1Department of Primary Care and General Practice, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
2Department of Cardiology, University of Hull, Castle Hill Hospital, Kingston upon Hull, UK
3Department of Cardiology, Hôpital Pontchaillou, Rennes, France
Received 21 October 2005; revised 3 November 2005; accepted 4 November 2005; online publish-ahead-of-print 11 November 2005.
* Corresponding author. Tel: +44 0121 414 7943; fax: +44 0121 414 3353. E-mail address: n.freemantle{at}bham.ac.uk
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Abstract |
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Methods and results This prospective analysis based on intention to treat data from all patients enrolled in the CARE-HF trial at 82 clinical centres in 12 European countries. A total of 813 patients with New York Heart Association class III or IV heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony were randomized to CRT plus medical therapy (n=409) vs. medical therapy alone (n=404). During a mean follow-up of 29.4 months CRT was associated with increased costs (4316, 95% CI: 13277485), survival (0.10 years, 95% CI: 0.010.21), and QALYs (0.22, 95% CI: 0.130.32). The incremental cost-effectiveness ratio was
19 319 per QALY gained (95% CI: 548245 402) and
43 596 per life-year gained (95% CI: 146 236223 849). These results were sensitive to the costs of the device, procedure, and hospitalization.
Conclusion Treatment with CRT appears cost-effective at the notional willingness to pay threshold of 29 400 (£20 000) per QALY gained.
Key Words: Cardiac resynchronization therapy Cost-effectiveness CARE-HF Quality-adjusted life-year
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Introduction |
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Despite the success of pharmacological therapy, heart failure remains associated with significant morbidity and mortality.4 New targets for therapy are being identified, many of which are aimed at specific groups of patients rather than the whole population. Cardiac resynchronization therapy (CRT), which aims to restore synchronous cardiac contraction, is one such therapy that aims to treat patients with cardiac dyssynchrony, a complex multi-component syndrome, which leads to a reduction in systolic performance, impaired ventricular filling, and contributes to systolic and diastolic mitral regurgitation.57 A series of randomized controlled trials has demonstrated that patients with heart failure from cardiac dyssynchrony, who have persistent, moderate, or severe symptoms despite standard pharmacological therapy, gain additional benefit from CRT in terms of improved symptoms, exercise capacity, ventricular function, and quality of life.812 The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial also showed that CRT, alone or combined with an implantable defibrillator (CRT-ICD), reduced the composite endpoint of death from any cause or hospitalization; however, although CRT-ICD significantly reduced mortality, the decrease in the risk of death with CRT alone compared with medical therapy was not statistically significant.13 Meta analyses and cost-effectiveness analyses based on results from these studies have left lingering uncertainty on both the effectiveness, in terms of survival, and cost-effectiveness of CRT and medical therapy compared with medical therapy alone.1418
Recent results from the CArdiac REsynchronization in Heart Failure (CARE-HF) trial have shown for the first time that CRT leads to improved survival in addition to improving symptoms, quality of life, and ventricular function.19 In this prospective cost-effectiveness analysis, we compared the incremental cost-effectiveness of CRT and medical therapy with medical therapy alone in terms of incremental cost per life-year gained and incremental cost per quality-adjusted life-year (QALY) gained on the basis of individual patient data from the CARE-HF trial.
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Methods |
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Estimating benefits
Effectiveness was defined in terms of QALYs and life-years gained associated with CRT during the trial.
Survival
The restricted mean survival was estimated for each patient within the trial on the basis of the time from randomization until death or censorship. The gain in survival associated with CRT was estimated from the difference in mean survival times between treatment groups. Extrapolation of the survival curves beyond the trial was undertaken to estimate the expected lifetime of the device beyond the study period. Survival was extrapolated using exponential, Weibull, log-normal, and log-logistic models. The exponential model was selected as it had the best model fit based on the Akaike Information Criterion.21 Further details are given in Appendix 1.
Quality of life
Patients' quality of life was assessed using the EQ-5D22 at baseline and 90 days post-randomization. The EQ-5D is a self-administered, validated, multi-attribute, preference-based measure of health status.22,23 Patients were asked to rate the severity of their current problems for five dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. EQ-5D health states were converted into utilities, where 1 is full health and 0 is dead, using preference data elicited from the UK general population.24 Quality of life was also assessed at baseline and 90 days, using the disease-specific Minnesota Living with Heart Failure Questionnaire (MLWHF).25,26 In addition, this instrument was also used to assess the long-term effects of CRT on quality of life at 18 months and at end-of-study. Utilities at 18 months and at end-of-study for all trial patients were estimated from MLWHF scores collected at 18 months and end-of-study on the basis of a mixed model of the relationship between change in EQ-5D score to change in MLWHF (baseline to 90 days), accounting for baseline EQ-5D and MLWHF scores and clinical variables, with clinical centres as random effects (Appendix 2).27 The variables included in the model were pre-specified on the basis of prior clinical knowledge to reduce the risk of optimism in the model.28 Missing EQ-5D scores at baseline and 90 days and missing MLWHF scores at baseline, 3 months, 18 months, and end-of-study were estimated by imputation, accounting for patients' characteristics on the basis of the following predictor variables: EQ-5D and MLWHF scores, gender, NYHA class, baseline IVMD, and baseline mitral regurgitation and treatment (for missing values post-baseline). A utility of zero was assigned at the time of a patient's death.24 For those patients who received a heart transplant or withdrew from the study, a utility score of 0 was assigned at the time of censorship.
Quality-adjusted life-years
QALYs were calculated for each patient from their survival and quality of life (based on EQ-5D utility scores at baseline, 3 months, 18 months, and end-of-study).29 QALYs were calculated for each patient through the area under the curve estimated through the linear interpolation of each individual patient-level estimate of health utility.
Estimating costs
Measurement of resource utilization
Resource use information was collected at baseline, 1, 3, 6, 9, 12, 18 months, every 6 months thereafter, and at the end-of-study.20 For each patient, data were collected on the number of attempts, success, and type of implant (CRT or CRT-ICD), length of hospital stay [ward, intensive care unit (ICU), and coronary care unit (CCU)], cardiac surgical procedures [coronary artery bypass graft (CABG), angioplasty (PTCA), and heart transplant], number of outpatient, cardiologist, or primary-care visits, and length of time spent in nursing or residential homes or in a rehabilitation centre. Cardiovascular medication use was estimated for patients on the basis of their cardiovascular medication logs. For those patients who were censored (due to planned heart transplant or withdrawal from the study), costs and benefits were accrued until censorship, but thereafter the patient was assumed to accrue no further costs or benefits.
Medical care
Within trial costs were generated for each patient on the basis of a UK health-care perspective in pounds sterling, and were converted to euros at a conversion rate of 1.47=£1. Cost per day spent in hospital, coronary or intensive care unit, in a residential or nursing home or rehabilitation centre and per day care or outpatient visit, primary care or cardiologist visit were estimated on the basis of the National Health Service reference costs.30,31 Cardiovascular procedure costs, specifically CABG, PTCA, and transplants, were based on UK Department of Health Healthcare Resource Group estimates (minus hospitalization costs for the mean length of stay, to avoid double counting of costs associated with hospitalization).3032 The costs of medications were obtained from the British National Formulary.33
Device costs and longevity
Costs of CRT and CRT-ICD devices vary within and across countries. The costs of these devices were therefore based on mean estimates of the manufacturer's list prices averaged across the models and countries involved in the CARE-HF trial. Each patient who underwent an implant attempt was assigned a procedure cost at the time of the attempt on the basis of an estimate derived from UK Healthcare Resource Group estimate of a pacemaker implant in patients with heart failure, accounting for the increased duration of the procedure.32 As implant failure was likely to result from failure to position the LV lead, patients with an implant failure were assigned a cost for the procedure and the LV lead only. For those patients with repeated implants, or for those patients who died during the study, the total cost of the device and leads was spread over the time from implantation until the time of death or time of next implant, respectively.
Patients who received a successful implant and survived until the end of the trial would still accrue benefits from the device after the end of the study. Applying the full capital cost of a device at the time of implant would therefore overestimate the cost of the device relative to the potential benefits.34 In order to account for this, the cost was spread over the potential lifetime of the device accounting for patient survival. Thus, only those costs incurred during the study period were included in the cost-effectiveness analysis. For the base-case analysis, both the CRT and CRT-ICD devices were assumed to have a battery life of 6 years.35
Statistical methods
All analyses were conducted using SAS software (version 9.12 SAS Institute). Analyses were undertaken according to the intention-to-treat principle.36 Bootstrap CIs were calculated for cost, life-year, and QALY differences between groups.37 The incremental cost per life-year gained and incremental cost per QALY because of CRT were estimated from the incremental costs and QALYs associated with CRT use. A bootstrap approach was used to estimate 95% CI for the incremental cost-effectiveness ratios.37 This approach incorporates uncertainty in both the patient-level estimates of costs and QALYs.
Discounting
For the base-case analysis, both costs and benefits were discounted at a rate of 3.5%, as recommended for UK public sector investments.38
Sensitivity analyses
Sensitivity analyses were used to explore the effect of hospitalization cost, device longevity, procedure cost, device cost, and the effect of discounting (undiscounted and 3% on both cost and benefits) on the results. The effect of assigning a utility of zero to patients at the time of censorship was also explored by applying the last value carried forward at the time of censorship. In addition, the effect of the model specification to predict utilities at 18 months and at end-of-study was evaluated through the development of a reduced model based on observed predictive relationships (Appendix 2).
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Results |
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Incremental cost-effectiveness
The incremental cost per QALY gained associated with CRT therapy was 19 319 (95% CI: 548245 402). The incremental cost per additional life-year gained of CRT therapy was estimated as
43 596/LYG (95% CI: 146 236223 849) (Table 2). Bootstrapped estimates of paired incremental costs and incremental QALYs are shown in Figure 1 using the cost-effectiveness plane. The probability of CRT being cost-effective compared with medical therapy alone, given a notional willingness-to-pay threshold of
29 400 (£20 000)/QALY, is 83% (Figure 2). On the basis of a willingness-to-pay threshold of
44 100 (£30 000)/QALY, CRT also appears likely to be cost-effective.39
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Discussion |
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The incremental cost-effectiveness of CRT estimated from the CARE-HF trial differs markedly from those obtained by Nichol et al.17 Their analysis did not include data from the pivotal CARE-HF trial, used a Markov model with Monte Carlo simulation, and a discount rate of 3%, which gave a median estimate of the incremental cost-effectiveness of using CRT of $107 800/QALY gained. However Nichol et al. recommend that their results should be interpreted cautiously, given the magnitude in the uncertainty of incremental costs and incremental effects. Crucially, it appears that the increase in both quantity and quality of life benefits were underestimated in their analyses compared with the prospective results from the CARE-HF trial.19
Our analyses have a number of strengths. We have evaluated, for the first time, the cost-effectiveness of CRT using a within-trial analysis on the basis of data from a large, prospective, randomized, controlled trial. The analysis is based on individual patient data collected at 82 centres across Europe and an average of 29.4 months follow-up. The cost-effectiveness study was specified a priori in the trial protocol and included data from all patients enrolled in the study.
A limitation of our analysis is that the results were analysed from a UK health-care perspective, as specified in the trial protocol. The costs associated with health-care delivery and devices will vary both within and across countries and in different health-care systems. Utility scores were derived on the basis of the multi-attribute EQ-5D, by applying utility scores to patients' health states, on the basis of UK population preference data.24 The strength of this position is that it takes into account the societal view. In addition, the UK value set appears to be similar to those elicited for other countries, including the US.4043
The estimate of within-trial life-years gained used in our analysis is appropriate for the approach that we use but underestimates the overall benefits of CRT, as it is restricted to the period of follow-up observed in the trial. The restricted mean survival benefit is also statistically inefficient when compared with survival analysis methods. Thus, although fit for the purpose for which it is applied in this within-trial analysis, it does not provide the best estimator of survival differences between the groups.
Although a within-trial health economic analysis is a strength, as it is based on individual patient data, it can also be seen as a limitation. An alternative model-based cost-effectiveness analysis would provide a fuller evaluation of the likely benefits and costs of therapy over the expected lifetime of patients and devices. However, a major disadvantage of a model-based cost-effectiveness evaluation is the strong assumptions that are required, particularly on survival extrapolated beyond the period observed in the trial. In addition, a model-based analysis cannot represent uncertainty as robustly as a within-trial analysis on the basis of observed data from individual patients.
Our results apply to patients who meet the inclusion and exclusion criteria used in the CARE-HF trial.19 Care should be taken in applying these data to patients excluded from the trial, such as those with few or no symptoms, patients with less evidence of dyssynchrony or less severe ventricular dysfunction, and those with atrial fibrillation.20 Further trials are being conducted to assess the effects and costs of CRT in other populations.44,45
It should also be recognized that CRT is not yet a mature technology. CRT may be useful in groups of patients other than those studied so far. Some patients randomized in existing studies may not have benefited from CRT. Further research is required to identify which variables best predict response to CRT. More accurate targeting of the intervention may avoid unnecessary patient morbidity and make CRT appear more cost-effective. Technological developments in the delivery of CRT are also likely to reduce costs by reducing implantation times and failures and by delivering more effective resynchronization to more eligible patients.
Potentially, the use of a CRT-ICD device which includes an implantable cardioverter defibrillator could prevent further sudden deaths. This may be especially desirable if there is no substantial increase in concomitant morbidity. Adding ICD therapy will have an additional cost, however. At present there is no good evidence of the incremental cost-effectiveness of CRT relative to CRT-ICD.
Important questions remain surrounding the cost-effectiveness of CRT, in particular the generalizability of our findings to the wider heart failure population and the incremental cost-effectiveness of CRT relative to CRT-ICD. This analysis based on data from the CARE-HF trial suggests that in NYHA III/IV patients with left ventricular dysfunction and dyssynchrony CRT is a cost-effective intervention.
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Acknowledgement |
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Conflict of interest: M.C., N.F., J.C., and J.-C.D. have received funding for research, travel and consulting from a number of companies which manufacture devices and drugs for the treatment of heart failure, including Medtronic Inc. No other conflicts of interest declared.
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Appendix 1 |
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Table A1 Model fit parameters
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Extrapolated KaplanMeier survival curves were fitted on the basis of the exponential function (Figure A1) and were used to predict the probability of survival beyond the study by treatment group (Table A2). This information was used to estimate the lifetime of the device battery accounting for patients' likely survival status.
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Appendix 2 |
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where is the intercept, ß17 are the regression coefficients, µ is the random effects parameter, and
is the random error.
Results
The results of mixed modelling to predict change in EQ-5D score on the basis of change in MLWHF score, baseline quality of life, and pre-specified clinical variables is shown (Table A3). The relationship between difference in MLWHF score and EQ-5D score, baseline quality of life, and gender were highly significant (P<0.0001).
Table A3 Regression analysis of change in EQ-5D score used in the base-case analysis as pre-specified in the analysis plan
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aThe relationship between change in EQ-5D and MLWHF scores was estimated on the basis of 90-day score minus baseline score for each patient still alive at 90 days.
Table A4 Results from the reduced model to predict change in EQ-5D score
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A reduced model was produced on the basis of stepwise selection of clinical variables that were statistically significant predictors of change in EQ-5D (Table A4) and was used to predict utilities at 18 months and end-of-study in the reduced model sensitivity analysis.
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References |
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