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Cost effectiveness of ramipril in patients at high risk for cardiovascular events: economic evaluation of the HOPE (Heart Outcomes Prevention Evaluation) study for Germany from the statutory health insurance perspective |
Schadlich P K, Brecht J G, Rangoonwala B, Huppertz E |
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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 The use of oral ramipril, given at 10 mg/day, for the treatment of patients with cardiovascular disease (CVD).
Economic study type Cost-effectiveness analysis.
Study population The study population comprised a hypothetical cohort of patients at high risk of cardiovascular events, who had the same characteristics as the patients included in the HOPE study. The HOPE inclusion criteria specified age 55 years or older and high risk for cardiovascular events because of previous coronary artery disease (CAD), cerebrovascular disease or peripheral arterial disease, or diabetes plus one additional risk factor. The exclusion criteria included treatment with an angiotensin-converting enzyme inhibitor or tocopherol (vitamin E), heart failure or a known left ventricular ejection fraction of less than 0.40, known proteinuria, and uncontrolled hypertension. A further exclusion criterion was previous stroke or a myocardial infarction (MI) less than one month before enrolment in the study.
Setting The setting appears to have been primary and secondary care. The economic study was carried out in Germany.
Dates to which data relate The effectiveness data and most resource use data were gathered from 1994 to 1999. The costs were estimated using 1998-2002 values, thus a single price year was not given.
Source of effectiveness data The effectiveness evidence was derived from a single study.
Link between effectiveness and cost data The costing was carried out retrospectively on the same sample of patients as that included in the clinical trial. However, data from patients included in the trial were used to derive the probabilities of events, while the costs resulting from these changes in morbidity were estimated using average case-related treatment expenses of the SHI in Germany
Study sample As the economic evaluation was based on a published study, few details of the design and other aspects of the trial were reported. A total of 9,297 patients were identified, of which 4,645 were included in the ramipril group and 4,652 in the control group. A sub-group of 3,577 patients with diabetes mellitus was also identified (1,808 in the ramipril group and 1,769 in the control group). The mean age of the whole sample was 66 years and 27% of the patients were female. Approximately 80% of patients had a history of CAD, 11% stroke or transient ischaemic attacks, and 44% peripheral vascular disease. Hypertension was observed in 47% of the patients.
Study design This was a randomised, double-blind clinical trial that was carried out in 267 centres in 19 countries. The average length of follow-up was 4.5 years. Data on outcome events and adverse effects were collected at follow-up visits scheduled for month 1 and 6, and then every 6 months thereafter. The loss to follow-up was not stated.
Analysis of effectiveness It was not stated whether the analysis of effectiveness was conducted on an intention to treat basis or on treatment completers only. The primary outcome measure was a composite end point of MI, stroke, or death from cardiovascular causes. However, the probabilities of the individual events associated with ramipril or placebo were reported. These included MI, coronary revascularisation, other revascularisations, stroke, cardiac arrest, heart failure, worsening angina pectoris, microvascular diabetic complications, new-onset diabetes mellitus, and death from any cause. The study groups were well matched at baseline.
Effectiveness results The probabilities of events with ramipril and placebo were as follows:
MI, 0.0988 versus 0.1225 (difference -0.0237; range: -0.0110 - -0.0365);
coronary revascularisations, 0.1313 versus 0.1571 (difference -0.0258; range: -0.0115 - -0.0401);
other revascularisations, 0.0284 versus 0.0260 (difference 0.0024; range: 0.0090 - -0.0042);
stroke, 0.0336 versus 0.0486 (difference -0.0150; range: -0.0069 - -0.0231);
cardiac arrest, 0.0080 versus 0.0127 (difference -0.0047; range: -0.0006 - -0.0088);
heart failure, 0.0304 versus 0.0344 (difference -0.0040; range: 0.0032 - -0.0112);
worsening angina pectoris, 0.1193 versus 0.1215 (difference -0.0022; range: 0.0110 - -0.0154);
microvascular diabetic complications, 0.1565 versus 0.1840 (difference -0.0274; range: -0.0073 - -0.0476);
new-onset diabetes mellitus, 0.0360 versus 0.0538 (difference -0.0178; range: -0.0071 - -0.0285);
death from any cause, 0.1038 versus 0.1223 (difference -0.0185; range: -0.0057 - -0.0314).
Clinical outcomes were also reported for the sub-group of diabetic patients. Generally, there were only minor differences compared with the HOPE study as a whole. The exception was a reduction in all-cause mortality, in which ramipril was about 1.7-fold more effective among patients with diabetes than among the entire study population.
Clinical conclusions The effectiveness data showed that better clinical outcomes were observed in patients treated with ramipril compared with placebo.
Modelling An analytic model was used to assess the clinical and economic impact of ramipril added to current medication in the cohort of patients enrolled in the HOPE study. The outline of the model was provided. Event rates estimated from the trial were used to derive both survival (benefit measure) and costs. The equations used to derive long-term costs and survival from the trial data were provided.
Measure of benefits used in the economic analysis The summary benefit measure was the life-years gained (LYG) by adding ramipril to the patients' current medication. LYG had two components:
LYG during the trial period of 4.5 years of the HOPE study, which assumed a constant annual mortality rate for the deaths observed in the ramipril and placebo groups; and
LYG beyond the end of the trial, which was estimated according to the declining exponential approximation of life expectancy (DEALE) method.
The LYG were estimated on the basis of age and gender-specific mortality rates found in the HOPE trial for the two treatment groups. An annual discount rate of 5% was applied to the estimated survival.
Direct costs The analysis of the costs was carried out from the perspective of the German SHI. It included the costs associated with ramipril and the treatment of cardiovascular events. The unit costs were reported for some items but, in general, the costs were presented as macro-categories. The price of ramipril was derived from public pharmacies, regulations governing patients' prescription charges and the discount received by the SHI. Hospital costs for the treatment of cardiovascular events were estimated using diagnosis-related groups. Other costs came from official reimbursement fees for outpatient medical treatments. The most recent cost data were used. For example, expenses were based on prices for ramipril as at 1 March 2002 in outpatient care and on 1998-2001 prices for inpatient and outpatient treatment of cardiovascular events. The costs associated with diabetes complications came from a published study. Resource use was derived from both data from the HOPE study and published sources. In fact, data from patients included in the HOPE were used to derive the probabilities of events, while the costs resulting from these changes in morbidity were estimated using average case-related treatment expenses of the SHI in Germany. Discounting was relevant, as the costs were incurred during a long timeframe, and an annual rate of 5% was applied.
Statistical analysis of costs The costs were treated deterministically in the base-case.
Indirect Costs The indirect costs were not taken into consideration.
Currency Euros (EUR). The exchange rates between EUR and US dollars ($) and German marks (DM) were EUR 1 = around $0.88 and EUR 1 = DM 1.95583.
Sensitivity analysis Univariate and probabilistic sensitivity analyses were carried out to assess the robustness of the base-case cost-effectiveness ratios. Worst- and best-case scenarios were also considered. Ranges of values were derived from confidence intervals around clinical results in the HOPE study, from the literature, or set by the authors. Details on the probabilistic distributions assigned to each variable were provided.
Estimated benefits used in the economic analysis The discounted LYG with ramipril over placebo were 0.1175 (range: 0.0589 - 0.1525; worst case: 0.0350; best case: 0.2042). In the sub-group of patients with diabetes mellitus, the discounted LYG with ramipril over placebo were 0.1945 (range: 0.1063 - 0.2495; worst case: 0.0596; best case: 0.3417).
Cost results The discounted drug acquisition costs (per patient) of adding ramipril to current medication was EUR 1,051. However, ramipril resulted in cost-savings of EUR 573 associated with a reduction in adverse events over placebo. Therefore, the discounted total costs per patient of adding ramipril to current medication were EUR 478.
Synthesis of costs and benefits An incremental cost-effectiveness ratio (ICER; i.e. the cost per LYG) was calculated to combine the costs and benefits of ramipril over current medication. In the base-case, considering the whole sample of patients, the ICER was EUR 4,074. In the sub-group of patients with diabetes mellitus, the ICER was EUR 2,486.
The deterministic sensitivity analysis suggested that the acquisition cost of ramipril had the greatest impact on the ICER.
Considering the whole sample of patients, in the best-case scenario, ramipril dominated current medication, which was both less effective and more expensive. In the worst-case scenario, the ICER was EUR 28,886. Considering only diabetic patients, ramipril dominated current medication in the best-case scenario, while in the worst case scenario, the ICER was EUR 19,995.
In 95% of the 10,000 simulations, the ICER of ramipril after 4.5 years of treatment was between EUR 1,290 and EUR 9,005 per LYG for the entire HOPE study population and between EUR 290 and EUR 6,115 per LYG in the diabetic sub-group.
Authors' conclusions Ramipril was a very cost-effective strategy for high-risk patients requiring treatment for the prevention of cardiovascular disease (CVD). The results of the analysis were sensitive to the cost of ramipril.
CRD COMMENTARY - Selection of comparators The selection of the comparator was appropriate because it reflected the current treatment pattern in the authors' setting. However, details of the current treatment were not provided. The authors highlighted the fact that the results found for ramipril 10 mg/day cannot be extended to other angiotensin-converting enzyme inhibitors or other dosages of ramipril. You should decide whether this is a valid comparator in your own setting.
Validity of estimate of measure of effectiveness The effectiveness evidence came from a clinical trial, which was appropriate for the study question. However, since the trial had already been published, limited information on the design and other characteristics of the primary study was reported. The methods of sample selection and randomisation were not reported. The study groups were comparable at baseline, which enhances the validity of the comparison. Few details of the patients' demographics, follow-up and outcome assessment were provided. The multi-centre and multi-country nature of the study enhances the representativeness of the patient sample. Further, the use of double-blinding reduces the potential impact of assessment bias. A sub-group analysis of patients enrolled in the primary trial was carried out. These issues tend to enhance the validity and robustness of the primary estimates.
Validity of estimate of measure of benefit LYG are a typical measure used to assess the benefits of treatments aimed to reduce the risk of CVD. The approach used to calculate the LYG was described in the technical appendix. Discounting was applied because of the long timeframe of the analysis. LYG can be compared with the benefits of other health care interventions.
Validity of estimate of costs The cost analysis was consistent with the perspective adopted in the study, not only in terms of the types of costs included in the study, but also the sources used in the analysis. The authors stated that the inclusion of indirect costs associated with productivity losses was not relevant because the average age of patients eligible for a ramipril prescription was higher than the mean age of retirement in Germany. The unit costs were not presented separately from the quantities of resources used for all items since most costs were presented as macro-categories. This limits the possibility of replicating the cost analysis in other settings. The costs were specific to the study setting and were assessed using deterministic estimates, but probabilistic distributions were assigned in the Monte Carlo simulation. The impact of changes in the base-case costs was assessed in the sensitivity analysis. A price year was not given, although the period during which the costs were gathered was reported.
Other issues The authors stated that their findings were consistent with the results reported in other economic evaluations of the HOPE trial. The issue of the generalisability of the study results to other settings was not explicitly addressed, but the use of deterministic and probabilistic sensitivity analyses enhances the external validity of the study. The study referred to patients at high-risk of developing CVD and this was reflected in the authors' conclusions.
Implications of the study The study results would appear to suggest that ramipril should be used for the treatment of CVD in high-risk patients. The authors also compared the ICER of ramipril with that of other established and widely used drugs in the secondary prevention of CVD in Germany, such as selected statins. The comparison showed that ramipril was more cost-effective than statins, which should further support an increase in ramipril use for the secondary prevention of CVD.
Source of funding Funded by Aventis Pharma Deutschland GmbH.
Bibliographic details Schadlich P K, Brecht J G, Rangoonwala B, Huppertz E. Cost effectiveness of ramipril in patients at high risk for cardiovascular events: economic evaluation of the HOPE (Heart Outcomes Prevention Evaluation) study for Germany from the statutory health insurance perspective. PharmacoEconomics 2004; 22(15): 955-973 Other publications of related interest Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE and MICRO-HOPE substudy. Lancet 2000;355:253-9.
Backhouse ME, Richter A, Gaffney L. Economic evaluation of ramipril in the treatment of patients at high risk for cardiovascular events. J Med Econ 2000;3:97-109.
Bjorholt I, Andersson FL, Kahan T, et al. The cost-effectiveness of ramipril in the treatment of patients at high risk for cardiovascular events: a Swedish sub-study to the HOPE study. J Intern Med 2002;251:508-17.
Lamy A, Yusuf S, Pogue J, et al. Cost implications of the use of ramipril in high-risk patients based on the Heart Outcomes Prevention Evaluation (HOPE) study. Circulation 2003;107:960-5.
Carroll CA, Coen MM, Piepho RW. Economic impact of ramipril on hospitalization of high-risk cardiovascular patients. Ann Pharmacother 2003;37:327-31.
Indexing Status Subject indexing assigned by NLM MeSH Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors /economics /therapeutic use; Cardiovascular Diseases /complications /drug therapy /economics; Cost-Benefit Analysis; Female; Humans; Male; Middle Aged; Ramipril /economics /therapeutic use; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome AccessionNumber 22004008403 Date bibliographic record published 31/05/2006 Date abstract record published 31/05/2006 |
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