The INTRABEAM® Photon Radiotherapy System for the adjuvant treatment of early breast cancer: a systematic review and economic evaluation.

BACKGROUND: Initial treatment for early breast cancer is usually either breast-conserving surgery (BCS) or mastectomy. After BCS, whole-breast external beam radiotherapy (WB-EBRT) is the standard of care. A potential alternative to post-operative WB-EBRT is intraoperative radiation therapy delivered by the INTRABEAM(®) Photon Radiotherapy System (Carl Zeiss, Oberkochen, Germany) to the tissue adjacent to the resection cavity at the time of surgery. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of INTRABEAM for the adjuvant treatment of early breast cancer during surgical removal of the tumour. DATA SOURCES: Electronic bibliographic databases, including MEDLINE, EMBASE and The Cochrane Library, were searched from inception to March 2014 for English-language articles. Bibliographies of articles, systematic reviews, clinical guidelines and the manufacturer's submission were also searched. The advisory group was contacted to identify additional evidence. METHODS: Systematic reviews of clinical effectiveness, health-related quality of life and cost-effectiveness were conducted. Two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to full texts of retrieved papers by one reviewer and checked by a second reviewer. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer, and differences in opinion were resolved through discussion at each stage. Clinical effectiveness studies were included if they were carried out in patients with early operable breast cancer. The intervention was the INTRABEAM system, which was compared with WB-EBRT, and study designs were randomised controlled trials (RCTs). Controlled clinical trials could be considered if data from available RCTs were incomplete (e.g. absence of data on outcomes of interest). A cost-utility decision-analytic model was developed to estimate the costs, benefits and cost-effectiveness of INTRABEAM compared with WB-EBRT for early operable breast cancer. RESULTS: One non-inferiority RCT, TARGeted Intraoperative radioTherapy Alone (TARGIT-A), met the inclusion criteria for the review. The review found that local recurrence was slightly higher following INTRABEAM than WB-EBRT, but the difference did not exceed the 2.5% non-inferiority margin providing INTRABEAM was given at the same time as BCS. Overall survival was similar with both treatments. Statistically significant differences in complications were found for the occurrence of wound seroma requiring more than three aspirations (more frequent in the INTRABEAM group) and for a Radiation Therapy Oncology Group toxicity score of grade 3 or 4 (less frequent in the INTRABEAM group). Cost-effectiveness base-case analysis indicates that INTRABEAM is less expensive but also less effective than WB-EBRT because it is associated with lower total costs but fewer total quality-adjusted life-years gained. However, sensitivity analyses identified four model parameters that can cause a switch in the treatment option that is considered cost-effective. LIMITATIONS: The base-case result from the model is subject to uncertainty because the disease progression parameters are largely drawn from the single available RCT. The RCT median follow-up of 2 years 5 months may be inadequate, particularly as the number of participants with local recurrence is low. The model is particularly sensitive to this parameter. CONCLUSIONS AND IMPLICATIONS: A significant investment in INTRABEAM equipment and staff training (clinical and non-clinical) would be required to make this technology available across the NHS. Longer-term follow-up data from the TARGIT-A trial and analysis of registry data are required as results are currently based on a small number of events and economic modelling results are uncertain. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013006720. FUNDING: The National Institute for Health Research Health Technology Assessment programme. Note that the economic model associated with this document is protected by intellectual property rights, which are owned by the University of Southampton. Anyone wishing to modify, adapt, translate, reverse engineer, decompile, dismantle or create derivative work based on the economic model must first seek the agreement of the property owners.

Implantable cardioverter defibrillators for the treatment of arrhythmias and cardiac resynchronisation therapy for the treatment of heart failure: systematic review and economic evaluation.

BACKGROUND: This assessment updates and expands on two previous technology assessments that evaluated implantable cardioverter defibrillators (ICDs) for arrhythmias and cardiac resynchronisation therapy (CRT) for heart failure (HF). OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of ICDs in addition to optimal pharmacological therapy (OPT) for people at increased risk of sudden cardiac death (SCD) as a result of ventricular arrhythmias despite receiving OPT; to assess CRT with or without a defibrillator (CRT-D or CRT-P) in addition to OPT for people with HF as a result of left ventricular systolic dysfunction (LVSD) and cardiac dyssynchrony despite receiving OPT; and to assess CRT-D in addition to OPT for people with both conditions. DATA SOURCES: Electronic resources including MEDLINE, EMBASE and The Cochrane Library were searched from inception to November 2012. Additional studies were sought from reference lists, clinical experts and manufacturers' submissions to the National Institute for Health and Care Excellence. REVIEW METHODS: Inclusion criteria were applied by two reviewers independently. Data extraction and quality assessment were undertaken by one reviewer and checked by a second. Data were synthesised through narrative review and meta-analyses. For the three populations above, randomised controlled trials (RCTs) comparing (1) ICD with standard therapy, (2) CRT-P or CRT-D with each other or with OPT and (3) CRT-D with OPT, CRT-P or ICD were eligible. Outcomes included mortality, adverse events and quality of life. A previously developed Markov model was adapted to estimate the cost-effectiveness of OPT, ICDs, CRT-P and CRT-D in the three populations by simulating disease progression calculated at 4-weekly cycles over a lifetime horizon. RESULTS: A total of 4556 references were identified, of which 26 RCTs were included in the review: 13 compared ICD with medical therapy, four compared CRT-P/CRT-D with OPT and nine compared CRT-D with ICD. ICDs reduced all-cause mortality in people at increased risk of SCD, defined in trials as those with previous ventricular arrhythmias/cardiac arrest, myocardial infarction (MI) > 3 weeks previously, non-ischaemic cardiomyopathy (depending on data included) or ischaemic/non-ischaemic HF and left ventricular ejection fraction ≤ 35%. There was no benefit in people scheduled for coronary artery bypass graft. A reduction in SCD but not all-cause mortality was found in people with recent MI. Incremental cost-effectiveness ratios (ICERs) ranged from £14,231 per quality-adjusted life-year (QALY) to £29,756 per QALY for the scenarios modelled. CRT-P and CRT-D reduced mortality and HF hospitalisations, and improved other outcomes, in people with HF as a result of LVSD and cardiac dyssynchrony when compared with OPT. The rate of SCD was lower with CRT-D than with CRT-P but other outcomes were similar. CRT-P and CRT-D compared with OPT produced ICERs of £27,584 per QALY and £27,899 per QALY respectively. The ICER for CRT-D compared with CRT-P was £28,420 per QALY. In people with both conditions, CRT-D reduced the risk of all-cause mortality and HF hospitalisation, and improved other outcomes, compared with ICDs. Complications were more common with CRT-D. Initial management with OPT alone was most cost-effective (ICER £2824 per QALY compared with ICD) when health-related quality of life was kept constant over time. Costs and QALYs for CRT-D and CRT-P were similar. The ICER for CRT-D compared with ICD was £27,195 per QALY and that for CRT-D compared with OPT was £35,193 per QALY. LIMITATIONS: Limitations of the model include the structural assumptions made about disease progression and treatment provision, the extrapolation of trial survival estimates over time and the assumptions made around parameter values when evidence was not available for specific patient groups. CONCLUSIONS: In people at risk of SCD as a result of ventricular arrhythmias and in those with HF as a result of LVSD and cardiac dyssynchrony, the interventions modelled produced ICERs of < £30,000 per QALY gained. In people with both conditions, the ICER for CRT-D compared with ICD, but not CRT-D compared with OPT, was < £30,000 per QALY, and the costs and QALYs for CRT-D and CRT-P were similar. A RCT comparing CRT-D and CRT-P in people with HF as a result of LVSD and cardiac dyssynchrony is required, for both those with and those without an ICD indication. A RCT is also needed into the benefits of ICD in non-ischaemic cardiomyopathy in the absence of dyssynchrony. STUDY REGISTRATION: This study is registered as PROSPERO number CRD42012002062. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Comparative cost-effectiveness models for the treatment of multiple myeloma.

OBJECTIVES: To compare cost effectiveness models for the first-line treatment of multiple myeloma, and explore the differences between the models' structure, parameters, assumptions and results. METHODS: Three cost effectiveness models for the treatment of multiple myeloma, were compared that had been developed to inform resource allocation in the UK for the chemotherapy regimens bortezomib, melphalan and prednisolone (BMP); and melphalan, prednisolone and thalidomide (MPT) versus melphalan and prednisolone (MP). The models used alternative approaches and assumptions to estimate the overall survival and progression-free survival for each of the interventions. Through the use of sensitivity analyses, the most influential parameters and assumptions of each of the models were identified. RESULTS: The models developed by the manufacturers gave conflicting results, with each manufacturer favouring their drug. The differences between the model results were determined by two parameters: the hazard ratio for overall survival for MPT vs. MP and the cost of bortezomib. CONCLUSIONS: Using models developed for assessing treatments for multiple myeloma we demonstrated that it was feasible to compare models, which then aided decision makers in making reimbursement decisions.

Psychosocial aspects of DNA testing for hereditary hemochromatosis in at-risk individuals: a systematic review.

AIM: To review the psychosocial benefits and harms of DNA testing for HFE-related hereditary hemochromatosis (HH) in at-risk individuals. BACKGROUND: HH is a common genetic disease in people of European descent. DNA-based predisposition testing is used for diagnosis or in the context of family testing, but there are concerns about potential psychosocial consequences. METHODS: Fifteen electronic databases (including Medline and Cochrane) were searched from inception to April 2007 to identify any quantitative or qualitative primary research that considered DNA testing of individuals considered at-risk of HH and reported psychosocial outcomes. Inclusion criteria, data extraction, and quality assessment were undertaken by standard methodology. RESULTS: Three observational studies met the inclusion criteria of the review; each had methodological limitations. On receipt of test results, anxiety levels fell or were unchanged; general health-related quality-of-life outcomes improved in some aspects, or were unchanged with respect to pretest result values. Outcomes were not reported separately for those referred for diagnosis and those with family history of HH. Results suggest that genetic testing for HH in at-risk individuals is accompanied by few negative psychosocial outcomes. CONCLUSION: The evidence on the psychosocial aspects of DNA testing for HH in at-risk individuals is limited. Further research might be required if other factors influencing the natural history of the disease phenotype are identified.

Cost-effectiveness of left ventricular-assist devices in end-stage heart failure.

With a limited supply of donor hearts, individuals with end-stage heart failure have been offered hope through the use of mechanical devices. Left ventricular-assist devices (LVADs) are a technology designed to work in parallel with the heart but have yet to see widespread use since uncertainty remains as to the cost-effectiveness of this evolving new technology. We have systematically reviewed evidence of cost-effectiveness for LVADs in the bridge-to-transplant and long-term chronic support indications. A total of 18 studies reporting costs were identified. Of these, only four studies reported results in cost-effectiveness terms; two in cost per life-year saved and two in cost per quality-adjusted life-year (QALY). The majority of the other studies were simple cost summations (cost per day or incremental cost) without consideration of efficacy. In the bridge-to-transplant indication, a Danish abstract reported a cost per life-year saved of DKK270k (US$48,000), a UK study reported a cost per QALY of GB pound39,787 (US$78,000) and a Canadian study reported a cost per life-year saved of Can$91,332 (US$86,000). Regarding the long-term chronic support indication, the same Canadian study reported a cost per life-year saved of Can$59,842 (US$56,000), whereas a US study reported a cost per QALY of $36,255-60,057. Assuming a willingness to pay the threshold of GB pound30,000 (US$59,000) per QALY, there is arguably stronger evidence to support the cost-effectiveness of LVAD technology for the long-term chronic support indication. However, the methodological quality of the majority of studies was poor, as was their generalizability, raising concerns over the reliability of these figures. With the limited and declining availability of donor hearts for transplantation, it appears that the future of this technology is in its use as long-term chronic support. Further analyses should be undertaken, particularly alongside randomized, controlled trials and utilizing second- and third-generation devices.

Clinical and cost-effectiveness of left ventricular assist devices as destination therapy for people with end-stage heart failure: a systematic review and economic evaluation.

OBJECTIVES: The clinical and cost-effectiveness of left ventricular assist devices as destination therapy for people with end-stage heart failure is assessed through a systematic review and economic evaluation. METHODS: Systematic review was performed of randomized controlled trials, quasiexperimental studies, case series, and case studies identified through searching eighteen electronic databases, bibliographies, and consultation with experts and manufacturers. Studies assessed survival, functional capacity, and quality of life. Cost-effectiveness was assessed through a 5-year decision analytic model to estimate the incremental cost-effectiveness ratio for using left ventricular assist devices compared with usual care. RESULTS: Six studies met the inclusion criteria, showing that left ventricular assist devices appear beneficial, improving survival and quality of life. Adverse events are a serious concern. The economic evaluation showed that left ventricular assist devices had a cost per quality adjusted life year of 170,616 pounds. Sensitivity analysis showed that the cost-effectiveness was not sensitive to changes in costs or utility. CONCLUSIONS: Although left ventricular assist devices appear clinically effective as destination therapy, it is unlikely they will be cost-effective unless costs decrease or the benefits of their use increase.

Clinical effectiveness and cost-effectiveness of implantable cardioverter defibrillators for arrhythmias: a systematic review and economic evaluation.

OBJECTIVES: The clinical effectiveness and cost-effectiveness of implantable cardioverter defibrillators (ICD) for arrhythmias was assessed. METHODS: A systematic review of the literature of systematic reviews and randomized controlled trials that reported mortality outcomes associated with implantable cardioverter defibrillators compared with antiarrhythmic drug therapy in people at risk of sudden cardiac death due to arrhythmias was undertaken. Economic evaluations were also sought. Inclusion criteria, data extraction, and quality assessment were undertaken by standard methodology. A decision analytic model was constructed using best available evidence to determine cost-effectiveness in a UK setting. RESULTS: Eight randomized controlled trials, two systematic reviews, and a meta-analysis met the inclusion criteria and were of variable quality. Evidence suggests that ICDs reduce mortality in both secondary and primary prevention, although the magnitude of benefit depends on baseline risk for sudden cardiac death. Incremental cost per quality-adjusted life year ranged from 52,000 UK pounds ($98,000) to over 200,000 UK pounds ($379,000), depending on mortality risk and assumptions made. CONCLUSIONS: Evidence suggests that ICDs reduce total mortality but may be cost-effective only in some subgroups of patients at high risk of ventricular arrhythmias. Further research is needed on risk stratification of patients in whom ICDs are most likely to be clinically and cost-effective.

Clinical and cost-effectiveness of left ventricular assist devices as a bridge to heart transplantation for people with end-stage heart failure: a systematic review and economic evaluation.

AIMS: To evaluate the clinical and cost-effectiveness of left ventricular (LV) assist devices (LVADs) as a bridge to transplant (BTT) for people with end-stage heart failure (ESHF) through a systematic review and economic evaluation. METHODS AND RESULTS: The systematic review and economic evaluation was conducted according to internationally recognized methods. The search strategy identified systematic reviews, randomized controlled trials, quasi-experimental studies, and observational studies evaluating the effects of LVADs on survival, functional capacity, and quality of life. Cost-effectiveness was assessed through a 5-year decision analytic model to estimate the incremental cost-effectiveness ratio of LVADs compared with usual care. Despite the poor methodological quality of the 18 studies included, LVADs appear beneficial improving survival, functional status, and quality of life. Adverse events are a serious concern. The economic evaluation showed that LVADs had a cost per quality adjusted life year of pound 65,242 (95% confidence interval pound 34,194-364,564). Sensitivity analysis showed that post-heart transplant survival gains, pre-heart transplant patient utility, and one-off costs associated with implantation determine cost-effectiveness. CONCLUSION: Although LVADs appear clinically effective as a BTT for people with ESHF, it is unlikely that they will be cost-effective unless costs decrease or the benefits of their use increase.

Clinical and cost-effectiveness of donepezil, rivastigmine, and galantamine for Alzheimer's disease. A systematic review.

OBJECTIVES: Systematic review of the clinical and cost-effectiveness of donepezil, rivastigmine, and galantamine for people suffering from Alzheimer's disease. METHODS: Sixteen electronic databases (including MEDLINE, the Cochrane Library, and Embase) and bibliographies of related papers were searched for published/unpublished English language studies, and experts and pharmaceutical companies were consulted for additional information. Randomized controlled trials (RCTs) and economic studies were selected. Clinical effectiveness was assessed on measurement scales assessing progression of Alzheimer's disease on the person's global health, cognition, functional ability, behavior and mood, and quality of life. Cost-effectiveness was presented as incremental cost per year spent in a nonsevere state (by Mini Mental Health State Examination) or quality-adjusted life-year. RESULTS: Twelve of 15 RCTs included were judged to be of good quality. Although donepezil had beneficial effects in Alzheimer's patients on global health and cognition, rivastigmine on global health, and galantamine on global health, cognition, and functional scales, these improvements were small and may not be clinically significant. Measures of quality of life and behavior and mood were rarely assessed. Adverse effects were usually mild and transient. Cost-effectiveness base case estimates ranged from 2,415 Pounds savings to 49,476 Pounds additional cost (1997 prices) per unit of effect for donepezil and a small savings for rivastigmine. Estimates were not considered robust or generalizable. CONCLUSIONS: Donepezil, rivastigmine, and galantamine appear to have some clinical effect for people with Alzheimer's disease, although the extent to which these translate into real differences in everyday life remains unclear. Due to the nature of current economic studies, cost-effectiveness remains uncertain and the impact on different care sectors has been inadequately investigated. Further research is needed to establish the actual benefits of acetylcholinesterase inhibitors (AChEls) for people with Alzheimer's disease and their caregivers, the relationship of these changes to clinical management, and careful prospective evaluation of resource and budgetary consequences.