostic tests.

Developments in next-generation sequencing technologies have driven the clinical application of diagnostic tests that interrogate the whole genome, which offer the chance to diagnose rare inherited diseases or inform the targeting of therapies. New genomic diagnostic tests compete with traditional approaches to diagnosis, including the genetic testing of single genes and other clinical strategies, for finite health-care budgets. In this context, decision analytic model-based cost-effectiveness analysis is a useful method to help evaluate the costs versus consequences of introducing new health-care interventions. This Perspective presents key methodological, technical, practical and organizational challenges that must be considered by decision-makers responsible for the allocation of health-care resources to obtain robust and timely information about the relative cost-effectiveness of the increasing numbers of emerging genomic tests.

Cost-effectiveness of treating chronic hepatitis C virus with direct-acting antivirals in people who inject drugs in Australia.

BACKGROUND AND AIM: Reducing the burden of hepatitis C virus (HCV) related liver disease will require treating people who inject drugs (PWID), the group at most risk of infection and transmission. We determine the cost-effectiveness of treating PWID with interferon-free direct-acting antiviral therapy in Australia. METHODS: Using a deterministic model of HCV treatment and liver disease progression, including a fixed rate of re-infection, the expected healthcare costs and quality-adjusted life years (QALYs) of a cohort of newly HCV-infected PWID were calculated for: no treatment; treatment after initial infection ("early-treatment"); and treatment prior to developing compensated cirrhosis ("late-treatment"). Incremental cost-effectiveness ratios (ICERs) were used to compare scenarios. RESULTS: Late-treatment was cost-effective compared to no treatment, with a discounted average gain of 2.98 (95%confidence interval 2.88-5.22) QALYs per person for an additional cost of $15,132 ($11,246-18,922), giving an ICER of $5078 ($2847-5295) per QALY gained. Compared to late-treatment, early-treatment gained a further discounted average of 2.27 (0.58-4.80) QALYs per person for $38,794 ($34,789-41,367), giving an ICER of $17,090 ($2847-63,282), which was cost-effective in approximately 90% of Monte-Carlo uncertainty simulations. For every 100 newly HCV-infected PWID, there were an estimated 40 (39-56) eventual liver-related deaths without treatment, compared to 7 (6-11) and 8 (7-13) with early-treatment and late-treatment available respectively. CONCLUSIONS: Treating HCV-infected PWID with new therapies is cost-effective and could prevent a significant number of liver-related deaths. Although late-treatment was the most cost-effective option, the cost per QALY gained for early-treatment compared to late-treatment is likely to be below unofficial Australian willingness to pay thresholds.

Enhanced antiviral treatment efficacy and uptake in preventing the rising burden of hepatitis C-related liver disease and costs in Australia.

BACKGROUND AND AIM: Chronic hepatitis C virus (HCV) infection is an important cause of advanced liver disease and liver-related deaths in Australia. Our aim was to describe the burden of HCV infection and consider treatment strategies to reduce HCV-related morbidity and mortality. METHODS: Baseline model parameters were based upon literature review and expert consensus with a focus on Australian data. Three treatment scenarios based on anticipated introduction of improved direct-acting antiviral regimens were considered to reduce HCV disease burden. Scenario 1 evaluated the impact of increased treatment efficacy alone (to 80-90% by 2016). Scenario 2 evaluated increased efficacy and increased treatment uptake (2550 to 13,500 by 2018) without treatment restriction, while Scenario 3 considered the same increases with treatment limited to ≥ F3 during 2015-2017. RESULTS: In 2013, there were an estimated 233,490 people with chronic HCV infection: 13,850 with cirrhosis, 590 with hepatocellular carcinoma (HCC) and 530 liver-related deaths. If the current HCV treatment setting is unchanged, threefold increases in the number of people with cirrhosis, HCC, and liver disease deaths will be seen by 2030. Scenario 1 resulted in modest impacts on disease burden (4% decrease in HCC, decompensated cirrhosis, and liver deaths) and costs. Scenario 3 had the greatest impact on disease burden (approximately 50% decrease in HCC, decompensated cirrhosis, and liver deaths) and costs, while Scenario 2 had slightly lesser impact. CONCLUSIONS: Considerable increases in the burden of HCV-related advanced liver disease and its complications will be seen in Australia under current treatment levels and outcomes. Introduction of improved direct-acting antiviral regimens with enhanced efficacy at current treatment levels will lead to limited impacts on this disease burden. A combination of increased treatment efficacy and greater uptake is required to achieve major reductions in advanced liver disease and related costs.

The cost-effectiveness of a pharmacogenetic test: a trial-based evaluation of TPMT genotyping for azathioprine.

BACKGROUND: Thiopurine-methyl transferase (TPMT) testing prior to the prescription of azathioprine in autoimmune diseases is one of the few examples of a pharmacogenetic test that has made the transition from research into clinical practice. TPMT testing could lead to improved prescribing of azathioprine resulting in a reduction in adverse drug reactions as well as an improvement in effectiveness. When allocating scarce resources robust evidence on cost-effectiveness is required. OBJECTIVE: This study aimed to evaluate the cost-effectiveness of a TPMT genotyping test to inform azathioprine prescribing in autoimmune diseases. The secondary aim of this study was to demonstrate the complexity of undertaking a trial-based evaluation of a pharmacogenetic test. METHODS: A prospective economic evaluation was conducted alongside the TARGET (TPMT: Azathioprine Response to Genotype and Enzyme Testing) study, a pragmatic controlled trial that randomized (1:1) patients to undergo TPMT genotyping before azathioprine (n = 167) or current practice (n = 166). Assuming the UK health service perspective and a time horizon of 4 months, resource-use and health status data were collected prospectively for all recruited patients. RESULTS: The mean incremental cost for TPMT genotyping and subsequent care pathways compared with current practice for the 4-month follow-up was -£421.06 (95% confidence interval -£925.15 to £89.75). Mean incremental quality-adjusted life-years were close to zero but negative: -0.008 (95% confidence interval -0.017 to 0.0002). Assuming a threshold of £20,000 per quality-adjusted life-year, the expected incremental net benefit of introducing the test is £256.89 (95% CI -£425.94 to £932.86). CONCLUSIONS: TPMT genotyping potentially offers a less expensive alternative than current practice, but it may also have a small but negative effect on health status. These findings are associated with significant uncertainty, and the causal effect of TPMT genotyping on changes in health status and health care resource use remains uncertain. The results from this study therefore pose a difficult challenge to decision makers.

COX-2 inhibition versus gastroprotection with dual COX inhibitors: an evidence-based approach.

Highly selective inhibitors of cyclooxygenase-2 (COX-2i) were introduced to minimize peptic ulcers and their complications caused by dual COX inhibitors (COXi). Co-prescribing a (generally cheap) dual COXi with a gastroprotectant is an alternative strategy, proven to reduce the incidence of NSAID-associated endoscopic ulcers. This review compares the efficacies of these two strategies and makes some estimates of their relative cost-effectiveness. In standard risk patients, endoscopic ulcers are reduced to about the same extent (around 70-80%) by either co-prescribing omeprazole or lansoprazole with a dual COXi or preferring a COX-2i alone. COX-2i reduced ulcer complications by a weighted mean of around 60% in comparative studies with dual COXi. There is little information about the influence of PPI on this endpoint, although one study using H. pylori treatment as a possible surrogate for placebo intervention found 77% protection against recurrent upper gastrointestinal bleeding by co-administered omeprazole. One direct comparison of the two strategies in high-risk patients (recent ulcer bleed) found quite high rates of re-presentation with bleeding ulcer using either strategy, and the differences between them were not significant. Drug costs in four Western countries were compared for each strategy. In one, the costs were similar, but in the others the combination of a cheap dual COXi with omeprazole was usually more expensive than using a COX-2i. The safest strategy in highest risk patients may be to co-prescribe a gastroprotectant with a COX-2i, with resulting higher drug costs but possibly offset by savings in other health costs. The efficacy and cost-benefit of this alternative approach warrants investigation.