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Cost-effectiveness of basal insulin from a US health system perspective: comparative analyses of detemir, glargine and NPH |
Valentine W J, Palmer A J, Erny-Albrecht K M, Ray J A, Cobden D, Foos V, Lurati F M, Roze S |
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Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology The study examined three insulin preparations for the treatment of patients with Type 1 diabetes. The preparations were long-acting insulin detemir (IDet), long-acting insulin glargine (IGlarg), and intermediate-acting Neutral Protamine Hagedorn (NPH). IDet is usually given twice daily in combination with mealtime insulin aspart. NPH is given twice daily supplemented by human soluble insulin. IGlarg is given once daily in combination with premeal insulin aspart.
Economic study type Cost-effectiveness analysis.
Study population The study population comprised patients with Type 1 diabetes.
Setting The setting was primary care. The economic study was carried out in the USA.
Dates to which data relate The effectiveness and resource use data were derived from studies published from 2002 to 2005. The price year was 2005.
Source of effectiveness data The effectiveness evidence was derived from published studies.
Modelling The published and validated Center for Outcome Research (CORE) Diabetes Model was used to project the long-term clinical and economic benefits associated with IDet treatment, either as a replacement for NPH or as an alternative to IGlarg. The time horizon of the model was 35 years. The CORE Diabetes Model is an interactive computer simulation model of diabetes comprising 15 interdependent sub-models that allow the investigation of diabetes complications. These include angina, myocardial infarction, congestive heart failure, stroke, peripheral vascular disease, diabetic retinopathy, macular oedema, cataract, hypoglycaemia, ketoacidosis, lactic acidosis, nephropathy, end-stage renal disease, neuropathy, foot ulcer, amputation and non-specific mortality. Each sub-model was a Markov model that used time-, state- and diabetes-type dependent transition probabilities. Patient cohorts were defined in terms of age, gender, baseline risk factors, and pre-existing complications.
Outcomes assessed in the review The outcomes estimated from the literature were:
the decrease in glycated haemoglobin (HbA1c);
the risk of hypoglycaemia;
the change in body weight, and
the utility weights.
All probabilities associated with the natural history of the disease and most utility values were derived from the published decision model. They were not reported in the current study.
Study designs and other criteria for inclusion in the review It was not stated whether a systematic review of the literature was undertaken to identify the primary studies, which might have been identified selectively. Treatment effectiveness was derived from two clinical trials. Each trial directly compared the treatment analysed. One trial compared IDet and NPH in a sample of 598 patients over an 18-week period, whilst the other compared IDet and IGlarg over a 26-week period. Demographics, risk factors, and complications of patients enrolled in each trial were provided. The characteristics of the other sources of data were not reported.
Sources searched to identify primary studies Criteria used to ensure the validity of primary studies The use of randomised, clinical trials based on direct comparisons should have ensured a high internal validity. The other data derived from the model had already been validated.
Methods used to judge relevance and validity, and for extracting data Number of primary studies included Five primary studies provided the data.
Methods of combining primary studies The primary data were not combined as each study provided a single series of estimates.
Investigation of differences between primary studies Results of the review In the first analysis (IDet versus NPH):
the decrease in HbA1c was 0.5% with IDet and 0.28% with NPH (statistically significant) after 18 weeks;
the risk of hypoglycaemia was 21% lower with IDet, (p<0.036);
the risk of major hypoglycaemia (defined as requiring third-party medical assistance) was non significantly reduced at an event rate of 58 per 100 patient-years with IDet versus 66 per 100 patient-years with NPH;
the rates of nocturnal hypoglycaemia and major nocturnal hypoglycaemia were significantly reduced in the IDet arm by 55% and 83%, respectively, (p<0.008 for both end points); and
the adjusted weight change was 1 kg lower in the IDet group than in the NPH group, (p<0.001).
In the second analysis (IDet versus IGlarg):
HbA1c decreased from 8.76% to 8.16% (-0.71% points) with IDet and from 8.70% to 8.19% (-0.62% points) with IGlarg (not statistically significant);
the risk of major hypoglycaemia was significantly reduced at an event rate of 6.5 per 100 patient-years with IDet versus 24.5 per 100 patient-years with IGlarg;
the rate of nocturnal hypoglycaemia was significantly reduced in the IDet arm by 32%, (p<0.05); and
the weight change was not statistically different between the groups, although there was a lower increase in body weight (0.52 kg) with IDet than there was with NPH (0.96 kg).
In terms of utilities values, major hypoglycaemic events were associated with an event disutility of -0.0121. All other hypoglycaemic events were associated with a value of -0.0052.
Measure of benefits used in the economic analysis The summary benefit measure used was the expected number of quality-adjusted life-years (QALYs). These were estimated using a modelling approach. The utility weights and survival data were derived from the literature. Life expectancy and incidence of diabetes-related complications were also estimated, although they were not combined with the costs. The benefits were discounted at an annual rate of 3%.
Direct costs The analysis of the costs was carried out from a societal perspective. It included the costs associated with treatment, complications and medications. The unit costs were not presented separately from the quantities of resources used. The costs were derived from Medicare reimbursement rates and average wholesale prices. Resource use was based on data derived from the published decision model. Discounting was relevant, as the long-term costs were estimated, and an annual discount rate of 3% was applied. The price year was 2005.
Statistical analysis of costs The costs were treated deterministically in the base-case.
Indirect Costs The indirect costs associated with lost productivity were included. This was appropriate given the societal perspective adopted for the analysis. Information on the unit costs and quantities of resources used was not presented. The calculation of costs considered data on average salaries, retirement age, and days of work missed because of complications. These data were derived from the US Department of Labor, Bureau of Labor Statistics. The price year was 2005 and an annual discount rate of 3% was used.
Sensitivity analysis Univariate sensitivity analyses were carried out to assess the impact of key model assumptions about change in HbA1c (improvements in HbA1c were identical or persisted for only 5 years), discount rate (range: 0 to 5%), duration of treatment effect, insulin costs (+/- 15%), and costs associated with the treatment of major hypoglycaemic events. Two alternative time horizons (5 and 10 years) were also considered. Alternative values were based on authors' opinions or were derived from the literature. A probabilistic approach was used to assess mean values (and standard deviations) of QALYs and costs in 1,000 patients passed through the model 1,000 times. These data were then used to generate cost-effectiveness acceptability curves.
Estimated benefits used in the economic analysis The results were presented for a cohort of 1,000 patients.
In the first analysis (IDet versus NPH), the discounted life expectancy was 14.869 (+/- 0.162) years with IDet and 14.701 (+/- 0.167) years with NPH (difference 0.168).
The discounted QALYs were 8.018 (+/- 0.087) with IDet and 7.32 (+/- 0.083) with NPH (difference 0.698).
Diabetes-related complications were reduced with IDet, especially retinopathy and nephropathy.
In the second analysis (IDet versus IGlarg), the discounted life expectancy was 14.231 (+/- 0.182) years with IDet and 14.144 (+/- 0.174) years with IGlarg (difference 0.087).
The discounted QALYs were 7.242 (+/- 0.094) with IDet and 7.179 (+/- 0.089) with IGlarg (difference 0.063).
Again, diabetes-related complications, especially retinopathy and nephropathy, were reduced with IDet.
Cost results The results were presented for a cohort of 1,000 patients.
In the first analysis (IDet versus NPH), the discounted direct costs were $118,746 (+/- 2,805) with IDet and $108,295 (+/- 2,942) with NPH (difference $10,451).
The discounted indirect costs were $141,809 (+/- 5,034) with IDet and $146,497 (+/- 5,214) with NPH (difference -$4,688).
The total discounted costs were $260,555 (+/- 7,839) with IDet and $254,792 (+/- 8,156) with NPH (difference $5,763).
In the second analysis (IDet versus IGlarg), the discounted direct costs were $108,208 (+/- 2,768) with IDet and $110,280 (+/- 2,691) with IGlarg (difference -$2,072).
The discounted indirect costs were $144,145 (+/- 5,456) with IDet and $147,248 (+/- 5,168) with IGlarg (difference -$3,103).
The total discounted costs were $252,354 (+/- 8,225) with IDet and $257,528 (+/- 7,859) with IGlarg (difference -$5,174).
Synthesis of costs and benefits Incremental cost-utility ratios were calculated in order to combine the costs and benefits of the alternative treatment strategies.
The incremental cost per QALY gained with IDet over NPH was $14,974. The cost-effectiveness acceptability curve showed that, with a threshold of $50,000 per QALY gained, there was a 100% probability of IDet being cost-effective. The deterministic sensitivity analysis showed that the base-case results were robust to variations in clinical and economic inputs.
In the comparison between IDet and IGlarg, IDet was dominant as it was both more effective and less costly. The cost-effectiveness acceptability curve suggested that, with a threshold of $50,000 per QALY gained, there was an 80% probability of IDet being cost-effective. The univariate sensitivity analysis showed that the results were most sensitive to changes in pharmacy acquisition costs. For example, with a 15% increase in the cost of IDet, the incremental cost per QALY gained was $1,126. Changes in other model inputs did not alter the conclusions of the analysis.
Authors' conclusions The use of insulin detemir (IDet) for the treatment of Type 1 diabetes was a cost-effective alternative to both Neutral Protamine Hagedorn (NPH) and insulin glargine (IGlarg) in the USA. Treatment with IDet resulted in increased life expectancy, improved quality of life, and reduced complication rates compared with NPH at a cost that was considered well within the limits of acceptability. In comparison with IGlarg, IDet was a dominant option, leading to lower costs and improved quality of life.
CRD COMMENTARY - Selection of comparators The authors provided a justification for the choice of the comparators, which were appropriately selected. The methods and frequency of administration of all treatments were described. You should decide whether they are valid comparators in your own setting.
Validity of estimate of measure of effectiveness The effectiveness data were derived from published studies, but the authors did not report the methods and conduct of a systematic review. Therefore, the clinical trials used to derive treatment effectiveness and the sources of utility values might have been identified selectively from the available literature. The use of a meta-analysis of clinical trials, as performed in a previous economic evaluation comparing IDet and NPH, might have been more appropriate. The authors stated that the clinical trial directly comparing IDet and IGlarg was the most recent source of comparative data. Clinical trials usually provide high-quality evidence, thus the primary estimates used in the analysis should be robust. The readers were referred to the published model for most of the details on the clinical data. The issue of uncertainty surrounding some clinical estimates was investigated in the sensitivity analysis.
Validity of estimate of measure of benefit The use of QALYs as the summary benefit measure was appropriate because they capture the impact of the interventions on two important dimensions of health (i.e. quality of life and survival). Diabetes affects overall patient quality of life and has the potential to be a life-threatening condition. QALYs have the further advantage of being comparable with the benefits of other health care interventions. The utility weights were derived from the literature. Other clinical end points that might be relevant for clinicians were also reported, although they were not combined with the costs. Discounting was performed, in accordance with US guidelines for cost-effectiveness analyses.
Validity of estimate of costs The analysis of the costs was consistent with the authors' stated perspective. The macro-categories of costs included were reported, but there was no detailed breakdown of the cost items. This reduces the possibility of replicating the analysis in other settings. Given the perspective of the analysis, the sources of data were reported and were appropriate. Statistical analyses of the costs were carried out in the sensitivity analysis, and the impact of variations in cost estimates was investigated in order to reflect, for example, contractual rebate adjustments. The price year was reported, which will facilitate reflation exercises in other time periods.
Other issues The authors compared their findings with those from a recent economic evaluation performed in the UK that had shown similar results. The issue of the generalisability of the study results to other settings was not explicitly addressed, although some sensitivity analyses were carried out on key economic and clinical inputs. This could enhance, in part, the external validity of the study. Most clinical and economic inputs associated with the natural history of diabetes were derived directly from the CORE Diabetes Model and were not reported in the paper. The authors acknowledged that the clinical trials were conducted predominantly within European health care settings, thus caution will be required when extrapolating the results of the analysis to the US setting.
Implications of the study The study results support the use of IDet for the treatment of patients with Type 1 diabetes.
Source of funding Supported by Novo Nordisk Inc., Princeton (NJ), USA.
Bibliographic details Valentine W J, Palmer A J, Erny-Albrecht K M, Ray J A, Cobden D, Foos V, Lurati F M, Roze S. Cost-effectiveness of basal insulin from a US health system perspective: comparative analyses of detemir, glargine and NPH. Advances in Therapy 2006; 23(2): 191-207 Other publications of related interest Because readers are likely to encounter and assess individual publications, NHS EED abstracts reflect the original publication as it is written, as a stand-alone paper. Where NHS EED abstractors are able to identify positively that a publication is significantly linked to or informed by other publications, these will be referenced in the text of the abstract and their bibliographic details recorded here for information
Palmer AJ, Roze S, Valentine WJ, et al. Cost-effectiveness of detemir-based basal/bolus therapy versus NPH-based basal/bolus therapy for type 1 diabetes in a UK setting: an economic analysis based on a meta-analysis results of four clinical trials. Curr Med Res Opin 2004;20:1729-46.
Palmer AJ, Roze S, Valentine WJ, et al. The CORE Diabetes Model: projecting long-term clinical outcomes and cost-effectiveness of interventions in diabetes mellitus (types 1 and 2) to support clinical and reimbursement decision-making. Curr Med Res Opin 2004;20(8 Suppl):5-26.
Heise T, Nosek L, Ronn B, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes 2004;53:1614-20.
Indexing Status Subject indexing assigned by NLM MeSH Adult; Cohort Studies; Cost-Benefit Analysis; Diabetes Mellitus, Type 1 /drug therapy; Drug Costs; Female; Health Care Costs; Humans; Insulin /administration & Insulin Detemir; Insulin Glargine; Insulin, Isophane /administration & Insulin, Long-Acting; Male; Models, Theoretical; Outcome Assessment (Health Care); Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; United States; derivatives /economics; dosage /adverse effects /agonists /analogs & dosage /economics AccessionNumber 22006001306 Date bibliographic record published 28/02/2007 Date abstract record published 28/02/2007 |
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