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Cost effectiveness of ramipril in patients with non-diabetic nephropathy and hypertension: economic evaluation of ramipril efficacy in nephropathy (REIN) study for Germany from the perspective of statutory health insurance |
Schadlich P K, Brecht J G, Brunetti M, Pagano E, 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 Ramipril or placebo plus conventional therapy in patients with non-diabetic nephropathy and hypertension.
Economic study type Cost-effectiveness analysis.
Study population The study population comprised a hypothetical cohort of 100 patients with non-diabetic nephropathy and hypertension in each treatment arm.
Setting The setting was the community; the economic analysis was carried out in Germany.
Dates to which data relate Effectiveness and resource use data were taken from studies published between 1991 and 1999. Cost data were taken from sources published between 1996 and 1999. The price year for ramipril costs was 1999, whereas the price year for the costs of renal replacement therapy (RRT) was 1996.
Source of effectiveness data Effectiveness estimates were taken from a single study, a review/synthesis of previously completed studies, and estimates.
Link between effectiveness and cost data The costing was carried out retrospectively for a hypothetical cohort of patients with non-diabetic nephropathy and hypertension, from each treatment arm.
Study sample For the single study elements (taken from the Ramipril Efficacy In Nephropathy (REIN) study) the study sample consisted of 166 patients (proteinuria exceeding 3.0 g per day), with 78 patients receiving ramipril and 88 patients receiving placebo. No power calculations were reported. The mean age of patients was around 49 years. There were 66 men in the ramipril group and 64 men in the placebo group, (p=0.06).
Study design This was a prospective, double-blinded, placebo-controlled, randomised controlled trial carried out at 14 centres in Italy. Patients were followed up for an average of 16 months. Less than ten patients from each group were in the trial for more than three years.
Analysis of effectiveness The analysis of the clinical study was based on intention to treat. The primary health outcomes used in the analysis were the glomerular filtration rate (GFR), the urinary protein excretion rate, and renal survival. Groups were comparable at analysis in terms of demographic characteristics.
Effectiveness results The mean decline in GFR per month was 0.53 ml/min per 1.73m^2 in the ramipril group and 0.88 ml/min per 1.73m^2 in the placebo group, (p=0.03) for those patients with at least three GFR measurements.
The urinary protein excretion rate decreased by 23% by month one, (p<0.01), and remained lower than baseline throughout the study, declining by 55% at 36 months.
The change in urinary protein excretion rate after randomisation differed between treatment groups, (p=0.002).
Eighteen patients in the ramipril group and 40 patients in the placebo group reached the combined endpoint of doubling the serum creatinine levels or end stage renal failure (ESRF), (p=0.02).
Seventeen patients in the ramipril group and 29 patients in the placebo group required dialysis or renal transplantation.
Clinical conclusions The authors argued that the clinical effectiveness of ramipril in patients with non-diabetic nephropathy and severe persistent proteinuria (over 3.0 g per day) had been clearly documented in the trial examined.
Modelling A three-year decision analytic model was used to determine the cost-effectiveness of ramipril or placebo plus conventional therapy in patients with non-diabetic nephropathy and hypertension.
Outcomes assessed in the review The review elements assessed chronic renal replacement therapy (RRT), and specifically the mortality rates for patients undergoing chronic RRT.
Study designs and other criteria for inclusion in the review Sources searched to identify primary studies Criteria used to ensure the validity of primary studies Methods used to judge relevance and validity, and for extracting data Number of primary studies included At least five primary studies were included in the review.
Methods of combining primary studies The results of individual primary studies were combined using a narrative method.
Investigation of differences between primary studies Results of the review The five-year all-cause mortality rate was 57%.
Low-risk patients had a four-year all-cause mortality rate of 5% and high-risk patients had a rate of 77%.
Average renal transplantation survival was 92.75%.
The proportion of renal transplantation loss requiring chronic dialysis again was 5.65%.
These data formed part of the input parameters used in the model.
Methods used to derive estimates of effectiveness Experts' opinions were also used to contribute estimates of effectiveness.
Estimates of effectiveness and key assumptions The time span between the onset of ESRD requiring chronic RRT and renal transplantation in those patients with transplantation was estimated to be 7 years.
Measure of benefits used in the economic analysis The number of patient years of chronic long-term dialysis avoided (PYCDA) was used as the measure of benefits. Benefits were discounted using an annual rate of 5%.
Direct costs Direct costs were discounted using an annual rate of 5%. Quantities and costs were reported separately. Direct costs related to the costs of ramipril in outpatient care and the costs of chronic RRT given by dialysis and renal transplantation. The quantity/cost boundary adopted was that of a third-party payer. The cost for renal transplantation and after care was based on expert opinion. Costs related to changes in morbidity were based on the average case-related treatment expenses of third-party payers in Germany. The frequency of different procedures was taken from the Health Report for Germany edited by the Federal Statistical Office and from expert knowledge. The price year for ramipril costs was 1999, whereas the price year for the costs of RRT was 1996.
Statistical analysis of costs Variability in the cost data was dealt with in the sensitivity analyses reported below.
Indirect Costs Indirect costs were not included.
Currency German marks (DM) with DM1 = US$0.55.
Sensitivity analysis Several types of sensitivity analysis were carried out. First, a best-case/worst-case scenario analysis was performed. Second, the cumulative incidence of ESRD was modelled using the Weibull method. Third, the impact of model parameters on incremental cost-effectiveness was quantified by the method of the total differential. Fourth, a Monte Carlo simulation was carried out.
Estimated benefits used in the economic analysis Treatment with ramipril added 3.9 PYCDA (corrected for all-cause mortality) (range: 3.6 - 4.0) at one year, compared with placebo.
Treatment with ramipril added 12.3 PYCDA (range: 10.4 - 13.1) at two years, compared with placebo.
Treatment with ramipril added 21.2 PYCDA (range: 16.3 - 23.7) at three years compared with placebo.
The Weibull method resulted in 1.1 fewer PYCDA per 100 patients after the total period of three years.
Cost results There were net savings with ramipril of DM 295,900 after one year, DM 988,225 after two years, and DM 1,739,170 after three years. There were net savings of DM 133,840 after one year under the worst-case scenario up to DM 3,159,780 after three years under the best-case scenario.
Synthesis of costs and benefits The incremental cost-effectiveness of ramipril over placebo was DM -76,715 after one year, DM -80,660 after two years, and DM -81,930 after three years.
The scenario analysis showed that savings per PYCDA varied between DM 37,000 and DM 130,000 after one year and between DM 45,300 and DM 134,800 after three years.
The cost of chronic dialysis per patient per year had the greatest impact on the amount of savings per PYCDA.
For 95% of the 10,000 simulation steps, the incremental cost-effectiveness of ramipril ranged between DM -69,460 and DM -94,595 per PYCDA.
Authors' conclusions The authors argued that adding ramipril to conventional treatment of hypertension in patients with non-diabetic nephropathy (proteinuria of over 3.0 g per day) was cost-effective.
CRD COMMENTARY - Selection of comparators The comparator was placebo. The rationale for this choice was clear given that it was used in the primary study.
Validity of estimate of measure of effectiveness The analysis was based on a prospective randomised controlled trial, which was appropriate for the study question. The study sample was representative of the study population. The authors reported demographic characteristics of patients in each group and showed that groups were comparable in terms of those characteristics. For the effectiveness data derived from the review/synthesis, the authors did not state that a systematic review of the literature had been undertaken. More details of the search strategy and the method of combining estimates from primary studies could have been provided. Variability in the input parameters used in the model was appropriately tested in the sensitivity analyses.
Validity of estimate of measure of benefit The estimation of benefits was appropriately obtained directly from the effectiveness analysis, by means of the modelling.
Validity of estimate of costs Some good features of the cost analysis were that most relevant direct cost categories were included, quantities and costs were reported separately, and sensitivity analyses were performed on cost estimates. This makes it possible to replicate the results in other settings. The perspective was also clearly stated, but the authors only examined those direct costs reimbursed by a third-party payer. This tends to limit the generalisability to NHS-type health care systems (as in the UK). Indirect costs, expenses for the treatment of adverse events, costs for non-ACE inhibitor anti-hypertensive medication, and costs for medical services incurred by the dose titration of ramipril were not considered. The authors used different reference years for the costs of ramipril and the costs of RRT, whereas one price year would have been preferable from the point of view of other settings/perspectives.
Other issues The authors made appropriate comparisons of their findings with those from other studies, but did not specifically address the issue of the generalisability of the results to other settings. The authors do not seem to have presented their results selectively. The study considered patients with non-diabetic nephropathy and hypertension and this was reflected in the authors' conclusions. The authors performed extensive sensitivity analyses on model parameters to test the robustness of the model and this enhances the reliability of the results. The authors did not discuss transferability issues surrounding the effectiveness estimates from the Italian trial to the German study context.
Implications of the study From the perspective adopted in this study (the German SHI), the findings indicate that adding ramipril to conventional treatment of hypertension in patients with non-diabetic nephropathy (proteinuria of over 3.0 g per day) is cost saving and clinically effective.
Source of funding Funded by Aventis Pharma Deutschland GmbH, D-65812 Bad Soden/Taunus, Germany.
Bibliographic details Schadlich P K, Brecht J G, Brunetti M, Pagano E, Rangoonwala B, Huppertz E. Cost effectiveness of ramipril in patients with non-diabetic nephropathy and hypertension: economic evaluation of ramipril efficacy in nephropathy (REIN) study for Germany from the perspective of statutory health insurance. PharmacoEconomics 2001; 19(5 Part 1): 497-512 Indexing Status Subject indexing assigned by NLM MeSH Angiotensin-Converting Enzyme Inhibitors /economics /therapeutic use; Cost-Benefit Analysis; Female; Humans; Hypertension /complications /drug therapy /economics; Male; Middle Aged; Nephrosis, Lipoid /complications /drug therapy /economics; Ramipril /economics /therapeutic use; Randomized Controlled Trials as Topic; Renal Dialysis /economics AccessionNumber 22001008231 Date bibliographic record published 31/05/2002 Date abstract record published 31/05/2002 |
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