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European Journal of Heart Failure 2002 4(4):553-558; doi:10.1016/S1388-9842(02)00087-9
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© 2002 European Society of Cardiology

Cost-effectiveness of the treatment of heart failure with ramipril: a Spanish analysis of the AIRE study

Warren Mark Harta, Carlos Rubio-Terresb,*, Francisco Pajuelob and Jose R. González Juanateyc

a EcoStat Consulting Group San Sebastián, Spain
b Scientific Department, Aventis Pharma, S.A., Servicios Científicos, C/Martínez Villergas 52, 28027 Madrid, Spain
c Cardiology Department, Complejo Hospitalario de Santiago Santiago de Compostela, Spain

* Corresponding author. Tel.: +34-91-724-5745; fax: +34-91-724-5699 E-address: carlos.rubio{at}aventis.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims: To estimate the cost-effectiveness of adding ramipril to conventional treatment in patients with heart failure after myocardial infarction from the perspective of the Spanish National Health System.

Methods and results: A retrospective analysis of the AIRE study was made, using previously published data from the clinical trial combined with local Spanish resource and cost data. A typical rehospitalisation for a heart failure episode would last an average of 11.6 days with an average cost of {euro}350.80 per day. The incremental cost of ramipril per life-year gained in the baseline case was {euro}1550.10 after 3.8 years of follow-up. Sensitivity analysis showed that the basic conclusions were robust in spite of extreme variations in the values of the key parameters of the model.

Conclusion: The use of ramipril in addition to conventional treatment in heart failure patients after myocardial infarction is cost-effective both according to currently accepted international standards of what constitutes a cost-effective intervention and also indirectly by comparing the results with similar pharmaceutical products financed under the Spanish National Health System.

Key Words: Heart failure • Cost-effectiveness • Ramipril • Spain

Received July 5, 2001; Revised November 22, 2001; Accepted February 4, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure is a major public health problem of increasing magnitude in industrialised nations as a consequence of an ageing population. During the last 20 years the incidence of heart failure has been rising, resulting in an increase in both the number of hospital admissions and deaths caused by the disease [1,2]. Its prevalence, between 1 and 2%, has also increased once again due to an ageing population and also due to better survival after myocardial infarction [3]. Heart failure is typically associated with repeated long hospital admissions and high mortality although this last characteristic has actually been declining in recent years [4–6]. A previously reported Spanish study, described hospitalisation and mortality rates between 1980 and 1993. An increase of 47% in the rate of hospitalisation (congestive heart failure was the leading cause of hospitalisation in persons aged 65 and over, accounting for 5% of all hospital admissions in this group) and a reduction of 23% in the mortality rate was shown [7]. In another Spanish study, the costs of heart failure were estimated to vary between 384.8 and 662.6 million euros and to account for between 1.8 and 3.1% of the overall budget of the Spanish National Health System (NHS) [8].

Since the majority of the total cost of treatment for heart failure can be attributed to hospital care, reducing both the number of admissions and the average length of these admissions could have significant economic consequences [9].

Recent studies have shown that the use of angiotensin-converting enzyme (ACE) inhibitors reduces the number of hospitalisations associated with heart failure and has a positive effect on morbidity and mortality [10–13]. Economic evaluations based on these studies [14–21] indicate that a range of ACE inhibitors are cost-effective, due mainly to an increase in the number of life-years gained and a reduction in the frequency of hospitalisations.

The Acute Infarction Ramipril Efficacy study (AIRE study) investigated more than 2000 patients over the age of 18 with clinical symptoms of heart failure after acute myocardial infarction [13]. The main objective of the AIRE study was to compare the effects of the addition of ramipril to conventional therapy with conventional therapy alone. Of the 1986 evaluable patients who were followed for an average of 15 months (range 6 months to 3.8 years), a significant reduction in total mortality from 23 to 17% was observed. Additionally, the risk of hospitalisation decreased significantly in the ramipril group, from an average 0.965–0.895 hospitalisations per patient.

An economic evaluation was undertaken with the aim of estimating the incremental cost-effectiveness of adding ramipril to traditional therapy for patients with heart failure following myocardial infarction, in the context and perspective of the Spanish NHS.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
Given that the perspective of the evaluation was that of the Spanish NHS only direct costs were included in the analysis. Costs and effectiveness were calculated for four groups according to the duration of the follow-up period (1–3.8 years).

The duration of inpatient hospital stay was not recorded in the AIRE study, hence it was necessary to estimate this parameter from Spanish sources. Specifically a large-scale hospital based survey in a region of Spain (Catalonia) was utilised to obtain these data for heart failure (International Classification of Diseases, no. 428) patients (total admissions and total length of stay from which an average length of stay was derived) [22]. The database included information from over 65 hospitals.

Costs of treatment included the additional cost of ramipril, the cost of hospitalisation and other resource items, including additional outpatient visits as a consequence of the hospital episode (it was assumed that there would be two additional visits). The consumption of other resource items such as concomitant medication, surgical interventions, diagnostic procedures, etc. was assumed not to be statistically different between the two groups.

A modelling approach was used based on a retrospective analysis of the existing data. The incremental cost-effectiveness ratio (ICE) of adding ramipril to conventional therapy was defined as:


Formula 1

(1)
where {Delta}CR refers to the incremental cost of the addition of ramipril to normal treatment, {Delta}CCHF refers to the additional cost of treating heart failure as a result of the effect of ramipril on hospitalisation (can be negative) and {Delta}LY refers to the difference in life-years obtained by adding ramipril. Incremental costs and life-years were estimated per patient and year. By summing these yearly results the incremental cost-effectiveness ratios for the different treatment durations considered was obtained.

The costs of ramipril were estimated on the basis of the daily dosage, the proportion of patients assigned to the ramipril group who actually used the product and the treatment period considered. Mid-yearly values (assuming a uniform distribution) of the proportion of patients on ramipril were calculated and used in the model, as it was assumed that these values would represent more adequately the true use of the ACE inhibitor in each yearly period. The cost of ramipril was obtained from the Spanish Catalogue of Pharmaceutical Specialties [23]. In the analysis this cost was adjusted in agreement with the observation rates and the duration of treatment.

The economic evaluation of the cost parameters was performed using average costs of an inpatient stay in a cardiology ward and an outpatient visit in an ambulatory setting. Costs from various sources from different years were combined and uprated to values for the year 2000 using the general consumer price index (there is currently no specific medical inflation index in Spain) from the National Statistics Institute [24] in Madrid.

The life-years gained as a consequence of intervention with ramipril and its impact on hospitalisation due to heart failure were estimated from the differences between the areas under the survival curves of mortality and of first rehospitalisation between the ramipril and the placebo group. These curves were obtained by the Kaplan and Meier method [25] and the results have been reported previously [26]. It was assumed that on completion of the study patients would have the same average survival rate.

It was necessary to discount both costs and life-years gained in order to determine the net present value of future costs and savings. The currently accepted discount rate suggested in Spain is 6% [27].

Sensitivity analysis was also undertaken. In the base case, the variables that were subjected to sensitivity analysis were the length of hospitalisation per heart failure episode, the cost per inpatient day in a cardiology ward, additional non-hospital costs and the discount rate.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Table 1 indicates the values of baseline variables used in the analysis derived from the AIRE study for the four treatment durations considered. The change in the probability of hospitalisation is negative representing a reduction in hospitalisation due to the addition of ramipril. The last two columns represent the life-years gained in each annual period both with and without discounting.


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  		Table 1 Key clinical data

 
The cost of ramipril was {euro}17.4 for a pack of 28 5-mg tablets. Among the patients assigned to ramipril, 9% received 0 mg per day, 14% received 5 mg daily and 77% received 10 mg daily [13]. Hence the average cost for a full year of ramipril was {euro}380. The length of hospitalisation for an episode of heart failure from the regional hospital database was estimated to be 11.6 days with an associated cost of {euro}350.8 per day based on the average of over 20 sources from hospital annual reports, data presented at scientific meetings and other published studies. In addition to the hospital costs in the base case it was assumed that two additional outpatient visits would be required at a cost of {euro}6.9 per visit. Other resources were included in the sensitivity analysis.

3.1. Cost-effectiveness of ramipril
In Table 2 the costs and incremental cost-effectiveness ratios by year of follow-up are summarised for four different periods. Column two is calculated from the average yearly cost of the ACE inhibitor and the patient time on ramipril. The main reduction in costs is evidently due to hospitalisation, in the base case the contribution of other components that might reduce further the cost of an episode of heart failure is minimal.


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  		Table 2 Baseline cost-effectiveness analysis due to the additional treatment with ramipril to conventional therapy for four periods

 
The baseline results of the cost-effectiveness analysis are presented in the final column with discounting of costs and benefits at a rate of 6%. In the baseline analysis the highest cost per life-year gained is less than {euro}5000. This value is reduced to little more than {euro}1500 per life-year gained after almost 4 years of treatment. There is a reverse in the downward trend of the incremental cost-effectiveness ratio at year 3 due to the increase in hospitalisation of ramipril patients during that year (Table 1).

3.2. Sensitivity analysis
Table 3 summarises the results of the effect on the incremental cost-effectiveness ratio due to changes in the values of key parameters (in the case of the price of ramipril this was not varied as the value used is the current established price in Spain subject to very minor yearly adjustments). The two components that affect the cost of rehospitalisation for heart failure were varied in a two-way sensitivity analysis. The cost per inpatient day was varied from {euro}180 to {euro}540 while the duration of stay was varied between a minimum of 6 days and a maximum of 18 days. All calculations were based on the maximum follow-up period of 3.8 years. The two extremes in the table (6 days at {euro}180 per day to 18 days at a cost of {euro}540 per day) permit an analysis of the stability of the results using extreme values. As is to be expected the incremental cost-effectiveness increases as the cost of a hospitalisation episode is reduced but the incremental cost-effectiveness ratio never exceeds {euro}3000 per life-year gained. At the other extreme, one observes that the option of ramipril added to conventional treatment actually dominates conventional treatment alone in the case of an 18 day stay at a cost of {euro}540 per day. In other words, the additional cost of ramipril is more than compensated for by the savings in reduced hospitalisation in addition to yielding greater clinical benefits.


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  		Table 3 Two-way sensitivity analysis on cost per inpatient day and length of episode of rehospitalisation for heart failure, discount rate and additional cost per episode of rehospitalisation after 3.8 years

 
A further analysis considers the impact of changing the discount rate within a reasonable range. One observes only minor changes as the discount rate is varied from 0 to 10%, an approximate change of {euro}25 per life-year gained per 2% change in the rate of discount. This is to be expected given that the maximum follow-up period is not considerable. Finally, an increase in the non-hospital costs (i.e. additional follow-up visits, further tests, etc.) associated with a rehospitalisation for heart failure was contemplated. These costs were varied between {euro}20 and {euro}100. It is evident that as this cost increases the incremental cost-effectiveness ratio for ramipril improves from {euro}1470 to {euro}1140 per life-year gained. The interpretation of this result is that by ignoring or reducing this component to a minimum (two additional outpatient visits in the baseline case) is not favourable to ramipril and we are hence making a conservative estimate of the incremental cost-effectiveness ratio for ramipril.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The results indicate that ramipril is very cost-effective in the treatment of heart failure after acute myocardial infarction whatever the assumptions or scenarios considered. Although there are no official criteria on what actually constitutes a cost-effective intervention in Spain, by comparing these results with those of other interventions currently reimbursed by the Ministry of Health they suggest that ramipril offers more additional years of life for a given level of investment. Indeed, in the light of the results of other published studies, the baseline cost per life-year gained of {euro}1550 is less than the {euro}3000 to {euro}250 000 described in other Spanish cost-effectiveness studies [28,29] which include interventions used in the prevention of coronary heart disease.

In addition, the economic results for ramipril in the AIRE study compare favourably with those obtained using other ACE inhibitors in the treatment of heart failure. In 1994, Paul et al. [17] developed a decision–analytic model to evaluate the cost-effectiveness of enalapril in comparison with standard therapy. In the base-case scenario, the principal findings of the study were that, relative to standard therapy, the incremental cost-effectiveness ratio for enalapril was $9700 ({euro}10 806) per life-year gained. In another analysis based on data from the Studies of Left Ventricular Dysfunction treatment trial, Butler and Fletcher [30] estimated the cost-effectiveness of enalapril administered over a 4-year period. Results ranged from a net saving to the worst case scenario of $21 737 ({euro}24 215) per year of life saved; a similar analysis performed in the United Kingdom supports the same conclusions [14]. In another study, Tsevat et al. [19] used results from the SAVE trial. Data on costs, health related quality of life, and 4-year survival were obtained directly from the SAVE trial. The basic results suggest that captopril has cost-effective ratio between $3600 and $60 800 ({euro}4010 to {euro}67 731) per QALY depending on age according to the limited-benefit model.

However, care should be taken when making comparisons between the different ACE inhibitor studies, as they do no usually refer to the same patient populations.

Comparisons can be more readily made with the economic evaluations based on the AIRE study which have been undertaken in a number of other European countries. In Germany [26] the average hospitalisation period for treatment of heart failure was 19.8 days given by national administrative statistics and costs per treatment day were obtained from national official statistics. Additional resource consumption in outpatient care directly linked to 1 such rehospitalisation was obtained by a retrospective analysis of commonly collected patient data. A discount rate of 5% was used. Ramipril had an average incremental cost-effectiveness ratio of DM2500 ({euro}1278) per life-year gained after 3.8 years of treatment (costs 1993 and 1995).

In the Swedish analysis [31] hospitalisation costs were derived from a subsample of the largest recruiters of the participating Swedish clinics in the AIRE study. A questionnaire was used to record length of stay in hospital for heart failure (average 8.1 days). The cost per hospital day was obtained from the Swedish Federation of County hospitals. In the baseline analysis the incremental cost per life-year saved was SEK 14,148 (1993 values) ({euro}1500) well within the generally accepted Swedish cost-effectiveness limit of SEK 100 000 ({euro}10 600) and the authors concluded that ramipril was clearly cost-effective.

An average length of stay due to heart failure of 12.2 days was estimated by five clinical specialists in a British evaluation [16]. The resource consumption was evaluated using daily treatment costs from a number of National Health Service hospitals. A discount rate of 6% was used and life-years gained were quantified using the Kaplan and Meier methodology. An extensive sensitivity analysis was undertaken of the key cost and effectiveness parameters. After 3.8 years of treatment ramipril had an incremental cost-effectiveness ratio of £255 ({euro}415) per life-year gained (1993 values).

Although it would appear that ramipril is cost-effective both in Spain and a number of other European countries there are a number of limitations to this study. Data on the length of hospitalisation were not recorded in the AIRE study, hence it was necessary to estimate this value from a Spanish database. However, the value used in the baseline analysis is neither greater nor smaller than the maximum and minimum values used in other European settings and the sensitivity analysis reveals that whatever the assumptions about length of stay or cost per day the basic conclusion remains that ramipril is cost-effective. Assumptions were made regarding the use of additional resources associated with a heart failure admission. However, once again, the sensitivity analysis dealt with this issue and found the results to be quite robust.

In conclusion, in the baseline case, the use of ramipril in addition to conventional therapy represents a cost-effective intervention both by international standards and on a local level the cost per life-year gained is less than other treatments currently financed. It would appear that ramipril is clinically effective at reducing mortality and hospitalisation in heart failure patients after acute myocardial infarction and achieves these benefits for an acceptable economic cost.


   Acknowledgements
 
Source of funding: Aventis Pharma, S.A.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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