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Cost effectiveness of extended treatment with low molecular weight heparin (dalteparin) in unstable coronary artery disease: results from the FRISC II trial |
Janzon M, Levin L A, Swahn E, FRISC II Investigators |
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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 Continued treatment (3 months) with subcutaneous low molecular weight heparin (dalteparin) was compared with placebo for the treatment of patients with unstable angina. Following an episode of unstable angina, the patients were given aspirin and at least 5 days' open label treatment with heparin, then either dalteparin or placebo for 3 months. Women weighing less than 80 kg and men weighing less than 70 kg received 5,000 IU dalteparin twice daily. All other patients in the intervention group received 7,500 IU twice daily.
Economic study type Cost-effectiveness analysis.
Study population The study population comprised patients with symptoms of cardiac ischaemia that were worsening or present at rest, or those in which an acute MI was suspected and the onset of the last episode was less than 48 hours before the initial dose of dalteparin or standard heparin. There were no age restrictions on the sample.
Patients were excluded from the study sample if they had an increased risk of bleeding or anaemia, an indication for thrombolysis or thrombolytic treatment had been administered in the last 24 hours, the patient had undergone angioplasty in the last 6 months, or was on a waiting list for coronary revascularisation procedures. Other criteria for exclusion were other acute or severe cardiac diseases, a renal or hepatic deficiency, clinically relevant osteoporosis, other severe illness, or a known hypersensitivity to dalteparin. Where it was thought that the patient would have difficulty participating in this or another (unspecified) study, they were also excluded from the study sample.
Setting The setting was secondary and tertiary care. The economic study was carried out in Sweden.
Dates to which data relate The effectiveness and resource use data were collected between June 1996 and August 1998. The cost data were collected in 1997, then inflated to 2000 using the consumer price index (1.1% between 1997 and 2000).
Source of effectiveness data The effectiveness data were derived from a single study.
Link between effectiveness and cost data A cost study was conducted at 36 of the participating centres, which comprised 80% of all the patients in the study.
Study sample The study sample comprised all patients (n=1,235) randomised to the non-invasive arm of the Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease (FRISC II) trial. The sample also included all patients (n=1,032) who were originally included in the FRISC II trial, but who were not randomised due to either late entry or contraindications. Thus, 2,267 patients participated in this medical trial. There were 1,049 patients randomised to the intervention group and 1,056 to the placebo group. A total of 162 patients were withdrawn from the study prior to the treatment period, but post-randomisation. No power calculations to determine the same size were reported. Further details of how the patients were recruited to the original FRISC II trial were reported elsewhere (see Other Publications of Related Interest).
Study design The study was a double-blind, multi-centred, randomised controlled trial. Fifty-eight centres in Scandinavia, including 36 in Sweden, were involved in the study. The authors stated that the hospitals in the study reflected the range of hospitals in Scandinavia and included small county hospitals and university hospitals. The patients were randomised by fax communication with an independent agent to receive either subcutaneous dalteparin or a placebo injection. In addition, randomisation was stratified by centre. The patients were followed up for 3 months. No details of the number or characteristics of the patients who were lost to follow-up were reported.
Analysis of effectiveness It was reported that the analysis of the effectiveness data was conducted on an intention to treat basis. However, the 162 patients who were withdrawn post-randomisation were not included at analysis. The primary health outcomes were either a MI or death within the study period. There were no statistically significant differences between the intervention and placebo groups in their age, gender ratio, risk factors for coronary disease, or prior and current cardiac disease.
Effectiveness results One month into the treatment period of the study, there was a 47% relative risk and a 2.8% absolute reduction in the risk of the patient either having an acute MI or dying in the intervention group, (p<0.002).
After 3 months of extended treatment, there was a 19% relative risk reduction and a 1.3% absolute risk reduction of MI in the group receiving dalteparin, compared with those receiving placebo. However, this difference was not statistically significant.
Clinical conclusions The study indicated that there was a reduction in the risk of having a MI or dying following an episode of unstable angina or suspected acute MI, if treatment with dalteparin were extended for one month.
Measure of benefits used in the economic analysis The outcome measure used was MIs or deaths avoided.
Direct costs The direct costs included in the study related to the health service provider. These costs were for hospital admissions, investigations, interventions, pharmaceuticals and outpatient care by physicians, nurses and physiotherapists.
The authors stated that a cost study was conducted in 36 of the participating centres, all 36 were Swedish. The units of each resource used and the total cost for each specific category of resource were reported separately for the analysis at 3 months. However, the unit costs were not reported. The analyses at the 1-month follow-up only provided the total cost for each broad category of resource used.
The data on the amount of each resource used were collected prospectively using a log in the main case report. Data on the cost of hospital admissions, investigations and interventions were obtained from all 36 of the Swedish hospitals participating in the study. The price of an inpatient stay was calculated by dividing the annual costs of running the ward (including physicians' fees) by the number of bed days. The price of the pharmaceuticals was obtained from Swedish pharmacy prices. The costs of outpatient care by physicians, nurses and physiotherapists were collected from 9 hospitals in south-eastern Sweden. These data were collected in 1997. The costs were reflated from 1997 to 2000 using the consumer price index (1.1%). No discounting was undertaken, which was appropriate given the timescale of the study was 3 months.
Statistical analysis of costs The cost data were analysed in a stochastic manner. The mean costs of the two groups in the study were compared using the t-test. The level of significance was 95%.
Indirect Costs The indirect costs were not included since the study took the perspective of the health care provider.
Currency Swedish kroner (SEK). All costs were converted to UK pounds sterling () using an exchange rate of 1 = SEK 14.71.
Sensitivity analysis Variability in the cost data was tested using a sensitivity analysis. An analysis of the extremes was carried to assess the impact of differing costs. The maximum and minimum costs reported by each of the centres that provided cost data were used.
Estimated benefits used in the economic analysis For details of the benefits used in the economic analysis, see the 'Effectiveness Results' section. The time period of the study was 3 months. No attempts were made to project the benefits of the treatment beyond this term.
Cost results The total cost for the 3-month study period was SEK 41,744 for the intervention group and SEK 35,005 for the placebo group (95% confidence interval, CI: 1,739 - 11,739; p=0.008).
After one month of follow-up, the total cost was SEK 15,573 for the intervention group and SEK 14,724 for the placebo group. However, this difference was not statistically significant.
Synthesis of costs and benefits The incremental cost-effectiveness ratio of giving dalteparin for one month after unstable angina or a suspected MI was SEK 30,300 (2,060) per avoided death or MI. The CI for this cost-effectiveness ratio ranged from a saving of SEK 78,000 (5,300) to an expense of SEK 139,000 (9,400). Incremental cost-effectiveness ratios could not be calculated for the 3-month period due to non significant effectiveness data.
The sensitivity analysis using minimum and maximum price levels gave cost-effectiveness ratios ranging from SEK 18,300 (1,200) to SEK 42,300 (2,900) per avoided event.
Authors' conclusions There was a significant cost-effective reduction in the risk of death or myocardial infarction (MI) during the first month of extended treatment with subcutaneous dalteparin.
CRD COMMENTARY - Selection of comparators The study used a placebo as the comparator for the intervention. This allowed any possible placebo effect to be accounted for and the active value of the treatment to be considered.
Validity of estimate of measure of effectiveness A double-blind, randomised controlled trial was an appropriate study design for the research question posed. The authors did not report who was subjected to blinding. The methods used to recruit the patients to the trial were not reported, thus it was difficult to ascertain whether the sample was fully representative of the population. The fact that no sample size calculations were reported, combined with the lack of statistically significant effectiveness results at 3 months, suggests that a larger sample might have yielded clearer results. As the baseline characteristics of the two groups in the study were the same, it is likely that there was no problem with confounding. In addition, the nature of the study design should have helped to minimise bias. However, it is worth considering whether the characteristics of the study sample match those in your own area of practice. The paper did not provide any details of the patients who were lost to follow-up, nor if and how data relating to these patients were included in the study. It is probable that the internal validity of the study is quite high.
Validity of estimate of measure of benefit The study used the number of MIs and deaths avoided as the measure of health benefit. Unfortunately it did not distinguish between deaths from cardiac disease and those from other causes that might have been unrelated to the patient's cardiac condition. The authors noted the limitations associated with their choice of benefit measure.
Validity of estimate of costs The economic analysis was undertaken from the perspective of the health care provider. It appears that all the costs that this organisation would incur have been included. A cost study was undertaken using a sub-sample of the centres participating in the study. The paper reported the resources used in both quantities and total costs. The statistical treatment of these strengthens the conclusions of the study. It also allows other health care providers to assess the data, and to apply the costs from their own setting so that the appropriateness of the treatment can be considered in their own practice. A sensitivity analysis was undertaken on the costs of the resources. The study would have been further strengthened had a sensitivity analysis been performed in which the amounts of resources were varied. This is particularly relevant considering the relatively small differences between the intervention and placebo groups. The price year of the cost data and its reflation were stated clearly, which will aid future reflation exercises for comparisons with other studies. The reproducibility of the results would have been increased if the total costs had been broken down into unit costs.
Other issues The authors did not compare their findings with those from other studies. In addition, they did not directly address the issue of generalisability of the results obtained. The study showed that extending treatment with dalteparin for one month was cost-effective in avoiding death and MIs, whereas extending treatment for 3 months was not. The authors concluded that this treatment is useful as a bridging measure until invasive procedures can be undertaken. The likely waiting time for invasive procedures should be considered prior to adopting this strategy.
Implications of the study The authors recommended that extended use of dalteparin is a cost-effective bridging measure prior to invasive procedures for patients with unstable coronary artery disease, once they are clinically stable.
Source of funding Supported by Pharmacia Corporation and the Health Research Council, Sweden.
Bibliographic details Janzon M, Levin L A, Swahn E, FRISC II Investigators. Cost effectiveness of extended treatment with low molecular weight heparin (dalteparin) in unstable coronary artery disease: results from the FRISC II trial. Heart 2003; 89(3): 287-292 Other publications of related interest FRISC II Investigators Long term low molecular mass heparin in unstable coronary artery disease: FRISC II prospective randomised multicentre study. Lancet 1999;354:701-7.
Indexing Status Subject indexing assigned by NLM MeSH Adult; Aged; Aged, 80 and over; Anticoagulants /economics /therapeutic use; Coronary Artery Disease /drug therapy /economics; Cost-Benefit Analysis; Dalteparin /economics /therapeutic use; Female; Follow-Up Studies; Hospitalization /economics; Humans; Male; Middle Aged; Prospective Studies; Sensitivity and Specificity AccessionNumber 22003000507 Date bibliographic record published 29/02/2004 Date abstract record published 29/02/2004 |
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