|Cholesterol-lowering therapy with pravastatin in patients with average cholesterol levels and established ischaemic heart disease: is it cost-effective
|Glasziou P P, Eckermann S D, Mulray S E, Simes R J, Martin A J, Kirby A C, Hall J P, Caleo S, White H D, Tonkin A M
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.
The study compared cholesterol-lowering therapy with pravastatin with no therapy (i.e. placebo).
Economic study type
The study population comprised patients who had unstable angina or an acute myocardial infarction, and a total cholesterol level ranging from 4.0 to 7.0 mmol/L. No further inclusion and exclusion criteria were reported.
A setting was not explicitly stated. The economic study was carried out in Australia.
Dates to which data relate
All the effectiveness and resource data were derived from the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial published in 1998 and another study published in 1996. The costs were derived from various sources published between 1992 and 1999. All the costs were reported for the price year 1998.
Source of effectiveness data
The effectiveness data were derived from a single study, the LIPID trial (see Other Publications of Related Interest).
Link between effectiveness and cost data
The costing was undertaken prospectively, both on the sample of patients used in the effectiveness study and on sub-samples (see Sample Size) derived from this sample.
Between June 1990 and December 1992, 9,014 patients aged 35 to 75 years (5,958 from Australia and 3,056 from New Zealand) from 85 centres were randomly allocated to receive pravastatin (n=4,512) or placebo (n=4,502).
The analysis was based on a double-blind randomised placebo-controlled trial that was conducted at 85 centres. The mean follow-up period was 6.0 years. Further information on the study design (e.g. method of randomisation, loss to follow-up, and blinding method) can be found in the 'parent' clinical trial (see Other Publications of Related Interest), which the authors have used in their economic evaluation.
Analysis of effectiveness
The basis of the analysis was intention to treat. The main outcomes used in the analysis were the number of deaths prevented and the life-years saved. Survival to the end of the study was estimated using Kaplan-Meier curves, with extrapolation for the estimates of life-years and quality-adjusted life-years (QALYs) gained. The authors mentioned that the baseline characteristics were well balanced in the two groups. However, no further details of the comparability of the two groups, or any adjustments for confounding factors, were reported.
The cumulative all-cause mortality was 14.1% in the placebo group and 11.0% in the pravastatin group. This represented a relative reduction of 23%, (p<0.001), and a 26% reduction in coronary deaths, (p<0.001).
The absolute difference in all-cause mortality was 3.0% (95% confidence interval, CI: 1.6 - 4.4).
The rate of haemorrhagic stroke was 4.4% in the placebo group and 3.4% in the pravastatin group, a relative reduction of 23% (p=0.02).
The authors reported the clinical results from the LIPID trial (see Other Publications of Related Interest), according to which, treatment with pravastatin in patients with established coronary heart disease and "average" cholesterol levels had been proven to be effective in reducing mortality.
Measure of benefits used in the economic analysis
The measures of benefits used were the deaths averted and the life-years saved. The QALYs were not calculated, as there was no statistical difference in quality of life scores between the groups. The benefits were not discounted in the baseline analysis, but they were discounted at a rate of 5% in a second analysis.
The costs to the health service were calculated in the study. These costs included hospitalisations, medication, visits to the doctor and diagnostic test costs. It is unclear whether the hospitalisation costs included overheads and capital costs. The quantities were reported separately from the costs, but the unit costs were reported only for those costs associated with ambulatory care and diagnostic tests. All the costs were adjusted to 1998 levels, but no details of the adjustment were given. The costs were not discounted in the baseline analysis, but they were discounted at a rate of 5% in a second analysis.
Statistical analysis of costs
The 95% CIs for the incremental costs were calculated from individual patient total costs for pravastatin, other medication and hospitalisations. A 95% CI for ratios of incremental costs per life saved were estimated from bootstrapping the incremental cost-effectiveness ratio distribution following the method of Briggs, using individual patients' cost and effect pairs, by treatment arm, in 10,000 bootstrap replications.
The indirect costs were not included in the analysis.
Australian dollars (Aus$).
A one-way sensitivity analysis was conducted to investigate variability in the data on the cost per life saved. The 95% CIs for the cost and effect factors were used.
Estimated benefits used in the economic analysis
The life-years saved and deaths averted were calculated, then used to calculate the cost-effectiveness ratios. The absolute benefits were not reported.
The total cost was Aus$95,611,388 in the pravastatin group (n=4,512) and Aus$80,787,768 in the placebo group (n=4,502).
Synthesis of costs and benefits
The incremental cost per death prevented during the trial was Aus$107,730 (95% CI from bootstrapping: 68,626 - 209,881).
When estimating survival beyond the 6-year follow-up of the trial, if the survival curves do not further diverge and no further costs are accrued, the expected cost per life-year saved (undiscounted) is Aus$7,695.
When discounting at a rate of 5% per year for the costs and benefits, the expected cost per life-year saved is $10,938.
The results from the sensitivity analysis indicated that the cost per life saved was most sensitive to uncertainty in absolute all-cause mortality.
The authors stated the "resultant cost-effectiveness of $107,730 per premature death prevented, or about $10,900 per discounted life-years saved, is within a range generally considered acceptable and is comparable with that of many other interventions".
CRD COMMENTARY - Selection of comparators
The authors chose the control of the trial as the comparator for the economic analysis. They did not discuss the existence of alternative therapies. If there are any, which is likely, it makes this study only a partial analysis.
Validity of estimate of measure of effectiveness
The analysis was based on a randomised controlled trial. The method used to select the sample was not described but, given the size of the sample, it might have been representative of the study population. The details given about the trial indicate that it was well conducted.
Validity of estimate of measure of benefit
The number of deaths prevented and the number of life-years saved were obtained directly from the effectiveness analysis.
Validity of estimate of costs
The study adopted a health care perspective and, appropriately, only the direct costs of health care were included. The costs were taken from published sources and adjusted to the year 1998, although details of the method of adjustment were not reported. The costs were reported separately from the quantities. The authors discounted both the benefits and costs at a rate of 5% per year, which represents the standard rate for an Australian cost-effectiveness analysis following Pharmaceutical Benefits Advisory Committee guidelines.
The authors tried to compare their results with the findings from other studies. In this effort, they stressed that comparisons are difficult due to differences in the populations, health care practices, and cost per unit resources. The issue of generalisability was addressed. Although the authors suggested that the absolute benefit is unlikely to be substantially influenced by country-specific factors, probably keeping the cost per life-year saved within a cost-effective range, they recommended that the modelling of country-specific cost-effectiveness is required. Secondly, the authors reported that the cost-effectiveness estimates do not necessarily generalise from the trial to the community, since the generalisability of the results will depend on factors such as relative-risk profiles and compliance.
Implications of the study
The authors concluded that the LIPID trial has shown that statin therapy is cost-effective when given in addition to dietary advice. Therefore, the Australian Pharmaceutical Benefits Scheme's guidelines should allow statin therapy and dietary treatment to start at the same time and without delay. The authors also stressed the need for further research on cost-effectiveness within particular sub-populations of patients with different characteristics (age, gender, lipid-profile), to identify which sub-groups of patients with ischaemic heart disease can be treated cost-effectively with an HMG-CoA reductase inhibitor.
Source of funding
Supported by a grant from the Bristol-Myers Squibb Pharmaceutical Research Institute.
Glasziou P P, Eckermann S D, Mulray S E, Simes R J, Martin A J, Kirby A C, Hall J P, Caleo S, White H D, Tonkin A M. Cholesterol-lowering therapy with pravastatin in patients with average cholesterol levels and established ischaemic heart disease: is it cost-effective. Medical Journal of Australia 2002; 177(8): 428-434
Other publications of related interest
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. New England Journal of Medicine 1998;339:1349-57.
Subject indexing assigned by NLM
Adult; Aged; Australia; Cholesterol /blood; Cost-Benefit Analysis; Diagnosis-Related Groups; Double-Blind Method; Hospitalization /economics; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors /economics /therapeutic use; Length of Stay; Middle Aged; Multicenter Studies as Topic; Myocardial Ischemia /drug therapy /economics /mortality; New Zealand; Pravastatin /economics /therapeutic use; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Survival Analysis
Date bibliographic record published
Date abstract record published