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BACKGROUND: Degenerative disc disease (DDD) is associated with chronic lower back pain that may have impacts on individual's quality of life and functional ability. Lumbar interbody fusion can be carried out with a variety of bone grafting products, the choice depends on several factors including the patient, site, procedure, cost and indication. This systematic review (SR) intends to validate and consolidate the existing evidence base supporting bone graft materials related to lumbar interbody fusion procedures for DDD, specifically anterior lumbar interbody fusion (ALIF) and oblique lumbar interbody fusion (OLIF).
METHODS: An SR was conducted in February 2023. Clinical and economic studies of adults with DDD in regions L2 to S1 undergoing lumbar interbody fusion with Infuse™, allograft, synthetic bone grafts, demineralized bone matrices or cell-based matrices were eligible for inclusion.
RESULTS: Twenty-one studies (reported in 25 publications) were included in the review. Eighteen studies (reported in 22 publications) reported clinical outcomes, while 4 studies reported economic outcomes. Nine studies (in 5 publications) investigated Infuse™, including 3 randomized controlled trials (RCTs), one cohort study and 4 case series. Ten studies investigated allograft bone, bone harvested from the vertebral spur combined with apacerum powder, or tricalcium phosphate soaked in autologous bone marrow aspirate, including one RCT, 2 cohort studies, and 7 case series.
CONCLUSIONS: The SR shows that Infuse™ offers comparable results to iliac crest bone graft with the benefit of not requiring harvested bone and offers significant benefits in surgical time and blood loss. There is a lack of comparative evidence for any other bone grafts identified in this SR, highlighting the need for further well-designed studies to be conducted in this area.
INTRODUCTION: Interventional single-arm trials (SATs) are increasingly being used as evidence, despite a lack of agreement on their validity and where they should sit in the hierarchy of evidence. We conducted a meta-epidemiological study to investigate whether there are systematic differences in outcomes and levels of between-study heterogeneity for SATs compared with their observational counterpart, single-arm cohort studies.
METHODS: We identified systematic reviews (SRs) of pharmacological interventions, published in 2023, that included both interventional and observational single-arm studies. For each SR, subgroup meta-analysis of dichotomous outcomes was conducted for included SATs and single-arm cohort studies to assess effect sizes, levels of heterogeneity and between group differences. In a sensitivity analysis, clinically heterogeneous primary studies were removed and analyses re-run.
RESULTS: 66 SRs contained single-arm studies, of which 13 reported meta-analyses of dichotomous efficacy outcomes. There was no overall risk difference for SATs compared with single-arm cohort studies (risk difference: -0.020, 95% CI: -0.092 to 0.052, p = 0.59). In the sensitivity analysis, there was a tendency to higher effect for single-arm cohort studies, but no significant difference (risk difference: -0.071, 95% CI: -0.161, 0.019, p = 0.12). There were high levels of between-study heterogeneity within both SATs (median; range I2: 54.8; 11.3-91.0) and single-arm cohorts (median; range I2: 77.2; 0-94.7) and heterogeneity remained high in the sensitivity analysis.
CONCLUSION: There do not appear to be systematic differences in outcome between SATs and single-arm cohort studies, but further research is recommended to confirm this finding. Levels of heterogeneity are high within both designs, even after attempts to reduce clinical heterogeneity. Because clinical heterogeneity had potentially been removed, remaining statistical heterogeneity may have been due to bias related to study conduct. Future work should utilize larger samples and additional methods to further clarify the relative validity of single-arm designs.
BACKGROUND: In 2021, there were an estimated 7.74 million people living with sickle cell disease (SCD) globally: a 41% increase from 2001 (Thomson et al. The Lancet Haematology, 2023). Regular automated red blood cell exchange (aRBCX) has been shown to improve control and management of SCD compared with manual red blood cell exchange (mRBCX) (Tsitsikas et al. Journal of Clinical Medicine, 2021). This study compared the expected clinical event frequency and economic impact of aRBCX with mRBCX in adults with SCD requiring regular disease-modifying transfusion treatments (DMTs). The study focussed on adults at high risk of clinical events and ineligible for, refractory to, or unwilling to take disease-modifying pharmacological treatments (e.g. hydroxyurea).
METHODS: A global individual patient-level simulation model was developed to estimate lifetime clinical events and costs of a heterogenous population of adults with SCD (aged over 18) requiring regular DMTs. A UK perspective was used in the base case. Adults received a DMT per cycle as per local recommendations. Monte Carlo methods were employed to determine the presence of iron overload at baseline and after mRBCX. Chelation therapy treats iron overload. Monte Carlo methods determined clinical event occurrence. Clinical events are not mutually exclusive in practice. Thus, an adult's clinical event history, in particular vaso-occlusive crises (VOCs), impacted subsequent clinical event and mortality rates. Clinical events impacted costs and health-related quality of life (HRQoL).
Findings from a pragmatic review informed efficacy, mortality, HRQoL and cost parameters. Where data were sparce, clinical experts were consulted to inform inputs and assumptions. Costs were sourced from national databases and literature and were inflated to 2022/23 if necessary. Costs and HRQoL were discounted in line with local guidelines. 250 lifetime simulations of 250 adults were run, with parameters varied probabilistically on their statistical distribution when appropriate.
RESULTS: The total number of lifetime acute clinical events reduced by 18% with aRBCX compared with mRBCX. VOC reduction comprised 96% of the total acute clinical event change. The total number of lifetime VOCs reduced from 66.04 (64.7 to 67.39) with mRBCX to 52.86 (51.25 to 54.47) with aRBCX.
aRBCX is more resource intensive and costly per administration than mRBCX. However, aRBCX required 49% fewer DMT administrations than mRBCX (43% fewer when considering DMTs and emergency transfusions). Adults receiving mRBCX spent on average 41.93 (41.09 to 42.76) months (14% of their adult life) on chelation therapy compared with 5.45 (5.43 to 5.48) months for those receiving aRBCX with iron overload at baseline.
Over a lifetime, aRBCX was expected to save £52,097 (£49,957 to £54,238) per person compared with mRBCX. Key drivers of this cost saving were the reduction in VOCs, DMTs and time on chelation therapy. aRBCX was cost saving compared with mRBCX in 99% of the probabilistic model runs.
DISCUSSION: aRBCX allows for increased success in achieving clinical targets, leading to improved control of SCD, fewer transfusions, fewer clinical events, and less time on chelation therapy. There is potential for large cost savings, allowing funds, hospital beds, and staff time to be redistributed.
The global model can be adapted to other healthcare settings where SCD prevalence and mortality are high. Research into the life-altering and cost-saving potential of aRBCX in these settings is essential to achieve the World Health Organisation's (WHO) goal of achieving universal health coverage by integrating SCD treatments into existing healthcare programmes in an equitable and cost-effective manner (WHO, Sickle strategic guidance framework, 2024).
BACKGROUND: Sickle cell disease (SCD) and all associated comorbidities were estimated to be the 12th most common cause of mortality in children younger than 5 years in 2021 (Thomson et al. The Lancet Haematology, 2023). Regular automated red blood cell exchange (aRBCX) improves management of SCD compared with manual red blood cell exchange (mRBCX) (Tsitsikas et al. Journal of Clinical Medicine, 2021). This study compared the expected clinical event frequency and economic impact of aRBCX with mRBCX in children with SCD requiring regular disease modifying transfusion treatments (DMTs). The study focussed on children at high risk of clinical events and ineligible for, refractory to, or unwilling to take disease modifying pharmacological treatments (e.g. hydroxyurea).
METHODS: A global individual patient-level simulation model was developed to estimate lifetime clinical events and costs of regular aRBCX compared with mRBCX in a heterogenous population of children aged 2 with no history of chronic events. The UK cost perspective was investigated. People received a DMT per cycle as per local recommendations. Monte Carlo methods determined the presence of iron overload. Chelation therapy treats iron overload. Monte Carlo methods determined clinical event occurrence. Clinical events are not mutually exclusive in practice. Thus, a person's clinical event history, in particular vaso-occlusive crises (VOCs), impacted subsequent clinical event and mortality rates. Clinical events impacted costs and health-related quality of life (HRQoL).
Findings from a pragmatic review informed efficacy, mortality, HRQoL and cost parameters. Where data were sparce, clinical experts were consulted to inform inputs and assumptions. Costs were sourced from national databases and literature and inflated to 2022/23 if necessary. Costs and HRQoL were discounted in line with local guidelines. A preliminary model run with 250 lifetime simulations of 250 children varied parameters probabilistically on their statistical distribution when appropriate.
RESULTS: Total acute clinical events were 19% lower with aRBCX compared with mRBCX. VOCs reduced by 20% from 117 (115 to 119) for mRBCX to 94 (91 to 96) for aRBCX. aRBCX also caused a reduction of 9% for ACS and 2% for strokes.
aRBCX is more resource intensive and costly per administration than mRBCX, but, aRBCX required 49% fewer DMT administrations than mRBCX (44% fewer when considering DMTs and emergency transfusions). People receiving mRBCX were anticipated to spend approximately 13% of their life on chelation therapy, totalling 6.4 (6.3 to 6.5) years. Only people with iron overload at baseline had chelation therapy with aRBCX, totalling 5.5 (5.4 to 5.5) months.
aRBCX was cost saving compared to mRBCX. Regular aRBCX was expected to save £109,964 (£107,275 to £112,653) per lifetime compared with mRBCX. This conclusion was consistent for 100% of the 250 probabilistic model runs and for scenarios where children received DMTs until adulthood and the lifetime of children at high risk of stroke.
DISCUSSION: aRBCX allows for increased success in achieving clinical targets leading to improved control of SCD, fewer transfusions, clinical events and time on chelation therapy. There is potential for large cost savings, allowing funds, hospital beds, and staff time to be redistributed.
The global model can be easily adapted to other healthcare settings where SCD prevalence and mortality are high. Research into the life-altering and cost-saving potential of aRBCX in these settings is essential to achieve the World Health Organisation's (WHO) goal of achieving universal health coverage by integrating SCD treatments into existing healthcare programmes in an equitable and cost-effective manner (WHO, Sickle strategic guidance framework, 2024).
OBJECTIVES: Increasing uptake and completion of Pulmonary Rehabilitation in people with COPD has the potential to deliver health benefit and reduce health inequalities. We have quantified the cost-effectiveness of enhancing PR access and completion by reviewing the cost-effectiveness literature for PR in COPD.
METHODS: A literature review identified studies that provided cost-effectiveness evidence for PR compared to no PR. The key metrics of interest were healthcare resource use and cost savings, and quality adjusted life year (QALY) gains. Healthcare resource use data were valued using the UK NHS National Tariff 2022/23. From the literature search we identified the QALY gain resulting from completion of PR. The value of the QALY gain resulting from PR completion was calculated using the standard willingness-to-pay threshold of £20,000 considered by the UK National Institute for Health and care Excellence (NICE).
RESULTS: We estimated a QALY gain resulting from completion of PR of 0.065 and value of the QALY gain was therefore calculated to be £1300 per person completing PR. We estimated the 12 month reduction in hospitalisation following completion of PR to be 8.2% giving a total cost reduction per patient of £245. We therefore calculated that up to £1545 could be spent per person with COPD to deliver PR cost-effectively.
CONCLUSION: Our analysis provides commissioners with the information they need to make informed decisions about planning and provision of PR. The data allows estimation of additional resources that could be deployed in addressing inequitable access to PR among disadvantaged and underserved populations whilst retaining cost effectiveness of the intervention.
OBJECTIVES: Health technology assessment (HTA) processes are applied throughout Europe to evaluate the comparative clinical and economic value of a novel intervention to inform resource allocation decision-making. Various economic evaluation frameworks are employed in European HTA submissions, including - predominantly - cost-effectiveness and cost-utility analyses and this research explores the clarity and standardisation (or lack thereof) of these evaluations in a European context.
METHODS: A pragmatic literature review was performed on all relevant European HTAs which covered the United Kingdom, Scandinavia, Western Europe, Central and Southern Europe. It is clear there is substantial amount of information generated by economic evaluations and systematic literature reviews, checklists such as CHEERs and PRISMA which are available to inform the standards and minimum amount of information for reporting, ensuring consistency and transparency. However, similar consideration is not given to the reporting of pharmacoeconomic guidelines, and between-country variation in the format, content and standard of reporting limits the comparability and transferability between guidelines.
RESULTS: Guidelines for agencies such as the TLV, SUKL and AIFA are also not universally available in additional languages. EU HTA Regulation, published in January 2022, aims to standardise clinical assessment of pharmaceutical interventions to enable a central assessment across the 27 EU markets. Joint Clinical Assessment is reportedly beginning implementation in January 2025, signalling increased cross-country collaboration in HTA. There is an opportunity for further standardisation in evidentiary requirement reporting.
CONCLUSIONS: By providing a standardised, validated template for reporting pharmacoeconomic guideline requirements would aid companies when planning clinical trials, ensuring the necessary patient outcomes are collected. Clearer reporting surrounding preferred methods, evidence sources (e.g. value sets, population norm data) may contribute to higher evidence standards. Consensus across EU HTA agencies may also inform standards for less established agencies, such as AIFA, aiding development of HTA procedures in their respective regions.
