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Economic evaluation of enoxaparin sodium versus heparin in unstable angina: a French sub-study of the ESSENCE trial |
Detournay B, Huet X, Fognani F, Montalescot G |
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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 Subcutaneous low-molecular weight heparin (enoxaparin) administered in a dose of 1mg of enoxaparin per kg of body weight twice daily for between 48 hours and 8 days (together with oral aspirin) as antithrombotic therapy for patients with acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction).
Economic study type Cost-effectiveness analysis.
Study population Men and non-pregnant women, aged at least 18 years, with underlying ischemic heart disease and with recent onset of angina at rest lasting at least 10 minutes and occurring within 24 hours of study inclusion. Patients were also required to have at least one of the following signs of myocardial ischaemia to be eligible for inclusion in the trial: new and transient ST segment shifts at least 0.1mV, T wave changes in at least 2 contiguous leads, past history of myocardial infarction (MI) or a documented history of a revascularisation procedure, noninvasive or invasive testing suggesting ischaemic heart disease. Exclusion criteria included the presence of a left bundle-branch block or pacemaker, persistent ST segment elevation, angina with an established precipitating cause (e.g., heart failure or tachydys-rhythmia), contraindications to anticoagulation, or a creatinine clearance rate of less than 30ml per minute.
Setting Hospital. The economic analysis was performed in France.
Dates to which data relate Effectiveness and resource use data were derived from patients enrolled for the ESSENCE clinical trial between October 1994 and May 1996. The price year was 1996.
Source of effectiveness data Effectiveness data were derived from a single study.
Link between effectiveness and cost data Costing was prospectively performed on both the whole study sample of the ESSENCE clinical trial and a subset (those treated in France) of the sample used in the effectiveness study.
Study sample Power calculations to determine the sample size were not reported. A total of 3,171 patients were enrolled between October 1994 and May 1996. 1,259 patients were enrolled in Canada, 936 in the USA, 710 in Europe (of whom 133 were treated in France) and 266 in South America. There were 1,607 in the intervention group with a mean (median) age of 63 (64) years and 1,564 in the comparator group with a mean (median) age of 64 (65) years. Of the 133 patients treated in France, 65 were in the UFH group and 68 in the enoxaparin group.
Study design This was a randomised double-blinded controlled trial. The study was multi-centred with 176 centres in 10 countries (Canada, the USA, South America and Europe). Follow-up was for 30 days. Patients were randomly assigned to the 2 groups but the method of randomisation was not reported. At least 1 dose of the study drug was administered to 98% of the sample and treatment was prematurely discontinued in 367 patients (11.6% of the sample), 207 of these (13.2%) were in the control group and 160 (10.0%) were in the intervention group. Blinding was achieved by giving all patients a subcutaneous injection at 12 hourly intervals, either of the study drug or a placebo, and an intravenous bolus and continuous infusion of either the study drug or a placebo. Dummy adjustments were also administered to aid in blinding. Diagnosis of outcomes was by predetermined protocols. The end points of the study were verified by a committee, who were blinded to the treatments given.
Analysis of effectiveness The effectiveness analysis was based on intention to treat. The primary outcome was the composite triple endpoint of death, myocardial infarction (or reinfarction), and recurrent angina by 14 days follow-up. A secondary outcome was the same endpoint at 48 hours and 30 days follow up. The 3 outcomes were also recorded individually. The incidence of major and minor haemorrhage (an adverse effect of treatment) was also recorded. Groups were statistically comparable in terms of age, weight, sex, family history, smoking and other risk factors and previous cardiac history. Comparisons of the two study groups, with adjustment for differences in country of origin, were performed using a logistic-regression model.
Effectiveness results The effectiveness results were as follows:
At 14 days the composite outcome of death, myocardial infarction or recurrent angina had occurred in 309 patients (19.8%) in the unfractionated heparin group and in 266 (16.6%) of the enoxaparin group. This was a statistically significant difference, (p=0.019), giving a relative risk reduction of 16.2% with enoxaparin sodium treatment.
At 48 hours, differences were not significant. Death, myocardial infarction or recurrent angina had occurred in 115 (7.4%) in the control and 99 (6.2%) in the intervention group,(p=0.18, odds ratio 0.83, 95% CI: 0.62 - 1.09).
At 30 days there was a statistically significant difference. Death, myocardial infarction or recurrent angina had occurred in 364 (23.3%) of the control group and 318 (19.8%) of the intervention group, (p=0.016, odds ratio 0.81, 95% CI: 0.68 - 0.96).
There was no significant difference between groups in serious haemorrhagic complications at 30 days although there was a difference in minor haemorrhages. 107 (7.0%) suffered major haemorrhage in the control group and 102 (6.5%) in the intervention group, (p=0.57). Patients in the enoxaparin group experienced more minor haemorrhage than patients in the UFH group (13.8% versus 8.8%, p<0.01).
Clinical conclusions Enoxaparin plus aspirin was more effective than unfractionated heparin plus aspirin in reducing the incidence of ischaemic events in patients with unstable angina at the expense of an increase of minor bleeding but not of major haemorrhagic events.
Measure of benefits used in the economic analysis No summary benefit measure was used for the economic analysis, and only individual clinical outcomes were reported. The economic study was reduced to a cost-minimisation analysis to avoid double-counting in the cost-effectiveness measure (using the primary clinical end-point both as a benefit measure and as a measure in the calculations of costs).
Direct costs Costs were not discounted due to the short time frame of the cost analysis. Some quantities were reported separately from the costs. Unit costs for 4 cost categories were reported separately. Overall, a total of four separate cost analyses were conducted: whole study population versus French patients only, and overall differences in the costs of procedures for which there was a statistically significant difference between the two treatments versus hospital resource consumption (reflected by the length of stay in the intensive care unit (ICU) and in non-ICU medical wards). Cost analysis covered the costs of coronary angiography, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass grafting (CABG), length of stay in ICU and the non-ICU length of hospitalisation. The perspective adopted in the cost analysis was claimed to be that of society. The cost data were obtained from a public sector institution for the patients treated in public hospitals and from a private hospital for the patients treated in private hospitals. The drug costs were obtained from a central pharmacy in Paris. The price year was 1996.
Statistical analysis of costs A statistical analysis of costs was not performed.
Indirect Costs Indirect costs were not considered.
Currency French Francs (Ffr). A conversion to euros was performed based on EUR 1.00 = Ffr 6.559.
Sensitivity analysis A series of one-way sensitivity analyses was carried out on the parameters affecting the total costs.
Estimated benefits used in the economic analysis Cost results The cost results were as follows:
Based on the differences in resource consumption, the total cost per treated patient in the whole population was Ffr10,127 for UFH and Ffr8,573 for enoxaparin sodium. The estimated average net cost saving was Ffr1,555 (range: Ffr1,234 - Ffr1,876) per treated patients with enoxaparin.
In the French patients, the total cost per treated patient was Ffr20,617 for UFH and Ffr10,624 for enoxaparin sodium. The estimated average net cost savings were Ffr9,993 (range: Ffr7,967 - Ffr12,019) per treated patients with enoxaparin.
Based on the duration of hospital stay, the total cost per treated patient in the whole population was Ffr22,747 for UFH and Ffr21,733 for enoxaparin sodium. The estimated average net cost savings was Ffr1,014 (range: Ffr542 - Ffr1,485) per treated patients with enoxaparin.
In the French patients, the total cost per treated patient was Ffr37,324 for UFH and Ffr34,519 for enoxaparin sodium. The estimated average net cost savings was Ffr2,804 (range: Ffr1,518 - Ffr4,090) per treated patients with enoxaparin.
The approach based on the difference in procedure rates was mainly sensitive to lower PTCA rate and to the unit cost applied to this procedure. The analysis based on length of stay differences for all patients was essentially dependent on the length of stay in ICU and ICU daily costs for the trial as a whole. However, for the French patients, length of stay in the non-ICU medical wards was the driving factor.
Synthesis of costs and benefits No synthesis of costs and benefits was carried out as the economic study was conducted on a cost-minimisation basis to avoid double-counting.
Authors' conclusions This French study confirmed earlier results, which show that enoxaparin sodium is cost saving in the treatment of unstable angina/non-Q wave MI.
CRD COMMENTARY - Selection of comparators A justification was given for the choice of the comparator (unfractionated heparin). It was defined as the standard care in the context in question. You, as a database user, should consider whether this is a widely used health technology in your own setting.
Validity of estimate of measure of effectiveness The effectiveness results are likely to be internally valid given the randomised nature of the study design and the fact that the effectiveness analysis was based on the intention to treat principle. Regarding the comparability of the two study groups, it was noted that the study groups were statistically comparable in terms of age, weight, sex, family history, smoking and other risk factors, and previous cardiac history. Comparisons of the two study groups with adjustment for differences in country of origin were performed using a logistic-regression model. The study sample appears to have been representative of the study population.
Validity of estimate of measure of benefit The authors did not derive a summary measure of health benefit due to the need to avoid a double-counting problem arising from using the same quantities both in the numerator and the denominator of the cost-effectiveness ratio. It was therefore decided to adopt a cost-minimisation approach.
Validity of estimate of costs Positive aspects of the cost analysis were as follows: some quantities were reported separately from the costs; adequate details of methods of cost estimation were given; the perspective adopted in the cost analysis and the price year were reported; some statistical analyses were performed on some resource use data. Limitations of the cost analysis were as follows: despite the authors' claim that a societal perspective had been adopted in the study, indirect costs (such as the costs of informal carers) were not included; statistical analyses appear not to have been performed on cost data, although a sensitivity analysis was performed. It was noted that applying French unit costs to resource consumption from the entire ESSENCE trial was appropriate due to the existence of differences in resource use regimes even inside a specific country; the differences among countries cannot act as a hindrance to the application of French unit costs to the international sample. A further strength of the study was deemed to be that cost calculations were performed from 4 different approaches. It was noted that the cost saving associated with the use of enoxaparin may have been underestimated due to the exclusion of some cost items such as the nursing time saved, decreased pharmacy management costs, etc.
Other issues The authors' conclusions appear to be justified given the sensitivity analysis performed. The issue of generalisability to other settings was not transparently addressed, although sensitivity analyses can enhance the generalisability of the study results (though it is not entirely clear whether the ranges used in the sensitivity analyses corresponded to the values observed in other countries). Appropriate comparisons do not appear to have been made with other studies. The issue of whether the study sample was representative of the study population was not addressed.
Implications of the study The long-term clinical/economic outcomes will have to be investigated in the future. It remains to be seen whether similar economic benefit applies to low molecular weight heparin's other than enoxaparin sodium.
Source of funding Partially funded by an unrestricted grant from Rhone-Poulenc Rorer Laboratories, Montrouge, France.
Bibliographic details Detournay B, Huet X, Fognani F, Montalescot G. Economic evaluation of enoxaparin sodium versus heparin in unstable angina: a French sub-study of the ESSENCE trial. PharmacoEconomics 2000; 18(1): 83-89 Other publications of related interest Cohen M, Demers C, Gurkinkel E P, the ESSENCE Study Group, et al. A comparison of low-molecular weight heparin with unfractionated heparin for unstable coronary artery disease. New England Journal of Medicine 1997;337:447-52.
Indexing Status Subject indexing assigned by NLM MeSH Angina, Unstable /complications /drug therapy /economics; Anticoagulants /economics /therapeutic use; Cost-Benefit Analysis; Enoxaparin /economics /therapeutic use; France; Heparin /economics /therapeutic use; Humans AccessionNumber 22000008238 Date bibliographic record published 30/06/2001 Date abstract record published 30/06/2001 |
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