Choice of Prosthetic Implant Combinations in Total Hip Replacement: Cost-Effectiveness Analysis Using UK and Swedish Hip Joint Registries Data.

BACKGROUND: Prosthetic implants used in total hip replacements (THR) have a range of bearing surface combinations (metal-on-polyethylene, ceramic-on-polyethylene, ceramic-on-ceramic, and metal-on-metal), head sizes (small [<36 mm in diameter] and large [≥36 mm in diameter]), and fixation techniques (cemented, uncemented, hybrid, and reverse hybrid). These can influence prosthesis survival, patients' quality of life, and healthcare costs. OBJECTIVES: To compare the lifetime cost-effectiveness of implants for patients of different age and sex profiles. METHODS: We developed a Markov model to compare the cost-effectiveness of various implants against small-head cemented metal-on-polyethylene implants. The probability that patients required 1 or more revision surgeries was estimated from analyses of more than 1 million patients in the UK and Swedish hip joint registries, for men and women younger than 55, 55 to 64, 65 to 74, 75 to 84, and 85 years and older. Implant and healthcare costs were estimated from local procurement prices, national tariffs, and the literature. Quality-adjusted life-years were calculated using published utility estimates for patients undergoing THR in the United Kingdom. RESULTS: Small-head cemented metal-on-polyethylene implants were the most cost-effective for men and women older than 65 years. These findings were robust to sensitivity analyses. Small-head cemented ceramic-on-polyethylene implants were most cost-effective in men and women younger than 65 years, but these results were more uncertain. CONCLUSIONS: The older the patient group, the more likely that the cheapest implants, small-head cemented metal-on-polyethylene implants, were cost-effective. We found no evidence that uncemented, hybrid, or reverse hybrid implants were the most cost-effective option for any patient group. Our findings can influence clinical practice and procurement decisions for healthcare payers worldwide.

State selection in Markov models for panel data with application to psoriatic arthritis.

Markov multistate models in continuous-time are commonly used to understand the progression over time of disease or the effect of treatments and covariates on patient outcomes. The states in multistate models are related to categorisations of the disease status, but there is often uncertainty about the number of categories to use and how to define them. Many categorisations, and therefore multistate models with different states, may be possible. Different multistate models can show differences in the effects of covariates or in the time to events, such as death, hospitalisation, or disease progression. Furthermore, different categorisations contain different quantities of information, so that the corresponding likelihoods are on different scales, and standard, likelihood-based model comparison is not applicable. We adapt a recently developed modification of Akaike's criterion, and a cross-validatory criterion, to compare the predictive ability of multistate models on the information which they share. All the models we consider are fitted to data consisting of observations of the process at arbitrary times, often called 'panel' data. We develop an implementation of these criteria through Hidden Markov models and apply them to the comparison of multistate models for the Health Assessment Questionnaire score in psoriatic arthritis. This procedure is straightforward to implement in the R package 'msm'.

Network meta-analysis combining individual patient and aggregate data from a mixture of study designs with an application to pulmonary arterial hypertension.

BACKGROUND: Network meta-analysis (NMA) is a methodology for indirectly comparing, and strengthening direct comparisons of two or more treatments for the management of disease by combining evidence from multiple studies. It is sometimes not possible to perform treatment comparisons as evidence networks restricted to randomized controlled trials (RCTs) may be disconnected. We propose a Bayesian NMA model that allows to include single-arm, before-and-after, observational studies to complete these disconnected networks. We illustrate the method with an indirect comparison of treatments for pulmonary arterial hypertension (PAH). METHODS: Our method uses a random effects model for placebo improvements to include single-arm observational studies into a general NMA. Building on recent research for binary outcomes, we develop a covariate-adjusted continuous-outcome NMA model that combines individual patient data (IPD) and aggregate data from two-arm RCTs with the single-arm observational studies. We apply this model to a complex comparison of therapies for PAH combining IPD from a phase-III RCT of imatinib as add-on therapy for PAH and aggregate data from RCTs and single-arm observational studies, both identified by a systematic review. RESULTS: Through the inclusion of observational studies, our method allowed the comparison of imatinib as add-on therapy for PAH with other treatments. This comparison had not been previously possible due to the limited RCT evidence available. However, the credible intervals of our posterior estimates were wide so the overall results were inconclusive. The comparison should be treated as exploratory and should not be used to guide clinical practice. CONCLUSIONS: Our method for the inclusion of single-arm observational studies allows the performance of indirect comparisons that had previously not been possible due to incomplete networks composed solely of available RCTs. We also built on many recent innovations to enable researchers to use both aggregate data and IPD. This method could be used in similar situations where treatment comparisons have not been possible due to restrictions to RCT evidence and where a mixture of aggregate data and IPD are available.

Indirect comparisons of ranibizumab and dexamethasone in macular oedema secondary to retinal vein occlusion.

BACKGROUND: Two treatments, ranibizumab and dexamethasone implant, for visual impairment due to macular oedema (ME) secondary to retinal vein occlusion (RVO) have recently been studied in clinical trials. There have been no head to head comparisons of the two treatments, and improvement measured as gain in Best Corrected Visual Acuity (BCVA) was reported using different outcomes thresholds between trials. To overcome these limitations, and inform an economic model, we developed a combination of a multinomial model and an indirect Bayesian comparison model for multinomial outcomes. METHODS: Outcomes of change from baseline in BCVA for dexamethasone compatible with those available for ranibizumab, reported by 4 randomised controlled trials, were estimated by fitting a multinomial distribution model to the probability of a patient achieving outcomes in a range of changes from baseline in BCVA (numbers of letters) at month 1. A Bayesian indirect comparison multinomial model was then developed to compare treatments in the Branch RVO (BRVO) and Central RVO (CRVO) populations. RESULTS: The multinomial model had excellent fit to the observed results. With the Bayesian indirect comparison, the probabilities of achieving ≥20 letters, with 95% credible intervals, at month 1 in patients with BRVO were 0.191 (0.130, 0.261) with ranibizumab and 0.093 (0.027, 0.213) with dexamethasone. In patients with CRVO, probabilities were 0.133 (0.082, 0.195) (ranibizumab) and 0.063 (0.016, 0.153) (dexamethasone). Probabilities of a gain in ≥10 letters in BRVO patients were 0.500 (0.365, 0.650) v 0.459 (0.248, 0.724) and in CRVO patients 0.459 (0.332, 0.602) v 0.498 (0.263, 0.791) for ranibizumab and dexamethasone treatments respectively. The comparisons also favoured ranibizumab at month 6 although changes to therapies after month 3 may have introduced bias. CONCLUSION: The newly developed combination of multinomial and indirect Bayesian comparison models indicated a trend for ranibizumab association with a greater percentage of ME patients achieving visual gains than dexamethasone at months 1 and 6 in a common clinical context, although results were not classically significant. The method was a useful tool for comparisons of probability distributions between clinical trials that reported events on different categorical scales and estimates can be used to inform economic models.

Cost-Effectiveness of Routine Monitoring of Long-Term Conditions in Primary Care: Informing Decision Modelling with a Systematic Review in Hypertension, Type 2 Diabetes and Chronic Kidney Disease.

BACKGROUND: Long-term conditions (LTCs) are major public health problems with a considerable health-related and economic burden. Modelling is key in assessing costs and benefits of different disease management strategies, including routine monitoring, in the conditions of hypertension, type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in primary care. OBJECTIVE: This review aimed to identify published model-based cost-effectiveness studies of routine laboratory testing strategies in these LTCs to inform a model evaluating the cost effectiveness of testing strategies in the UK. METHODS: We searched the Medline and Embase databases from inception to July 2023; the National Institute for Health and Care Institute (NICE) website was also searched. Studies were included if they were model-based economic evaluations, evaluated testing strategies, assessed regular testing, and considered adults aged >16 years. Studies identified were summarised by testing strategies, model type, structure, inputs, assessment of uncertainty, and conclusions drawn. RESULTS: Five studies were included in the review, i.e. Markov (n = 3) and microsimulation (n = 2) models. Models were applied within T2DM (n = 2), hypertension (n = 1), T2DM/hypertension (n = 1) and CKD (n = 1). Comorbidity between all three LTCs was modelled to varying extents. All studies used a lifetime horizon, except for a 10-year horizon T2DM model, and all used quality-adjusted life-years as the effectiveness outcome, except a TD2M model that used glycaemic control. No studies explicitly provided a rationale for their selected modelling approach. UK models were available for diabetes and CKD, but these compared only a limited set of routine monitoring tests and frequencies. CONCLUSIONS: There were few studies comparing routine testing strategies in the UK, indicating a need to develop a novel model in all three LTCs. Justification for the modelling technique of the identified studies was lacking. Markov and microsimulation models, with and without comorbidities, were used; however, the findings of this review can provide data sources and inform modelling approaches for evaluating the cost effectiveness of testing strategies in all three LTCs.

The impact of vaso-occlusive crises and disease severity on quality of life and productivity among patients with sickle cell disease in the US.

AIM: Sickle cell disease (SCD) is a lifelong blood disorder affecting approximately 100,000 individuals in the United States (US). A number of new treatments have recently become available to improve SCD clinical outcomes, but it is unclear how treatment innovations that reduce disease severity could affect patients' humanistic and economic outcomes. METHODS AND MATERIALS: To answer this question, an online survey of US adult residents with a self-reported SCD diagnosis was conducted. Humanistic outcomes based on health-related quality of life (HRQoL)) were assessed during and outside of vaso-occlusive crises (VOCs). Economic outcomes were measured by annual household income and whether the respondent received disability insurance. RESULTS: Among the 301 respondents completing the survey, average age was 34.4 years and 73.4% were female. Average HRQoL, measured using health utilities, were 0.311 (95% CI: 0.286, 0.337) during a VOC and 0.738 (0.720, 0.756) not during a VOC. The likelihood of claiming disability insurance was correlated with more frequent VOCs (0 VOCs: 12% vs. ≥4 VOCs: 47%, p = .002) and disease severity (Severity Class II: 16% vs. Severity Class III: 39%, p = .03). There was a weak relationship between VOC frequency and household income (0 VOCs: $47,488 vs. ≥4 VOCs: $34,569, p = .06) and no evidence of a relationship between disease severity class and income (Severity Class II: $42,443 vs. Severity Class III: $36,842, p = .29). CONCLUSION: In conclusion, disease severity, strongly predicted worse self-reported HRQoL, moderately predicted increased likelihood of collecting disability insurance, and weakly predicted lower household income levels.

Directly Acting Oral Anticoagulants for the Prevention of Stroke in Atrial Fibrillation in England and Wales: Cost-Effectiveness Model and Value of Information Analysis.

Objectives. Determine the optimal, licensed, first-line anticoagulant for prevention of ischemic stroke in patients with non-valvular atrial fibrillation (AF) in England and Wales from the UK National Health Service (NHS) perspective and estimate value to decision making of further research. Methods. We developed a cost-effectiveness model to compare warfarin (international normalized ratio target range 2-3) with directly acting (or non-vitamin K antagonist) oral anticoagulants (DOACs) apixaban 5 mg, dabigatran 150 mg, edoxaban 60 mg, and rivaroxaban 20 mg, over 30 years post treatment initiation. In addition to death, the 17-state Markov model included the events stroke, bleed, myocardial infarction, and intracranial hemorrhage. Input parameters were informed by systematic literature reviews and network meta-analysis. Expected value of perfect information (EVPI) and expected value of partial perfect information (EVPPI) were estimated to provide an upper bound on value of further research. Results. At willingness-to-pay threshold £20,000, all DOACs have positive expected incremental net benefit compared to warfarin, suggesting they are likely cost-effective. Apixaban has highest expected incremental net benefit (£7533), followed by dabigatran (£6365), rivaroxaban (£5279), and edoxaban (£5212). There was considerable uncertainty as to the optimal DOAC, with the probability apixaban has highest net benefit only 60%. Total estimated population EVPI was £17.94 million (17.85 million, 18.03 million), with relative effect between apixaban versus dabigatran making the largest contribution with EVPPI of £7.95 million (7.66 million, 8.24 million). Conclusions. At willingness-to-pay threshold £20,000, all DOACs have higher expected net benefit than warfarin but there is considerable uncertainty between the DOACs. Apixaban had the highest expected net benefit and greatest probability of having highest net benefit, but there is considerable uncertainty between DOACs. A head-to-head apixaban versus dabigatran trial may be of value.

Choice of implant combinations in total hip replacement: systematic review and network meta-analysis.

Objective To compare the survival of different implant combinations for primary total hip replacement (THR). Design Systematic review and network meta-analysis. Data sources Medline, Embase, The Cochrane Library, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and the EU Clinical Trials Register.Review methods Published randomised controlled trials comparing different implant combinations. Implant combinations were defined by bearing surface materials (metal-on-polyethylene, ceramic-on-polyethylene, ceramic-on-ceramic, or metal-on-metal), head size (large ≥36 mm or small <36 mm), and fixation technique (cemented, uncemented, hybrid, or reverse hybrid). Our reference implant combination was metal-on-polyethylene (not highly cross linked), small head, and cemented. The primary outcome was revision surgery at 0-2 years and 2-10 years after primary THR. The secondary outcome was the Harris hip score reported by clinicians.Results 77 studies were included in the systematic review, and 15 studies (3177 hips) in the network meta-analysis for revision. There was no evidence that the risk of revision surgery was reduced by other implant combinations compared with the reference implant combination. Although estimates are imprecise, metal-on-metal, small head, cemented implants (hazard ratio 4.4, 95% credible interval 1.6 to 16.6) and resurfacing (12.1, 2.1 to 120.3) increase the risk of revision at 0-2 years after primary THR compared with the reference implant combination. Similar results were observed for the 2-10 years period. 31 studies (2888 patients) were included in the analysis of Harris hip score. No implant combination had a better score than the reference implant combination.Conclusions Newer implant combinations were not found to be better than the reference implant combination (metal-on-polyethylene (not highly cross linked), small head, cemented) in terms of risk of revision surgery or Harris hip score. Metal-on-metal, small head, cemented implants and resurfacing increased the risk of revision surgery compared with the reference implant combination. The results were consistent with observational evidence and were replicated in sensitivity analysis but were limited by poor reporting across studies.Systematic review registration PROSPERO CRD42015019435.

Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis.

Objective To compare the efficacy, safety, and cost effectiveness of direct acting oral anticoagulants (DOACs) for patients with atrial fibrillation.Design Systematic review, network meta-analysis, and cost effectiveness analysis. Data sources Medline, PreMedline, Embase, and The Cochrane Library.Eligibility criteria for selecting studies Published randomised trials evaluating the use of a DOAC, vitamin K antagonist, or antiplatelet drug for prevention of stroke in patients with atrial fibrillation.Results 23 randomised trials involving 94 656 patients were analysed: 13 compared a DOAC with warfarin dosed to achieve a target INR of 2.0-3.0. Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94), dabigatran 150 mg twice daily (0.65, 0.52 to 0.81), edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of stroke or systemic embolism compared with warfarin. The risk of stroke or systemic embolism was higher with edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with warfarin. Apixaban 5 mg twice daily (0.71, 0.61 to 0.81), dabigatran 110 mg twice daily (0.80, 0.69 to 0.93), edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major bleeding compared with warfarin. The risk of major bleeding was higher with dabigatran 150 mg twice daily than apixaban 5 mg twice daily (1.33, 1.09 to 1.62), rivaroxaban 20 mg twice daily than apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and rivaroxaban 20 mg twice daily than edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial bleeding was substantially lower for most DOACs compared with warfarin, whereas the risk of gastrointestinal bleeding was higher with some DOACs than warfarin. Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with warfarin.Conclusions The network meta-analysis informs the choice of DOACs for prevention of stroke in patients with atrial fibrillation. Several DOACs are of net benefit compared with warfarin. A trial directly comparing DOACs would overcome the need for indirect comparisons to be made through network meta-analysis.Systematic review registration PROSPERO CRD 42013005324.