|Economic evaluation of high vs low dosage lisinopril in patients with chronic heart failure
|Scalone L, Mantovani L T
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 health interventions under study were two different dosages of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor for the treatment of patients with chronic heart failure (CHF): high-dosage lisinopril (32.5-35 mg/day) versus low-dose lisinopril (2.5-5 mg/day).
Economic study type
The study population comprised a group of patients with New York Heart Association (NYHA) class II, III, or IV symptoms of heart failure associated with a left ventricular ejection fraction less than or equal to 30% despite treatment with diuretics for at least two months.
The setting was primary care. The economic study was carried out in Milan, Italy.
Dates to which data relate
Data on effectiveness and resource use were gathered from October 1992 to September 1997. The price year was 2001.
Source of effectiveness data
The effectiveness evidence came from another study, the Assessment of Treatment with Lisinopril and Survival Study (ATLAS).
Link between effectiveness and cost data
The costing was conducted retrospectively on the same sample of patients as that used in the effectiveness study.
Power calculations were performed in the preliminary phase of the study and suggested that a sample size of 3,000 patients was required on the basis of the following assumptions: recruitment would be completed in 18 months with the last patient followed for 36 months, the 1-year mortality rate in the high-dose group would be 19%, and the study would have 90% power to detect a 15% relative difference in mortality between the treatment groups (alpha=0.02). The method of sample selection was not reported. Of the 3,793 patients who entered the tolerability pre-phase of the study, 629 patients were excluded before randomisation due to death, side-effects, and administrative reasons. Thus the final sample included 3,164 patients: 1,596 were included in the low-dose group and 1,568 in the high-dose group.
This was a double-blind, multicentre, randomised controlled trial, carried out in 287 centres in 19 countries in North America, Europe, and Australia. The method of randomisation was not reported. The median follow-up was 47.5 months (range: 39 - 58 months). No patient was lost to follow-up with respect to vital status.
Analysis of effectiveness
The analysis of the clinical study was based on intention to treat. Several clinical outcomes were evaluated in the ATLAS trial, but the main endpoints (relevant for the present analysis) were all-cause mortality and cardiovascular deaths. The authors stated that the two groups were comparable at baseline with respect to all pre-treatment characteristics.
There was an 8% lower risk of all-cause mortality and a 10% lower risk of cardiovascular mortality in the high dose-group compared with the low-dose group, but none of these differences reached statistical significance. However, there was a 12% lower risk of death or hospitalisation in the high-dose group than in the low-dose group, and this was statistically significant, (p=0.002).
The effectiveness study showed that high-dose lisinopril was more effective than the low-dose strategy in reducing the risk of death and hospitalisation, although some of the differences did not reach statistical significance.
Measure of benefits used in the economic analysis
The benefit measure used in the economic analysis was life-years saved (LYS) with the two interventions. This was derived from the survival data obtained in the effectiveness study and using the Kaplan-Meier method for all-cause mortality. A 5% discount rate was applied to benefits gained after the first year.
Discounting was relevant and a 5% rate was used as costs were incurred over a period longer than two years. Unit costs were not reported separately from quantities of resources used. The health service costs included in the analysis were drugs, visits, and hospitalisations over the follow-up period. Drug dosage was based on data derived from the trial as initial dosage was adapted to patients' needs. Hospitalisations referred only to cardiovascular events. Costs associated with the management of adverse events were not included as there was no statistically significant difference in the rate of complications. The perspective adopted in the study was that of the Italian NHS. The estimation of resource use was based on data collected alongside the clinical trial. Unit costs were based on diagnosis-related group (DRG) tariffs for hospitalisation and retail prices for drugs. The price year was 2001.
Statistical analysis of costs
No statistical analyses of costs were conducted.
Indirect costs were not included in the analysis.
One-way sensitivity analyses were conducted to evaluate the robustness of the estimated cost-effectiveness ratios to variations in the following variables: average dosage, hospitalisation costs, number of hospitalisations avoided, cardiovascular deaths avoided, and LYS. All these factors were varied by +/- 10%.
Estimated benefits used in the economic analysis
The estimated number of cardiovascular deaths were 401.6 with low-dosage and 371.8 with high-dosage, thus the high-dosage lisinopril led to 29.8 deaths avoided. The estimated difference in discounted LYS was 75.80.
The estimated discounted total costs in the sample of 1,000 patients over the overall study period were Euro 6,217,918 in the low-dosage group and Euro 6,118,610 in the high-dosage group. Thus the cost-saving associated with high-dosage lisinopril was Euro 99,307.
Synthesis of costs and benefits
The authors calculated the incremental cost-effectiveness ratio in order to combine the costs and benefits of the two treatments. However, high-dosage lisinopril was the dominant strategy as it was more effective and less costly than low-dose lisinopril, this conclusion being robust in all sensitivity analyses. The threshold analysis showed that the price, which would equalize the estimated costs of the two treatments, was Euro 0.112/mg for the 5 mg box and Euro 0.05/mg for the 20 mg box.
The authors concluded that, in Italy, the treatment of CHF with high-dose lisinopril was more effective and less expensive than the treatment based on a low-dose protocol. This was explained by the reduction in mortality and hospitalisation rates.
CRD COMMENTARY - Selection of comparators
The authors compared two different dosages of lisinopril, which represented a widely used medication within the group of ACE inhibitors used for the treatment of CHF. You, as a user of this database, should decide whether they are two dosages valid in your own setting.
Validity of estimate of measure of effectiveness
The internal validity of the analysis was high as the effectiveness study was based on a double-blind, multicentre, randomised trial, which was appropriate for the study question. However, the study was published elsewhere and no other published source was used to derive the effectiveness evidence.
Validity of estimate of measure of benefit
Discounted survival was used as the summary benefit measure used in the analysis. It appears to have been appropriate and permits the comparison of the benefits of the present interventions with those associated with other health technologies.
Validity of estimate of costs
The perspective adopted in the study was reported and it appears that all relevant categories of costs were included in the analysis. The price year was mentioned and unit costs were reported separately from quantities of resources used. The sources of data concerning costs and resource consumption were reported. Costs were specific to the study setting and few sensitivity analyses were conducted. No statistical analyses were conducted in the base case. The authors stated that some assumptions were necessary for some categories of costs due to the lack of appropriate DRG tariffs.
The authors did not compare their findings with those from other studies and did not address the issue of the generalisability of the study results to other settings. The overall external validity of the analysis was low. The authors noted some limitations of their analysis and stated that even assuming that the two treatments were equally effective, the subsequent cost-minimisation analysis would have favoured the high-dose strategy, which was cost-saving under every scenario.
Implications of the study
The study suggests that the therapy based on high-dosage lisinopril should be prescribed for the management of patients with CHF. This is particularly relevant in Italy where almost all costs of the treatment are borne by the NHS.
Source of funding
Supported by an educational grant from AstraZeneca Spa, Basiglio, Milan, Italy.
Scalone L, Mantovani L T. Economic evaluation of high vs low dosage lisinopril in patients with chronic heart failure. Pharmacoeconomics - Italian Research Articles 2002; 4(2): 45-55
Subject indexing assigned by CRD
Clinical Trials as Topic; Costs and Cost Analysis; Drug Costs; Heart Failure /drug therapy /prevention & Hospital Costs; Italy; Lisinopril /administration & Morbidity; Mortality; control; dosage /therapeutic use /economics
Date bibliographic record published
Date abstract record published