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European Journal of Heart Failure 2008 10(9):869-877; doi:10.1016/j.ejheart.2008.06.018
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© 2008 European Society of Cardiology

Cost effectiveness of cardiac resynchronization therapy in the Nordic region: An analysis based on the CARE-HF trial

P. Blomströma,*, M. Ekmanb, C. Blomström Lundqvista, M.J. Calvertc, N. Freemantlec, S. Lönnerholma, G. Wikströma and B; Jönssond

a Department of Cardiology, University Hospital in Uppsala Stockholm, Sweden
b European Health Economics Stockholm, Sweden
c Department of Primary Care and General Practice, University of Birmingham Edgbaston, Birmingham, Uk
d Stockholm School of Economics Stockholm, Sweden

* Corresponding author. Department of Cardiology, University Hospital in Uppsala, SE-751 85 Uppsala, Sweden. Tel.: +46 18 611 3142. E-mail address: per.blomstrom{at}akademiska.se (P. Blomström).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The aim of this study was to investigate the cost-effectiveness of cardiac resynchronization therapy (CRT) in Denmark, Finland and Sweden. The analysis was based on the CARE-HF trial, a randomised clinical trial investigating the efficacy of adding CRT (n=409) to optimal pharmacological treatment (n=404) in patients with moderate to severe heart failure with markers of cardiac dyssynchrony. The average follow-up time was 29.4 months.

Methods: The health effects were measured in terms of quality-adjusted life years (QALYs) gained. Data on health care resource consumption from CARE-HF was combined with costs for CRT implantation and hospitalisation from university hospitals in Denmark, Finland and Sweden. Calculations were based on patients' expected life time. The expected device lifetime (6 years) was used for CRT, and no additional gains in clinical effects were assumed after the 6 years.

Results: The cost-effectiveness ratio per QALY gained was {euro} 4800 in Denmark, {euro} 3600 in Finland and {euro} 6700 in Sweden. The 95% confidence intervals for the cost per QALY gained varied between a lower limit of {euro} 1169 in Finland to an upper limit of {euro} 17,482 in Sweden. These values were all below the threshold for being cost-effective in Denmark, Finland and Sweden.

Conclusion: The study indicates that CRT is a cost-effective treatment in Scandinavian health care settings compared to traditional pharmacological therapy and can therefore be recommended for routine use in patients with moderate to severe heart failure and markers of dyssynchrony.

Key Words: Cost-effectiveness analysis • Exonomic evaluation • Heart failure • Cardiac resynchronization therapy • CARE-HF

Received December 5, 2007; Revised May 28, 2008; Accepted June 30, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Cardiovascular diseases are the most common causes of death in Western societies [1], and are associated with high health care costs [2]. Heart failure has developed into a major public health problem and is the most common primary diagnosis among hospitalised patients aged over 65 years, and the most frequent discharge diagnosis within internal medicine [3]. It is thus currently among the most important causes of morbidity and mortality for elderly people [4].

Standard therapy for heart failure involves diuretics, angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers [5]. Treatment with beta-blockers and ACE inhibitors has proved to be cost-effective [6,7]. Despite improvements in new pharmacological therapy, the prognosis remains poor for many patients with heart failure. The mortality rate is 4 to 8 times higher than that of the general population of the same age [8]. Randomised controlled trials have shown that the addition of cardiac resynchronization therapy (CRT) to standard and optimized pharmacological treatment improves symptoms, exercise capacity, ventricular function, and quality of life, and reduces complications and mortality, in patients with moderate or severe symptoms of heart failure [9]. The CArdiac REsychronization in Heart Failure (CARE-HF) trial has shown for the first time that CRT leads to improved survival in addition to improving symptoms and quality of life [10,11].

CRT is recommended in patients with severe heart failure, i.e. New York Heart Association (NYHA) function class III-IV with broad QRS complex >120 ms, and left ventricular dysfunction with LVEF <35%, who despite optimal pharmacological therapy have not improved [5,9]. CRT is also indicated in patients with severe heart failure if hypotension or bradycardia makes effective medical therapy difficult. Clinical routines associated with device implant procedures, post implant monitoring of patients and device follow-ups may vary significantly between different countries.

The purpose of this study was therefore to assess the cost-effectiveness of CRT in a Nordic health care setting based on the CARE-HF trial. In order to adapt the results from the clinical trial so that the economic evaluation accurately reflects the cost-effectiveness in the Nordic countries, we used data from CARE-HF, combined with information from Nordic data sources on unit costs for CRT and hospitalisations.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Clinical data
The CARE-HF trial included 813 patients with heart failure due to left ventricular systolic dysfunction and markers of cardiac dyssynchrony [10]. Patients were randomised (with stratification by NYHA class) to receive pharmacological therapy alone (n=404) or in combination with CRT (n=409). The primary end point was death from any cause or an unplanned hospitalisation for a documented major cardiovascular event. Major events included worsening heart failure, myocardial infarction, unstable angina, arrhythmia, stroke, or other major cardiovascular event (e.g., pulmonary embolism or ruptured aortic aneurysm). Hospitalisation due to a serious procedure-related complication (e.g. infection, pericardial haemorrhage, or tension pneumothorax) was also counted as a major event. Only the first event in each patient was included in the analysis. The principal secondary end point was death from any cause. Quality of life, which was also a secondary end-point, was measured with the Minnesota Living with Heart Failure (MLWHF) questionnaire at baseline, 3 months, 18 months, and the end of study, and the EuroQoL EQ-5D instrument at baseline and 3 months [10,12,13]. The mean follow-up time was 29.4 months. The primary end point was reached by 159 patients in the CRT arm, compared with 224 patients in the arm receiving pharmacological treatment alone (HR 0.63; 95% CI 0.51 to 0.77; P<0.001). There were 82 deaths in the CRT arm, compared with 120 in the medication arm (HR 0.64; 95% CI 0.48 to 0.85; P<0.002) [10].

2.2. Health economic analysis
The economic study type used included a cost-effectiveness analysis, thus including any economic analysis with a clinical effectiveness outcome, and a cost-utility analysis. The outcome unit used to measure cost-effectiveness was cost per quality-adjusted life-years gained (QALYs), which not only measures cost-effectiveness in terms of longevity but also takes into account improvements in lifestyle, assessing quality of life using the EuroQoL EQ-5D questionnaire. Apart from QALYs, effectiveness was measured in terms of survival gained due to CRT, during the clinical study and extrapolated beyond the trial [14].

The cost per QALY gained was then compared to a threshold value, i.e. the "willingness to pay" (WTP) per QALY gained, which should reflect how much a target group (general public or a group of patients) would be willing to give up (from surplus income) to acquire an additional QALY.

Health utilities based directly on the EQ-5D score were available in the study at baseline and three months. Health utilities were estimated at 18 months and the end of study based on a mixed model of the relationship between change in EQ-5D score to change in MLWHF as described by Calvert et al. [15]. A utility of zero was applied to patients at death. For the extrapolated analysis, beyond the end of follow-up in the clinical trial, a last observation carried forward approach was used, which means that the last utility for each patient was applied to further lifetime gains.

2.2.1. Survival analysis
Two different approaches were used to estimate survival benefit due to CRT. For the main analysis, extrapolated survival beyond the clinical trial was used in order to capture the long-term benefits of CRT therapy. The survival time within the trial follow-up period was estimated from Kaplan-Meier curves. We assumed that patients surviving throughout the clinical trial had an expected additional lifetime that was determined by fitting a parametric survival function to the clinical-trial data, accounting for age. It was assumed that the survival in the treatment and control group followed two different exponential survival curves estimated from the respective within-trial survival curves for up to six years after randomisation (equal to the estimated lifetime of the battery). After six years, the mortality rate was equalized in both groups and followed an exponential survival curve estimated from the whole patient sample (treatment group and control group together). The patients were followed for life. These assumptions were varied in the sensitivity analyses (see below).

For the within-trial approach, only costs and health effects accrued within the follow-up time were accounted for.

In Fig. 1, a schematic description of the approach is shown. The extrapolated curves in Fig. 1 start when trial follow-up ends, which means that the extrapolated survival curve will start at a higher level in the CRT group compared with the control group. The difference in survival can then be illustrated as the difference in area between the total survival curves (Kaplan-Meier curves from trial continued with extrapolated survival curves). However, the actual calculations were performed on a patient-per-patient basis. For individual patients alive at the end of follow-up, the survival was modelled as the sum of the follow-up time within the trial, and simulated survival times stochastically drawn from exponential distributions.


Figure 01
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  		Fig. 1 Within-trial survival and predicted survival curves beyond the end of follow-up in the clinical trial. CRT=Cardiac resynchronization therapy.

 
2.2.2. Estimation of costs
The health care resources used were identified from the clinical study. Hospitalisation costs were collected from local and national sources in Denmark, Finland and Sweden. Costs are expressed in Euros and in 2006 prices. Whenever needed, prices were converted to 2006 prices by using the consumer price index for each country [16-18]. Since there were no significant differences between the treatment group and the control group in terms of pharmaceutical consumption, the pharmaceutical costs were excluded from the analysis.

The inpatient care cost was calculated in two ways depending on the type of hospitalisation. It was either based on cost per hospital admission as measured by diagnosis-related groups (DRGs), for events such as CABG, PCI and heart transplantation, or based on cost per day for other cardiovascular hospitalisations, e.g. worsening of heart failure. The DRG prices were based on official hospital price lists and other published sources [19-28]. The cost for cardiac outpatient visits and the cost per day in cardiology, intensive care unit (ICU) and cardiac care unit (CCU) stay, and other wards, were also extracted from hospital price lists [19-27,29,30]. The unit costs from hospital price lists are listed in Table 1.


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  		Table 1 Unit costs ({euro}) from hospital price lists

 
The costs for CRT device, implantation procedure and hospitalisation were taken from the actual costs from clinics that perform these procedures in Denmark, Finland, and Sweden. In Sweden, for example, the costs were based on figures from seven university hospitals, representing all the major centres where CRT devices are implanted. The cost for CRT devices and implantation procedures was then estimated as the mean cost of the figures obtained from the centres. We treated the complete cost for device, implantation procedure and hospitalisation as one unit, and did not make any separate estimate of the device costs (including leads), and the costs for implantation procedure and hospitalisation. Since a surviving patient may have use of the device for several years beyond the follow-up of the trial, the cost was calculated as an annuity, i.e. a yearly stream of fixed costs over the lifetime of the device, rather than as a lump sum cost at the time of the intervention [31]. The full cost of the device was attributed to patients who died or were transplanted. For patients with CRT who survived until the end of the study the costs were spread over the entire battery lifetime of the device, i.e. 6 years in the main analysis.

In the main analysis, both the health effects and the costs were discounted at a rate of 3% [32].

2.3. Methods used to investigate uncertainty of data
2.3.1. Statistical simulation techniques
Bootstrapping is a statistical method for estimating the sampling distribution of an estimator by sampling with replacement from the original sample [33]. The methodology used here for estimating the uncertainty of the data combines bootstrap resampling of data from the clinical trial with stochastic modelling of the expected remaining lifetime after the clinical trial for the patients who were alive after the end of follow-up. Resampling was performed for the CRT group and for the control group separately. In each group, 2000 resamples with sizes equal to the original sample sizes were drawn with replacement (n=409 for CRT and n=404 for control). Each individual patient who was resampled from the clinical trial data by the bootstrap technique, and who was alive at the end of follow-up, was assigned an expected additional lifetime drawn from an exponential distribution. The confidence intervals were then calculated by the percentile method, i.e. to obtain a 95% confidence interval, we take the 0.025*Nth and 0.975*Nth largest values estimated through bootstrap resampling (N=2000). Unless otherwise stated, the level of significance was 5%. In cases where the confidence interval for the cost-effectiveness ratio had an ambiguous interpretation because of the statistical distributions of costs and health effects, the net benefit method was used instead [34]. The WTP per life year gained was set to {euro} 50,000 in the net benefit method. The choice of {euro} 50,000 as WTP per life year is in line with valuations used in previous studies [35]. The net monetary benefit is then calculated as "Mean difference in Life Years per patient"*"Willingness to Pay per Life Year"–"Mean cost per patient".

2.3.2. Sensitivity analysis
This analysis tests the robustness of the analysis. The deterministic variables for which there is uncertainty are varied over a range and the related changes in the final results are analysed.

The uncertain parameters that were judged to be critical for the cost-effectiveness results in the main analysis, and for which the sensitivity was assessed, were the average additional lifetime after the end of follow-up, the discount rate, and the difference in survival between the CRT group and the control group. The discount rate for both costs and health effects was varied between 0% and 5%. The discount rate for the health effects was also set to 0%, while keeping the discount rate for costs at 3% in the main analysis. The assumption regarding the survival after the end of follow-up was varied in several ways [36]. In the main analysis, different survival curves were assumed for the treatment and the control group for 6 years. Then the same survival curve was used in both groups for the remaining lifetime.

The sensitivity analyses further tested the following four situations: 1) the same mortality rate was assumed for all after the end of follow-up, and a timeframe of up to six years for patients alive at the end of follow-up; 2) differences in mortality rates were assumed to persist in the treatment and the control groups after the end of follow-up, as the survival curves in the study seem to diverge rather than converge over time [11] within a 6 year timeframe; 3) the same assumptions as in the first case, but no truncation of survival at 6 years; and 4) different mortality rates in both groups after the end of follow-up for the whole of the remaining lifetime of the patients.

The sensitivity of the within-trial results to device lifetime was also assessed by varying the device life between 5 and 7 years. This was not performed for the base-case analysis, because the extrapolated results are relatively less affected by the device lifetime as the complete cost of the device was always accounted for in this analysis, while it was not for those who survived beyond the follow-up time in the within-trial analysis.

A cost-effectiveness acceptability curve was produced to describe the uncertainty surrounding the estimate of cost-effectiveness, and shows the probability that an intervention is cost-effective compared with the alternative for a range of threshold values for the willingness to pay per QALY [37].


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Main results
The costs associated with medical therapy and additional CRT therapy, are shown in Table 2. The results indicate that Sweden had the highest costs and Finland the lowest costs both in the CRT arm and for medical therapy alone. The incremental cost per QALY gained associated with CRT therapy was also higher in Sweden with a cost per QALY gained of {euro} 6493 (95% CI: {euro} 2669-17,482), compared to {euro} 3571 in Finland (95% CI: {euro} 1169-10,153). Denmark was in the middle with a cost per QALY gained of {euro} 4759 (95% CI: {euro} 1553-12,637).


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  		Table 2 Cost and health effects in the main analysis

 
Fig. 2 shows the cost-effectiveness acceptability curves for the main analysis in Denmark, Finland and Sweden. Given a willingness to pay threshold larger than {euro} 50,000 per QALY, the probability that CRT is cost-effective is above 99% for all three countries.


Figure 02
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  		Fig. 2 Cost-effectiveness acceptability curves for the base-case analysis ({euro}). QALY=Quality-adjusted life year.

 
3.2. Within-trial analysis
The results from the within-trial analysis are shown in Table 3. Compared to the main analysis, which was based on an analysis extended beyond the clinical trial, both costs and health effects are lower. The cost per QALY was once again the highest in Sweden with a cost per QALY gained of {euro} 9425, compared to {euro} 5040 in Denmark and {euro} 2610 in Finland. In the analysis for life years gained, the net benefit approach was used, as the confidence interval was not well defined due to statistical reasons. The net monetary benefit per patient was {euro} 3949 in Denmark, {euro} 4466 in Finland, and {euro} 2899 in Sweden.


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  		Table 3 Cost and health effects in the within-trial analysis

 
3.3. Sensitivity analysis
The results of the sensitivity analyses show that the cost-effectiveness results are relatively stable for variations in the discount rate, and the battery lifetime of the CRT device (Table 4). The largest variation was obtained by varying the survival assumptions after the end of follow-up. For Denmark, for example, the ICER is {euro} 9915 per QALY gained if the same mortality rate is assumed for all patients after the end of the clinical trial, and the analysis truncated at 6 years. If different survival curves are modelled for CRT and the control group for the entire lifetime of the patients, then the ICER falls to {euro} 3064 per QALY gained. Similar patterns were observed for Sweden and Finland, and in no cases were the variations in results large enough to change the conclusions from the analysis.


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  		Table 4 Sensitivity analysis

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In the main analysis, the cost-effectiveness ratio per QALY gained was {euro} 4800 in Denmark, {euro} 3600 in Finland and {euro} 6500 in Sweden. The 95% confidence intervals for the cost per QALY gained varied between a lower limit of {euro} 1169 in Finland to an upper limit of {euro} 17,482 in Sweden. A notable difference between the main analysis and the within-trial analysis is that the lower limit of the confidence interval was not defined in the latter as CRT was cost saving. In the extended analysis the complete cost for device, implantation, and hospitalisation were included, but not in the within-trial analysis. With a mean follow-up of 29.4 months, and a battery lifetime of 6 years, less than half of the total cost for device and implantation is included in the within-trial analysis. This also gave a higher variability in the analyses of uncertainty, and wider confidence intervals.

4.1. The rationale for using an extended analysis
As noted by Calvert et al. [15], the within-trial approach underestimates the total benefit of CRT, since survival is truncated at the end of follow-up. In the present analysis we instead used an extended analysis as main analysis, which in our opinion may give a more realistic estimate of the health benefits of CRT. The within-trial approach to estimating the health effects is conservative, as more patients were alive at the end of follow-up in the treatment group than in the control group. Even if the mortality rates would be equal in the treatment groups after the end of follow-up, the treatment that was superior at the end of follow-up would continue to accumulate life expectancy gains after the trials ends [36]. Our approach in this study may therefore offer a more realistic picture of the long term benefits of CRT than a within-trial approach. This was the primary rationale for using the extended analysis as main analysis in the present study.

4.2. Comparison with previous studies
An economic evaluation using costs based on a UK healthcare perspective was performed based on the results from the CARE-HF trial [15]. This was the first cost-effectiveness analysis of CRT using within-trial analysis on the basis of data from a large, prospective, randomised, controlled trial. In the within-trial analysis of our study, the analysis was performed essentially according to the same methodology as in Calvert et al. [15], but with the difference that the complete cost for device, implantation and hospitalisation were transformed to a 6-year annuity rather than the device cost alone. If the present study had used a methodology similar to the one used in the UK analysis by Calvert et al. for the within-trial analysis, the results would also have been very similar. For a within-trial analysis with only the device costs distributed as an annuity, the ICER would have been {euro}17,804 per QALY gained in our analysis, which is quite close to the incremental cost-effectiveness ratio in the UK study, which was {euro}19,319 per QALY gained (95% CI: {euro}5482-45,402). In the UK analysis, only the cost for the device was treated as an investment and distributed as an annuity over 6 years. In the within-trial analyses for the Nordic countries, both the device and implantation cost was treated as an investment. We think that this is a reasonable approach, given that without the implantation, the device is obviously not of much use to the patient. It therefore makes sense to treat the implantation cost (including hospitalisation) as part of the total investment cost for the device. A question may then be: What about treating, for example, the cost for a CABG in the same way? An important difference between CRT and CABG is, however, that it is less clear how the "lifetime" of a CABG procedure should be defined, whereas the battery lifetime of a CRT device can be regarded as a natural timeframe for treating also the implantation and hospitalisation cost associated with CRT as an investment. A further difference between our analysis and the UK study is that we did not treat hospitalisation after the implantation as a separate post. Since the current length of stay for CRT implantation is on average shorter in the Nordic countries than in CARE-HF, this contributes to the slightly lower cost differences in our analysis.

Yao et al. constructed a Markov model with Monte Carlo simulation to assess costs, life years, and QALYs associated with CRT (±ICD) and medical therapy alone in patients with heart failure and cardiac dyssynchrony based mainly on data from CARE-HF [38]. For a patient who is 65-years-old when therapy is initiated, the incremental cost-effectiveness of CRT compared with medical therapy alone was estimated at {euro} 7538 per QALY gained (95% CI {euro} 5325-11,784), and {euro} 7011 per life year gained (95% CI {euro} 5346-10,003). This is quite close to the main analysis for Sweden in this analysis. The difference can probably be explained by one of the limitations in our study. We did not assume any extra costs for CRT after 6 years, which means that the costs are assumed to be equal in both groups. Even though we assumed that the mortality rate would also be equalized after 6 years, there is still a survival benefit in the CRT group after this point in time, since more patients are alive in the CRT group at 6 years after randomisation. In the analysis by Yao et al. [38], on the other hand, batteries were assumed to be replaced for surviving patients in the CRT group every 6 years, with a battery replacement cost equal to the device cost plus one cardiac out-patient visit day.

The beneficial effects of CRT on symptoms, quality of life, ventricular function, and blood pressure found in the CARE-HF trial are similar to those reported in previous trials, e.g. the COMPANION trial [10,39]. The COMPANION trial showed a significant reduction in mortality if CRT was combined with an implantable defibrillator, but the CARE-HF trial was the first to show a significant reduction in mortality from CRT alone [10]. The results from an economic evaluation based on the COMPANION trial indicated that CRT via pacemaker or pacemaker-defibrillator in combination with pharmacological therapy is cost-effective relative to pharmacological therapy alone, according to generally accepted threshold values for the cost-effectiveness ratio [40]. The cost-effectiveness ratios were $19,600 and $43,000 per QALY gained for CRT via pacemaker and pacemaker-defibrillator respectively.

4.3. Threshold value for the cost-effectiveness ratio
A conclusion regarding the cost-effectiveness of a treatment requires a defined threshold level for the cost-effectiveness ratio. The threshold generally represents the maximum societal willingness to pay per life year or quality-adjusted life year (QALY) gained. However, there is no widespread consensus regarding the highest acceptable cost per QALY gained [35,41]. The WHO has argued for international threshold values of three times the gross domestic product per capita [35]. In the US, threshold values of $ 50,000-100,000 per year of life gained have been recommended in some studies [42,43]. In a survey among health economists about what threshold value to use in a cost-effectiveness analysis, Newhouse reported a mean value of $ 60,000 per year of life gained [44]. In Sweden, values around $100,000 ({euro} 70,000) have been mentioned based on the willingness to pay for saving lives on the Swedish roads [45].

Even if there is no formal threshold for the cost-effectiveness ratio, the cost per QALY gained that was found in this analysis may be considered as favourable [41,44]. The median cost per QALY gained ranged from a minimum {euro} 1222 in Finland a maximum of {euro} 13,882 in Sweden. If a methodology similar to the one used in the cost-effectiveness study by Calvert was used, the cost per QALY for Sweden was {euro} 17,804, which may still be considered as cost-effective. The upper bounds of the 95% confidence intervals for the cost-effectiveness ratio also appear to be acceptable given the discussed thresholds, with the highest one in the sensitivity analysis being {euro} 33,863 per QALY gained for Sweden.

4.4. Limitations
The extrapolation of survival from the clinical trial results requires a number of assumptions that can be difficult to validate. Although survival beyond the trial was estimated based on data from the trial, it is difficult to know whether this accurately reflects the uncertainty that would be observed with long term follow-up in a real-life setting. Another limitation is that we used a last-value-carried-forward (LVCF) approach for the estimation of QoL after the end of the clinical trial. The pharmaceutical costs were excluded from the analysis, as there was no significant difference between the CRT group and the control group in consumption of pharmaceuticals. This might introduce a bias, as patients in the CRT group live longer and may therefore consume more pharmaceuticals over the long term. However, in the within-trial analysis, there was no indication that the patients in the CRT group consume more pharmaceuticals despite a slightly longer average follow-up time due to better survival.

In conclusion, these results show that CRT is a cost-effective treatment in Scandinavian health care settings compared to traditional pharmacological therapy and can therefore be recommended for routine use in heart failure patients with markers of dyssynchrony.


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

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