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Results of an economic model to assess the cost-effectiveness of enoxaparin, a low-molecular-weight heparin, versus warfarin for the prophylaxis of deep vein thrombosis and associated long-term complications in total hip replacement surgery in the United States |
Botteman M F, Caprini J, Stephens J M, Nadipelli V, Bell C F, Pashos C L, Cohen A T |
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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 A low molecular weight heparin (i.e. enoxaparin, 30 mg twice daily for 7 days) and warfarin (7 days, 5 mg/day) were used for the prophylaxis of deep vein thrombosis (DVT) in patients undergoing total hip replacement surgery (THRS).
Economic study type Cost-effectiveness analysis and cost-utility analysis.
Study population The study population comprised a hypothetical cohort of elderly patients undergoing THRS.
Setting The setting was a hospital and secondary care. The economic study was carried out in the USA.
Dates to which data relate The effectiveness data were derived from studies published between 1983 and 2001. The resource use data and costs were derived from studies published from 1995 to 2000. The price year was 2000.
Source of effectiveness data The effectiveness evidence was derived predominantly from a synthesis of completed studies.
Modelling A decision analytic model was used to determine the clinical and economic outcomes associated with warfarin versus enoxaparin for the prophylaxis of DVT in a hypothetical cohort of patients aged 72 years (65% female). To consider both the short- and long-term impact of treatment on the natural history of DVT in the study cohort, the model was split into two parts. The acute-phase model was based on a decision tree, while the post-acute phase was based on a Markov process. After THRS, patients could develop DVT and subsequently die or survive (in the latter case, they entered the post-acute phase as DVT survivors). Those who did not develop DVT entered the post-acute phase via the no-DVT state and could experience moderate or severe PTS and die, otherwise they remained well and were at risk of idiopathic PTS. Each patient was followed until 100 years of age or until death. The patients were treated according to their diagnosis, which could be correct or incorrect. DVT treatment entailed a little risk of mortality. The model distinguished between the first and subsequent years post-PTS to allow for differences in diagnostic and treatment patterns.
Outcomes assessed in the review The outcomes derived from the literature were all probability values that were considered in the decision model. These included:
the rate of DVT and other disease,
the efficacy of the treatments,
diagnostic yield of the procedures used,
the rates of survival,
the morbidity and mortality associated with treatment, and
utility values.
Study designs and other criteria for inclusion in the review The authors stated that a comprehensive review of the literature was carried out only to identify the rates of DVT in the two main treatment arms. Only randomised clinical trials were considered. Details of the other primary studies were not provided. Survival curves were derived from US life expectancy tables.
Sources searched to identify primary studies Criteria used to ensure the validity of primary studies Methods used to judge relevance and validity, and for extracting data Number of primary studies included Twenty-four primary studies provided the evidence.
Methods of combining primary studies The rates of DVT derived from clinical trials were combined by estimating the average value after all patients had been pooled, as they formed part of a single study.
Investigation of differences between primary studies Results of the review Some data used in the model were only reported in the depiction of the decision tree. Other data were clearer:
the rate of DVT was 13.6% (95% confidence interval, CI: 10.8 - 16.4) in enoxaparin patients and 21.3% (95% CI: 18.9 - 23.8) in warfarin patients;
31.5% of patients with severe PTS would have an open ulcer and 68.5% would have a healed ulcer;
20.8% of recurrent VTEs were PEs;
in patients who did not develop a DVT after surgery, the rate of idiopathic DVT was 160 per 100,000 and the rate of PE was 70 per 100,000.
In terms of utility values, age- and gender-specific estimates were:
for women, 0.71 (+/- 0.10) in the 65 - 74 age group, 0.67 (+/- 0.11) in the 75 - 84 age group, and 0.67 (+/- 0.10) in the 85 years and older age group; and
for men, 0.73 (+/- 0.11) in the 65 - 74 age group, 0.68 (+/- 0.10) in the 75 - 84 age group, and 0.61 (+/- 0.07) in the 85 years and older age group.
Other utility values were 0.98 (+/- 0.04) for mild-to-moderate PTS and 0.93 (+/- 0.07) for severe PTS.
The decrements in utility, expressed as days lost equivalent to the duration of hospitalisation, were:
6.2 days (range: 4.7 - 7.8) for DVT in the acute phase,
7.7 days (range: 5.8 - 9.6) for PE in the acute phase,
5.9 days (range: 2.7 - 8.9) for DVT in the post-acute phase, and
7.1 days (range: 3.6 - 10.7) for PE in the post-acute phase.
Measure of benefits used in the economic analysis The summary benefit measure used was the number of quality-adjusted life-years (QALYs). The QALYs were obtained from the decision model. An annual discount rate of 3% was applied. Both utility weights and survival data were derived from the literature. Other disease-related model outputs were also reported.
Direct costs An annual discount rate of 3% was used because of the long time horizon of the model. The unit costs were presented separately from the quantities of resources used for almost all items. The health services included in the economic evaluation were physician or nurse office visits, diagnostic tests, medical supplies, medication, hospitalisations, and surgical procedures. The cost/resource boundary of the health care payer was adopted. The costs were derived from typical Medicare reimbursement rates. The resource use data were derived from authors' opinions and published evidence. The price year was 2000.
Statistical analysis of costs The costs were treated deterministically.
Indirect Costs The indirect costs were not considered in the economic evaluation.
Sensitivity analysis Univariate sensitivity analyses were carried out on all model inputs. The analyses were conducted to examine the robustness of the estimated cost-utility ratios to variations in all model inputs, and to identify those parameters that had the greatest impact on the results of the analysis. Monte Carlo simulations were also performed using 5,000 trials. In addition, two acceptability curves were constructed to determine the short- and long-term impact of the alternative strategies. Finally, two alternative scenarios were considered. In the first, the assumption that all DVTs could lead to PTS or recurrent VTE was investigated. In the second, the survival of patients who experienced an acute DVT episode was set equal to the survival of patients who did not experience a DVT.
Estimated benefits used in the economic analysis In the short-term analysis (acute-phase model), enoxaparin led to a reduction in both the number of DVT cases (77 per 1,000 surgical procedures), which were 213 with warfarin and 136 with enoxaparin, and the number of DVT-related deaths (from 11 to 7 per 1,000 procedures). The estimated QALYs were 8.82 with enoxaparin and 8.78 with warfarin (gain of 0.04 QALYs).
In the whole model (including long-term costs and consequences), enoxaparin reduced the incidence of PTS by 21 cases per 1,000 initial patients for surgery in comparison with warfarin.
A similar reduction was observed for idiopathic VTE cases (89 with warfarin and 69 with enoxaparin). The estimated QALYs were 7.43 with enoxaparin and 7.27 with warfarin (gain of 0.16 QALYs).
Cost results In the short-term analysis, enoxaparin led to a cost-saving of $133 per patient. In the long-term analysis, enoxaparin led to a cost-saving of $89 per patient.
Synthesis of costs and benefits Incremental cost-effectiveness and cost-utility ratios were calculated to combine the costs and benefits of the prophylactic strategies.
In the short-term analysis, the incremental cost per DVT avoided with enoxaparin over warfarin was $1,728 and the incremental cost per death avoided was $34,477. The cost per QALY gained was $3,733.
In the long-term model, enoxaparin dominated warfarin, which was less effective and more expensive.
The results of the univariate sensitivity analysis showed the base-case results to be fairly robust.
The model inputs that had the greatest impact on the results were the incidence rate of DVT after prophylaxis, the long-term mortality rates, the cost of enoxaparin and warfarin, and the incidence of PTS and idiopathic VTE.
Similar results were observed in the Monte Carlo simulations.
The acceptability curves showed that in 95% of cases, the cost per QALY with enoxaparin relative to warfarin was equal or below $11,100 in the short-term model and $1,250 in the long-term model.
The scenario analysis showed that even with unfavourable assumptions, enoxaparin had an acceptable cost-utility ratio.
Authors' conclusions Compared with warfarin, enoxaparin used as primary prophylaxis in patients undergoing total hip replacement surgery (THRS) was cost-effective in the short-tem and cost-saving in the long-term. This conclusion was robust and held under several scenarios. If enoxaparin replaced warfarin for the 160,000 THRS procedures performed annually in the USA, approximately $14 million would be saved and more than 25,000 quality-adjusted life-years (QALYs) would be gained.
CRD COMMENTARY - Selection of comparators The authors stated that enoxaparin and warfarin were two commonly prescribed agents used for the universal prophylaxis of DVT. You should decide whether they are valid comparators in your own setting.
Validity of estimate of measure of effectiveness The effectiveness evidence came from data derived from published studies. It was unclear whether a systematic review of the literature had been undertaken for all model inputs. Some data were derived from a group of clinical trials, which ensured the validity of the estimates. Since no information on the design of other estimates was provided, it is not possible to examine the validity of the sources used. The issue of uncertainty in the estimators was addressed in the sensitivity analysis. Moreover, the authors justified the choice of the values of some estimators used in the model.
Validity of estimate of measure of benefit The summary benefit measure was appropriate to capture the impact of the interventions on quality of life and survival. Discounting was carried out, as recommended in US guidelines. The source of the utility values was reported. QALYs are easily compared with the benefits of other health care interventions.
Validity of estimate of costs The authors stated explicitly the perspective adopted in the study. It appears that all the relevant categories of costs have been included in the analysis. The resource use data and the unit costs were presented separately, which enhances the possibility of replicating the study. The source of the data was provided for all items. The costs were derived from reimbursement charges, which were used as proxies for true costs. The price year was given, which aids reflation exercises in other settings. No statistical analyses of the costs were performed, but the costs were varied in the sensitivity analysis. Discounting was applied, owing to the long timeframe of the model. The total costs were estimated using modelling. The authors stated that the indirect costs were not included, not only because they were not relevant to the perspective adopted in the study but also because of the typical retirement age of the patients considered in the model. However, the inclusion of the costs of formal and informal caregivers would have further favoured the cost-effectiveness of enoxaparin.
Other issues The authors did not compare their findings with those from other economic evaluations of enoxaparin and warfarin. In fact, the authors discussed the choice of model inputs on the basis of published studies. The issue of the generalisability of the study results was not explicitly addressed, but extensive sensitivity analyses were carried out. These had a positive impact on the external validity of the analysis. The study referred to elderly patients undergoing THRS and this was reflected in the authors' conclusions.
Implications of the study The study results supported the use of enoxaparin for the prophylaxis of patients undergoing THRS in the USA.
Source of funding Supported in part by Aventis Pharmaceuticals (NJ), USA.
Bibliographic details Botteman M F, Caprini J, Stephens J M, Nadipelli V, Bell C F, Pashos C L, Cohen A T. Results of an economic model to assess the cost-effectiveness of enoxaparin, a low-molecular-weight heparin, versus warfarin for the prophylaxis of deep vein thrombosis and associated long-term complications in total hip replacement surgery in the United States. Clinical Therapeutics 2002; 24(11): 1960-1986 Other publications of related interest Handoll HH, Farrar MJ, McBirnie J, Tytherleigh-Strong G, Milne AA, Gillespie WJ. Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures. The Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD000305. DOI: 10.1002/14651858.CD000305.
Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet 2001;358:9-15.
Indexing Status Subject indexing assigned by NLM MeSH Aged; Aged, 80 and over; Anticoagulants /economics /therapeutic use; Arthroplasty, Replacement, Hip; Cost-Benefit Analysis; Drug Costs; Enoxaparin /economics /therapeutic use; Female; Humans; Male; Models, Economic; Monte Carlo Method; Postoperative Complications /economics /prevention & Quality of Life; Secondary Prevention; United States; Venous Thrombosis /economics /prevention & Warfarin /economics /therapeutic use; control; control AccessionNumber 22003007666 Date bibliographic record published 30/04/2005 Date abstract record published 30/04/2005 |
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