1CORE Center for Outcomes Research, Basel, Switzerland, 2HEDM, Health Economics and Disease Management, Meise, and Ghent University, Ghent, Belgium, 3Section of Nephrology, Rush-Presbyterian St Lukes Medical Center, Chicago, Illinois, USA and 4Service de Néphrologie, Centre Hospitalier Universitaire de Grenoble, France
Correspondence and offprint requests to: Dr Andrew J. Palmer, CORE Center for Outcomes Research, St Johanns-Ring 139, CH-4056 Basel, Switzerland. Email: ap{at}thecenter.ch
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Abstract |
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Methods. A Markov model simulated progression from nephropathy to DSC, ESRD and death in patients with hypertension, type 2 diabetes and overt nephropathy. Treatment-specific probabilities were derived from IDNT. Country-specific ESRD-related data were retrieved from published sources. Delay in onset of ESRD, life expectancy and mean lifetime costs were calculated for patients with a baseline age of 59 years. Future costs were discounted at 3% per annum (p.a.), and clinical benefits were discounted at 0 and 3% p.a.. Extensive sensitivity analyses were performed.
Results. Onset of ESRD was delayed with irbesartan by 1.41 and 1.35 years vs amlodipine and control, respectively. When a 10-year time horizon was considered, delay in ESRD onset led to anticipated improvements in life expectancy of 0.13 years vs amlodipine and 0.26 years vs control. Irbesartan was associated with cost savings of €14 949 and €9205/patient in Belgium, and €20 128 and €13 337 in France, vs amlodipine and control, respectively. The results were robust under a wide range of plausible assumptions.
Conclusions. Treating patients with hypertension, type 2 diabetes and overt nephropathy using irbesartan was both cost- and life-saving compared with amlodipine and control.
Keywords: amlodipine; hypertension; irbesartan; nephropathy; type 2 diabetes
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Introduction |
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The Irbesartan in Diabetic Nephropathy Trial (IDNT) was a multicentre, double-blind, placebo controlled study assessing the effect of irbesartan (angiotensin II-receptor blocker) vs amlodipine (dihydropyridine calcium channel blocker) or placebo on the progression of diabetic renal disease and all-cause mortality in hypertensive patients with type 2 diabetes and proteinuria [3]. Irbesartan treatment resulted in a reduction of 23% in the combined endpoint of death, ESRD and doubling of serum creatinine (DSC) compared with amlodipine (P = 0.006) and a 20% reduction compared with the control group (P = 0.02). We developed a Markov model (a common approach to simulate long-term progressive diseases [4]) to extrapolate the results of the IDNT and project long-term clinical and cost outcomes. This article provides a description of the methodology used and reports the findings of this long-term simulation. While other treatment agents like ACE inhibitors are also used in this patient group, and health-economic comparisons with ACE inhibitors and other medications would be interesting if appropriate clinical data were available, we restricted the analysis to the treatments assessed in the IDNT due to lack of direct clinical comparisons between angiotensin II-receptor blockers and ACE inhibitors.
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Subjects and methods |
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In this analysis, the model consisted of five primary health states (Figure 1), with all patients starting in the no progression state:
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Clinical data inputs (transition probabilities)
Probabilities from the states no progression and DSC are summarized in Table 1. The duration of the IDNT was up to 5 years with 2.9 years as the mean length of total patient follow up. Transitional probabilities for the first 3 years of the model were obtained from the actual number of annual events in the IDNT clinical trial. For the remainder of the model, an average of probabilities across those first 3 years was used for each arm.
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Mortality rates for patients in the no progression and DSC states were assumed to be equal as there is no evidence that patients with DSC (and not progressing to ESRD) have a higher mortality rate than those without DSC. To calculate the annual probabilities of dying, the mean annual death rates in each treatment arm over the 2.9-year follow up period were converted to transition probabilities using the RatetoProb function of the DATA software. For the first 10 years of the model, mortality data from the IDNT were used [3].
Age was taken into account from year 10, based on the published evidence that mortality doubles every 10 years in type 2 diabetes patients [7]. Mortality was age-adjusted by doubling it with every 10-year increase in age (after the first 10 years of simulation).
When a simulated patient developed ESRD, the probabilities of death or changing between the dialysis and renal transplant states were assumed to be independent of treatment arm. The model outcome was adapted to the French and Belgian settings by incorporation of country-specific ESRD management and outcomes data for Belgium and France where available (Table 2) [810]. There were two main exceptions to this:
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To determine study drug medication costs (irbesartan 75, 100 and 300 mg, and amlodipine 2.5, 5 and 10 mg), exposure time by dose was calculated for all patients in the IDNT study. The cost of each dose was calculated from the INAMI tariffs for Belgium and the VIDAL database for France. The cost of study medication was calculated by dividing the number of days exposed to each dose by the number of patients, multiplied by the mean duration of follow up, multiplied by the cost of that dose (Table 3).
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Cost estimates for transplant or dialysis due to ESRD were based on total third party reimbursement (Table 4) [8,1115]. Cost figures specific to ESRD of diabetic aetiology (or better still, type 2 diabetes aetiology) were not available for Belgium. However, Lins has reported full annual costs of managing patients with ESRD in Belgium based on reports from nephrology centres, which were used for this analysis [8,12]. These figures related to all patients treated with renal replacement therapy. Cost estimates for France were derived from several sources. Jungers et al. [11] reported the following distribution of dialysis patients for Ile-de-France: 68.3% in-centre; 31.7% out-centre (self-care haemodialysis 18.5%, home haemodialysis 1.7%, or peritoneal dialysis 11.6%). Engel et al. [14] published the specific cost of diabetic ESRD patients. Taking into account the relative weights of the different types of dialysis [11], a cost of €56 768 per year was estimated. Average length of hospital stay was estimated to be 13.4 days at a cost per day of €327.72 [15,16]. Taking the cost of hospitalization into account, the total cost for dialysis in France was €61 159. These figures relate to diabetes patients (not subdivided by type of diabetes); Cogny et al. [13] described transplantation costs for a single centre in France. Costs of transplantation in the first, second and third years were calculated to be €19 026, €6306 and €5309, respectively. These costs did not include the costs of more recent immunosuppressive therapy like tacrolimus. The addition of tacrolimus to the immunosuppressive regimen may not necessarily increase the total costs associated with transplantation, as the acquisition costs of the medications are offset by reductions in hospitalizations and rejections. It is therefore unclear if the exclusion of tacrolimus from the cost analysis following transplantation leads to an under- or over-estimation of the total costs following transplantation [17]. Costs were converted to 2002 values based on a 3% annual actualization rate.
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Sensitivity analysis
One-way sensitivity analyses were performed on total costs and life expectancy to assess the impact of different assumptions on the results. The impact of discount rates for costs and life expectancy was evaluated by varying discount rates between 0 and 6%. Sensitivity analysis was performed on the extrapolation of transition probabilities beyond the 3-year trial period. In the base case analysis, transitional probabilities for the first 3 years of the model were obtained from the actual number of annual events in the IDNT clinical trial. For the remainder of the model, an average of probabilities across those first 3 years for each treatment arm was used. As an extremely conservative assumption for sensitivity analysis, it was assumed that the probabilities would return to those of the control group after the 3-year trial period in all treatment arms (i.e. only the within-trial effects of irbesartan and amlodipine were considered).
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Results |
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In the Belgian setting life expectancy was improved in the irbesartan group compared with the amlodipine and control groups, as anticipated from the delayed onset of ESRD. Non-discounted life expectancy (discounted at 3% p.a. shown in brackets) was 10.59 (8.57) years with irbesartan, 9.88 (8.11) years with amlodipine and 9.68 (7.95) years in the control group. This corresponds to improvements with irbesartan of 0.71 (0.46) years vs amlodipine and 0.91 (0.62) years vs control. When a 10-year time horizon was used, improvements in undiscounted life expectancy (discounted shown in brackets) with irbesartan were 0.13 (0.10) and 0.26 (0.22) years vs amlodipine and control, respectively. In addition, total lifetime costs were lower in the irbesartan cohort than in the other treatment groups. Total lifetime costs (discounted 3% p.a.) were €76 777 with irbesartan, €97 940 with amlodipine and €88 662 with control (cost savings of €21 163 and €11 885 for irbesartan vs amlodipine and control, respectively). After 10 years, cost savings of €14 949 and €9205 vs amlodipine and control, respectively, were projected (Figure 3).
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Breakdown of the per patient costs revealed that the cost of irbesartan and amlodipine made up 24% of the total costs considered in this analysis, whereas ESRD costs contributed to 9499%. Reduction in ESRD costs in the irbesartan treatment arm was one of the major factors that led to overall cost savings in the irbesartan treatment arm (Table 5). The cost savings were due mainly to ESRD avoided with irbesartan and became evident after 3 years of treatment. In the Belgian setting, after only 5 years, costs savings were €5180 and €2973 vs amlodipine and control, respectively. In the French setting after 5 years, cost savings were €7557 and €5058 vs amlodipine and control, respectively. Eighty per cent of the overall savings were achieved within 911 years of treatment (Figure 3).
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The parameter with the greatest single impact on life expectancy was the annual probability of death in the state no progression (taken from the IDNT), closely followed by the annual probability of death in the state ESRD treated with dialysis (taken from country-specific published sources). It was calculated that irbesartan would remain life saving compared with amlodipine with up to a 14% increase in the probability of dying in the no progression state in the irbesartan treatment arm. In comparison with placebo, irbesartan remained life saving with up to a 21% increase in this probability.
The parameter with the greatest single impact on total lifetime costs was the annual costs of dialysis. In the unlikely case that the costs of dialysis in Belgium fell below €3220 (compared with €44 580 used in the base case analysis), irbesartan would no longer be cost saving compared with amlodipine. The annual cost of irbesartan had the fourth greatest impact on total lifetime costs. The annual cost of irbesartan treatment would have to be higher than €1680 per patient (compared with the current cost of €353.66) to lead to an overall cost increase compared with no treatment (or €2764 compared with amlodipine).
Under the conservative assumption that only the within-trial (first 3 years) effects of irbesartan and amlodipine were considered (after which transition probabilities corresponded to those of the control arm), non-discounted life expectancies (discounted at 3% shown in brackets) in the Belgian setting were 9.98 (8.17) years for irbesartan, 9.76 (8.02) years for amlodipine and 9.68 (7.95) years for the control arm. Total lifetime costs were €88 213 in the irbesartan group, €93 697 for amlodipine and €88 662 in the control group. Thus, even with very conservative assumptions about the long-term effectiveness of the medications, irbesartan remained both cost and life saving compared with amlodipine and control.
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Discussion |
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This is confirmed by the present modelling study, which demonstrated that a reduction in progression to DSC and ESRD associated with irbesartan treatment leads to an important improvement in life expectancy and reduction in total lifetime costs of medications and ESRD per patient compared with treatment with amlodipine or control. The anticipated gains in non-discounted life expectancy (due to delay in the onset of ESRD) compare very well with other established interventions in health care [18]. Cost savings with irbesartan treatment instead of amlodipine or standard blood pressure control alone begin to occur after 3 years of therapy (the within-trial period of the analysis).
The results of the model were robust under a wide range of plausible assumptions about the long-term effectiveness of drug therapy and costs of complications and medications, even in the extreme case assuming no effect of irbesartan or amlodipine after the 3-year trial period. This sensitivity analysis indicates that the conclusion of the study would probably not change in a real-life setting, even taking into account the difference between efficacy in the clinical trial situation (as in the IDNT) and real-life effectiveness.
There were some limitations in this modelling study. Data derived from the IDNT were applied whenever possible in the model. Some of these probabilities, although different within treatment arms, were not statistically significant. This is often the case when a clinical trial is used as a basis for an economic analysis, as the trial is powered to show a difference only in the primary endpoint, which is not the only relevant endpoint used in an economic analysis. For example, the probability of death from any cause was not significantly different between treatment arms after the within-trial follow up period, but the IDNT was not powered for an analysis of this secondary outcome [5]. However, the significant delay in the onset of ESRD seen with irbesartan during the trial period was projected to lead to important improvements in life expectancy, primarily due to avoidance of the excess mortality associated with the onset of ESRD. The sensitivity analyses revealed that those probabilities, which were significantly different in the IDNT (for example progression to DSC) had a large impact on the outcomes, and variation of these probabilities within plausible ranges did not alter the relative outcomes. The mortality probabilities following transplantation were taken from US figures, and included racial subgroups with higher mortality rates. This may have led to a slight over-estimation of the mortality, although the impact on the results is minimal due to the low rates of transplantation in Belgium and France. On the other hand, we assumed that there was no increase in mortality when patients progressed to DSC. Because irbesartan delayed progression to DSC, this may have led to an under-estimation of the associated improvements in life expectancy.
The ESRD treatment costs used in the model were not type 2 diabetes-specific. In the US setting, costs of renal replacement therapies are typically higher for diabetes patients than other patients [10]. Additionally, the costs for transplant maintenance in France were derived from a period when the use of tacrolimus and other expensive immunosuppressive agents was not common. These two factors led to a possible underestimation of the costs of renal replacement therapy compared to the current approach with more expensive immunosuppressants, in turn leading to an underestimation of the cost savings to be expected with irbesartan.
It should be noted that the population of the IDNT represented patients with advanced diabetic nephropathy, and as such these results should only be taken in the context of these patients and not in those with microalbuminuria. Moreover, the purpose of the IDNT was to investigate the effects of irbesartan, amlodipine or placebo on the progression to DSC, ESRD or death from any cause, independent of blood pressure control. In all three treatment arms, blood pressure at baseline was similar. During the study follow up, there was no significant difference in mean arterial blood pressure between the amlodipine and the irbesartan groups, but the control group had a mean arterial blood pressure 3.3 mmHg higher than the two active groups. The differences in outcomes between the active groups cannot, therefore, be explained by differences in blood pressure control, but instead may lie in the different mechanisms of action irbesartan and amlodipine. When the disparity in blood pressure control between the irbesartan and placebo groups was adjusted for, the magnitude of renal benefit afforded by irbesartan did not decrease significantly [3].
One of the main limitations of the study relates to the fact that the model does not consider ACE inhibitors, beta-blockers or other angiotensin 2-receptor blockers as treatments for type 2 diabetes patients with hypertension and nephropathy. In this analysis we attempted to model the health economic outcomes of the IDNT and were therefore limited to the treatment arms included in this particular trial. In fact, no head-to-head clinical comparisons of irbesartan and ACE inhibitors, beta-blockers or other angiotensin 2-receptor blockers have been published in this population at the time of writing, making direct comparison in the modelling setting difficult. The cost-effectiveness of angiotensin-receptor blockers vs ACE inhibitors would be particularly interesting when appropriate clinical data become available. Data from a study of ACE inhibitors in non-diabetic renal patients has indicated that benazepril is cost saving in the US setting [19]. Treatment of patients with chronic renal insufficiency with benazepril was associated with a total cost saving of more than USD 4000 ( €3692) per patient over 3 years and USD 23 500 (
€21 690) per patient when extrapolated to 10 years. The data suggest that ACE inhibitor treatment has a significant impact on costs for renal patients and highlight the need for clinical studies comparing antihypertension therapies in patients with type 2 diabetes, hypertension and nephropathy to form the basis of an economic investigation.
In conclusion, this modelling study demonstrated that the delay in progression to DSC and ESRD by treating patients with type 2 diabetes, hypertension, and overt nephropathy with irbesartan led to both reductions in overall costs and anticipated improvements in life expectancy compared with treatment with amlodipine or antihypertensive therapy alone.
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Acknowledgments |
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Conflict of interest statement. All authors involved received consultants fees from Bristol-Myers Squibb and Sanofi-Synthelabo.
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References |
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