Cost-Effectiveness of Percutaneous Coronary Intervention in Optimally Treated Stable Coronary PatientsCLINICAL PERSPECTIVE
Background— The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluations) trial compared the effect of percutaneous coronary intervention (PCI) plus optimal medical therapy with optimal medical therapy alone on cardiovascular events in 2287 patients with stable coronary disease. After 4.6 years, there was no difference in the primary end point of death or myocardial infarction, although PCI improved quality of life. The present study evaluated the relative cost and cost-effectiveness of PCI in the COURAGE trial.
Methods and Results— Resource use was assessed by diagnosis-related group for hospitalizations and by current procedural terminology code for outpatient visits and tests and then converted to costs by use of 2004 Medicare payments. Medication costs were assessed with the Red Book average wholesale price. Life expectancy beyond the trial was estimated from Framingham survival data. Utilities were assessed by the standard gamble method. The incremental cost-effectiveness ratio was expressed as cost per life-year and cost per quality-adjusted life-year gained. The added cost of PCI was approximately $10 000, without significant gain in life-years or quality-adjusted life-years. The incremental cost-effectiveness ratio varied from just over $168 000 to just under $300 000 per life-year or quality-adjusted life-year gained with PCI. A large minority of the distributions found that medical therapy alone offered better outcome at lower cost. The costs per patient for a significant improvement in angina frequency, physical limitation, and quality of life were $154 580, $112 876, and $124 233, respectively.
Conclusions— The COURAGE trial did not find the addition of PCI to optimal medical therapy to be a cost-effective initial management strategy for symptomatic, chronic coronary artery disease.
Received June 11, 2008; accepted July 10, 2008.
In chronic coronary artery disease, in contrast to acute coronary syndromes, clinical trials have not shown percutaneous coronary intervention (PCI) to reduce cardiovascular events.1–6 COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluations), a randomized trial comparing PCI plus optimal medical therapy (PCI group) with optimal medical therapy alone (medical therapy group), demonstrated no difference in the primary end point of death or myocardial infarction.7 PCI had an advantage, however, in angina control.8 To further evaluate the role of PCI in the management of chronic coronary artery disease, we studied the relative costs and cost-effectiveness of adding PCI to medical therapy.
Editorial see p 4
Clinical Perspective p 20
The methods used in COURAGE have been described previously.7,9,10 At 50 US and Canadian centers with local institutional review board approval, 2287 patients were randomized between 1999 and 2004 to the PCI group or medical therapy group after written informed consent was obtained. An independent data and safety monitoring board monitored COURAGE for safety and efficacy. Data management and analyses were performed solely by data-coordinating centers, with trial executive committee oversight.
Patients with stable coronary artery disease were eligible for inclusion. Entry criteria included >70% stenosis in ≥1 major epicardial coronary artery with objective evidence of myocardial ischemia or ≥1 coronary stenosis >80% and classic angina without provocative testing.
Patients received aspirin and post-PCI clopidogrel in accordance with treatment guidelines.11 Patients received aggressive therapy for hyperlipidemia, hypertension, and angina. Lifestyle counseling focused on smoking cessation, physical activity, and dietary modification. Follow-up was for a minimum of 30 months.
The Seattle Angina Questionnaire (SAQ) was used to assess angina-specific health status at baseline and during follow-up. On the basis of the approach of Weintraub et al8 and Wyrwich et al,12 clinically significant improvements in SAQ scores were defined as ≥8-, ≥20-, and ≥16-point differences for the domains of physical limitation, angina frequency, and quality of life, respectively.
Economic Analysis Plan and Assessment of Cost
The economic analysis plan was to compare costs of each treatment arm and perform an incremental cost-effectiveness analysis.13,14 Costs included in the analysis were direct medical care costs for hospitalizations, pharmaceuticals, and outpatient care. Costs after the first year and life expectancy were discounted at 3% annually.11 The analysis used 2004 US dollars, with resource use and clinical outcomes from all 2287 patients.
Cardiovascular healthcare resource use associated with the index hospitalization and all follow-up hospitalizations was recorded prospectively. Resource utilization included (1) initial PCI (inpatient or outpatient), index hospitalization, or outpatient care other than PCI; (2) subsequent hospitalizations (including subsequent PCI); (3) medications, including 1 month of clopidogrel after PCI; (4) outpatient visits; and (5) cardiovascular tests during follow-up.
Initial and subsequent hospitalizations were assigned a diagnosis-related group as used in the US Medicare program by coders blinded to treatment group, in which coded variables were used. Costs for each diagnosis-related group were estimated with average Medicare reimbursement rates15,16 obtained from the Medicare Part A (MEDPAR) data file.17 Outpatient PCI, outpatient physician office visits and procedures, tests, or emergency room visits were coded by current procedural terminology and assigned a cost based on the Medicare fee schedule. The cost for outpatients was estimated by including the cost of a nursing home, intermediate-care facility, rehabilitation facility, outpatient visits, emergency visits, outpatient cardiac rehabilitation visits (cardiac-related visits only), home visits by nurses, and imaging for ischemia. All medications were assigned a cost based on the Red Book average wholesale price for lisinopril (for angiotensin-converting enzyme inhibitors), amiodarone (for antiarrhythmic drugs), warfarin (for anticoagulant drugs), simvastatin (for statins), metoprolol (for β-blockers), amlodipine (for calcium channel blockers), digoxin (for cardiac glycosides), hydrochlorothiazide (for diuretics), and isosorbide mononitrate (for nitrates). All changes in medications and utilities (see below) were assumed to have taken place midway between monitoring visits. The last year of in-trial cost in each treatment group was used to project future costs and utility beyond the trial. For lifetime cost, the average Medicare participant per capita expenditure of $5219 in 2004,17 together with the cost difference in the last 2 years between the 2 treatment groups, was used to estimate cost beyond the trial period. Nonparametric tests, including the Wilcoxon rank-sum test, were performed to compare costs and outcomes.
Utility and Life Expectancy Estimation
Quality-adjusted life-years (QALYs) were calculated by multiplying survival by utility, a measure of health status scaled from 0 (death) to 1 (perfect health). COURAGE used the U-Titer computer program to conduct the SAQ and to assess utility by standard gamble assessments.8 The U-Titer program is an automated, modular utility-assessment software package designed to implement the rating scale, category scaling, standard gamble, and chronic and temporary time tradeoff methods of assessing patients’ preferences. In addition to calculating utilities, the U-Titer program records information on the process experienced by the user. A multiple partial imputation strategy was used to estimate missing utility values.18 Utilities in COURAGE were comparable to the utilities of coronary disease in the Cost-effectiveness Analysis Registry,19 a reliable source of community utilities. Therefore, it was reasonable to assume that utilities assessed in COURAGE were consistent with community preferences for health states. The last year of utilities in each treatment group was used to project future utilities beyond the trial. It was assumed in lifetime analyses that for the first 2 years beyond the trial, the utility trend would follow trends in the last year of the study, but after that, the difference between the treatment groups would disappear.
Life expectancy for patients with and without nonfatal events was estimated from the Framingham Heart Study,20,21 a 40-year epidemiological study. The original Framingham Heart Study measured the potential burden of cardiovascular disease by transforming epidemiological measures into time-based life-years lost to or lived with the disease. Specifically, multistate life tables of the Framingham Heart Study cohort were used for all COURAGE patients to calculate expected survival for each patient in the study (Data Supplement Table I). Sex- and age-specific estimates of life-years lost because of events that occurred during the trial were obtained by subtracting life expectancy estimates for individuals with events from life expectancy estimates for individuals with coronary disease but without events.22 For patients who experienced multiple events of different types during the trial, lost life expectancy was estimated assuming a hierarchy of death, stroke, and myocardial infarction. For example, if a patient had stroke and myocardial infarction, the event of stroke would be used to estimate the lost life expectancy. These estimates were then applied to each patient in the COURAGE population, and average life-years lost was calculated for both treatment groups. The difference between treatment groups in average life-years lost because of events (death, stroke, and myocardial infarction) yielded an estimate of life-years gained with PCI. In-trial utility values were used to quality-adjust survival beyond the trial period.
Estimation of Cost-Effectiveness
The cost-effectiveness of PCI was expressed as the incremental cost-effectiveness ratio (ICER), defined as the additional cost of PCI divided by the life-years gained and QALYs gained. Bootstrap methods (5000 replicates) were used to estimate the 95% confidence intervals (CIs) for both cost and life-years gained with PCI.23 Traditional 1-way sensitivity analyses included varying life-years gained for the PCI group compared with the medical therapy group by 10% to 40%. Probabilistic sensitivity analysis was conducted to assess the impact of the simultaneous changes of all the variables involved in the cost and life-years gained.24 The probability assumptions of effectiveness were derived from American Heart Association statistics25 and the Cardiovascular Health Study.26 Monte Carlo simulation was performed to derive the differences in QALYs and mean cost between the 2 treatment groups. In addition, ICERs were calculated for 1 additional patient to have clinically significant improvement in angina frequency, physical functioning, and quality of life.
The authors had full access to the data and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Summary of the Clinical Data
Of 2287 patients in COURAGE, 1149 were randomized to the PCI group and 1138 to the medical therapy group. Baseline clinical characteristics, together with the distribution of patients among 3 health systems, were similar in the 2 groups (Table 1). The majority of patients (88%) had angina at randomization. Sixty-nine percent of patients had multivessel coronary artery disease, and 95% had resting ECG changes or inducible ischemia. No significant difference was observed for the primary end point of death or myocardial infarction (19.0% in the PCI group, 18.5% in the medical group, P=0.62)) at a median 4.6 years of follow-up.7
Table 2 shows index and follow-up resource utilization by treatment group (diagnosis-related group and current procedural terminology unit costs are shown in Data Supplement Table II). On average, the initial cost was $12 162in the PCI group and $752 in the medical therapy group; the subsequent in-trial cost was $22 681 in the PCI group and $23 966 in the medical therapy group.
Life-Years Lost, Life-Years Gained, Utilities, and QALYs Lost
The utility values (baseline, 1 year, 2 years, and 3 years) between the 2 treatment groups and their corresponding CIs are shown in Table 3. These differences in the utility values between treatment groups at each measurement period were numerically small although statistically significant at 3 months and 3 years. Table 3 also shows the completeness of patients in standard-gamble utility assessment (percent missing) for both treatment groups. There were no significant differences between patients whose utility was present and patients whose utility was absent (Data Supplement Table III) at 6 months, and the patient characteristics of those with and without utility measurements at other time points were similar (data not shown), which suggests that the utility values were missing at random.
With data from the Framingham database (Data Supplement Table I), projected survival based on age, sex, and cardiovascular events was calculated. Table 4 shows in-trial and lifetime survival and quality-adjusted survival by treatment group. There was no significant trend toward life expectancy gain as a result of the use of PCI. The addition of initial PCI to optimal medical therapy offered no benefit in life-years (0.034; 95% CI −0.092 to 0.152) or QALYs (0.049; 95% CI −0.057 to 0.166) gained.
In-Trial and Lifetime Costs
Table 5 presents in-trial and lifetime costs. Total in-trial cost remained significantly higher (by $10 125) for the PCI group ($34 843 versus $24 718, 95% CI of the difference $8082 to $12 167). The cost of revascularization during the in-trial period for the PCI group was significantly higher by $10 532 ($14 901 versus $4368, 95% CI of the difference $9888 to $11 177). The in-trial cost of other hospitalizations was similar for both groups ($9499 for the PCI group versus $9844 for the medical therapy group). The in-trial cost of medication was $3418 and $3573, and the cost of outpatient services was $7025 and $6933 in the PCI and medical therapy groups, respectively. The total number of revascularization procedures was much higher in the PCI group. Accordingly, the difference in total in-trial cost between the treatment groups was mainly due to the difference in initial cost, which was $11 410 higher in the PCI group ($12 162 versus $752). Thus, the initial difference in cost between treatment groups carried forward and was never recovered.
Because more than 90% of patients were alive at the end of the trial, lifetime analyses were appropriate to project future costs and utility beyond the trial. The lifetime cost in the PCI group was $9451 higher than in the medical therapy group ($99 820 versus $90 370), a significant difference (95% CI $6729 to $12 173).
Cost-Effectiveness Analysis, In-Trial and Lifetime
The point estimate for the in-trial ICER for PCI was $206 229 per QALY gained (Table 6). The frequency with which medical therapy dominated PCI and the absence of domination by PCI indicate considerable probability that medical therapy alone provided better clinical outcome at lower cost (Table 6; Figure 1A). A cost-effectiveness acceptability curve (Figure 1B) shows that the bootstrap-derived cost-effectiveness estimates were rarely <$50 000 per QALY gained, and a minority were <$100 000 per QALY gained.
Uncertainty exists about years of life lost because of early death and the impact of nonfatal myocardial infarction or stroke on subsequent life expectancy. The corresponding life-years gained for the PCI group compared with the medical therapy group may be either larger or smaller than estimated in the preceding base-case analysis. Thus, when the estimated life-years gained for the PCI group compared with the medical therapy group was varied from a 40% decrease to a 40% increase, the ICER varied from $418 270 to $197 180 per life-year and from $296 200 to $121 130 per QALY gained (Figure 2). This represents a scale of extra life-years gained from 0.05 to a loss of 0.022 and of QALYs gained from 0.078 to a loss of 0.034. To achieve a point estimate of <$50 000 and $100 000 per life-year gained or QALY, respectively, PCI would need to offer an advantage over medical therapy of 0.38 and 0.19 life-years or 0.60 and 0.30 QALYs, respectively.
Another 1-way sensitivity analysis was performed to assess the robustness of the cost-effectiveness results due to costs related to restenosis. This is important because drug-eluting stents would have produced a lower restenosis rate than observed in COURAGE, in which bare-metal stents were used. If the costs of repeat PCI performed within 12 months after the first PCI were excluded, and the assumption were made that the diagnosis-related group for PCI would be $600 higher with drug-eluting stents and that clopidogrel would be continued for 1 year after PCI, the in-trial ICER for PCI compared with the medical therapy group would be $176 430 and $197 465 per life-year gained or QALY gained, respectively, with fewer than 1% of bootstrap samples <$50 000 per life-year gained. Given the assumption that drug-eluting stents had been used, the lifetime ICER for the PCI group compared with the medical therapy group would be $263 660 and $164 590, with 3.45% and 9.61% <$50 000 per life-year or QALY gained.
The characteristics of variables used in the probabilistic sensitivity analysis are shown in Table V in the Data Supplement. The distributional assumptions of the cost data were based on the actual data in the present study, and their ranges come from relevant sources.25,26
Figure 3A presents the contour plot of simulated distribution of mean differences in cost and effectiveness in QALYs based on the probabilistic sensitivity analysis over a lifetime. It reveals that the lifetime QALYs gained could range from -0.5 to 0.5 years for the PCI group compared with the medical therapy group, but the cost for the PCI group would always be significantly larger, varying from $4000 to $16 000. The ellipses indicate 50%, 95%, and 99% CIs of the simulated lifetime ICERs. The cost-effectiveness acceptability curve (Figure 3B) shows that even given the greater variation in this sensitivity analysis than noted purely by the play of chance in the base case (Figure 1A and 1B), there was only a 25% probability of PCI being cost-effective at the $50 000 threshold and a 41% probability at the $100 000 threshold. The probability of PCI being dominated by medical therapy was 43%.
Cost per Patient for Improvement of Angina-Related Health Status
Compared with the medical therapy group, the PCI group experienced significantly better improvement in SAQ physical limitation and quality-of-life scores from 1 to 6 months and in angina frequency from 1 to 36 months after randomization (Data Supplement Table IV).8 Table 7 shows that there were 8.97%, 6.55%, and 8.15% more patients in the PCI group at 6 months with clinically significant improvement in physical limitation, angina frequency, and quality of life, respectively. Given the assumption of $10 125 in-trial additional cost per patient for PCI, the ICERs for 1 patient having a significant improvement in angina-related health status are shown in Table 7.
The main results from COURAGE demonstrated no difference between the PCI and medical therapy groups in death or myocardial infarction7; however, PCI improved quality of life over a period that ranged from 1 to 3 years.8 The present economic analysis showed that PCI plus medical therapy was more expensive than medical therapy alone, almost entirely because of the initial cost of the procedure. Thereafter, resource utilization and costs tracked largely in parallel. Simply stated, the additional cost of the initial PCI in stable coronary disease is never recovered. There was also little difference in survival or quality-adjusted survival. Thus, the point estimates for the ICERs for potential PCI benefit were large compared with conventional benchmarks, and in addition, a large percentage of the distribution showed PCI to be dominated by medical therapy. Although the greatest uncertainty is in the differential life expectancy, these results are robust to variations in relative gain in life expectancy with PCI.
The cost for an improvement in symptoms is difficult to evaluate in cost-effectiveness analysis because it is difficult to compare the ICERs from such analysis to other forms of therapy for other disease states. Nonetheless, societal willingness to pay to improve angina for 1 year would almost certainly be a higher number than the willingness to pay for an additional QALY. Indeed, the approximately $150 000 for 1 patient to derive a clinically significant improvement in angina frequency with PCI would probably not meet a societal willingness-to-pay threshold. This analysis may be criticized because angina may not represent all benefits and risks of PCI compared with medical therapy, although it is generally considered to be the primary outcome improved by PCI. Although there were differences in angiographic nuclear perfusion surrogates, there were no other differences noted in clinical outcomes.7,27 Thus, health status, specifically angina, is a meaningful measure of outcome for cost-effectiveness analysis.
The cost-effectiveness of revascularization compared with medical therapy for chronic coronary artery disease has been studied previously. Weinstein and Stason28 developed a simulation based on the trials from the 1970s to early 1980s and found that coronary surgery offered a cost per QALY gained that ranged from $3800 in left main disease to $30 000 for single-vessel disease. Before any clinical trial data were available comparing PCI with medical therapy, Wong et al developed a simulation study that found balloon angioplasty to be cost-effective for severe angina.29 Claude et al30 evaluated revascularization in the elderly with PCI or coronary surgery as appropriate and found a cost of $6900 Euros per event averted. Although there have been 11 previous trials of PCI versus medical therapy, there have been no trial-based cost-effectiveness analyses of PCI relative to medical therapy.31
Cost-effectiveness analysis is performed from a societal basis; however, costs are from a payer or provider perspective. It is also not generally possible to account for all costs. Diagnosis-related group–based costing is from a payer perspective and may not adequately account for resource utilization. Resource utilization in different healthcare systems may vary, and it is thus an assumption that costs from one healthcare system can be assigned equally to care provided in another healthcare system. Resource use beyond the trial period is based on a model, not on measurement. Also, projection of life expectancy and cost beyond the trial period must be based on models developed from the literature. Evaluation of utility, used to make quality adjustments for survival, is also problematic. Utility could only be measured in a minority of subjects, with data for the rest derived from statistical modeling. Despite the many limitations, the results of the present sensitivity analyses were robust.
The COURAGE trial did not find the addition of PCI to medical therapy to be a cost-effective initial management strategy for symptomatic, chronic coronary artery disease. The cost for 1 patient to have clinically significant improvement in angina for between 6 and 36 months8 exceeds $100 000. The economic outcomes in COURAGE are consistent with the clinical outcomes, which show that it is safe to defer PCI. The present analysis suggests that such an initial management strategy will achieve appreciable savings in health expenditures.
Sources of Funding
This study was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development, in collaboration with the Canadian Institutes for Health Research; unrestricted research grants were obtained from Merck & Co, Pfizer Pharmaceuticals, Bristol-Myers Squibb Medical Imaging, Fujisawa, Kos Pharmaceuticals, Data Scope, AstraZeneca, Key Pharmaceutical Co, Ltd, Sanofi-Aventis, Inc, First Horizon, and Nycomed Amersham. All industrial funding in support of the trial was directed through the Department of Veterans Affairs.
Dr Weintraub reports receiving consulting fees from Sanofi-Aventis, GlaxoSmithKline, Indigo Pharmaceuticals, and Cardiovascular Therapeutics and receiving grant support from Sanofi-Aventis, AstraZeneca, Otsuka, and Bristol-Myers Squibb. Dr Spertus reports receiving consulting fees from Otsuka and United Healthcare and grant support from Amgen, Bristol-Myers Squibb, Sanofi-Aventis, and Lilly. Dr Spertus holds a copyright to the Seattle Angina Questionnaire. Dr Jurkovitz reports receiving grant support from Bristol-Myers Squibb, Cardiovascular Therapeutics, Otsuka, Sanofi-Aventis, and AstraZeneca. Dr Boden reports receiving consulting fees from Pfizer, Merck, PDL Biopharma, Bristol-Myers Squibb, Abbott, and Cardiovascular Therapeutics and receiving lecture fees from Sanofi-Aventis, Kos Pharmaceuticals and Novartis. The remaining authors report no conflicts.
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The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluations) trial found no benefit to an initial management strategy of percutaneous coronary intervention (PCI) plus optimal medical therapy over optimal medical therapy alone for the treatment of chronic coronary artery disease; however, there was a benefit in the treatment of angina, depending on the particular measure, for ≈2 years. The present report considers the cost and cost-effectiveness of PCI in addition to optimal medical therapy. PCI is initially more expensive than medical therapy. Although the cost difference narrows somewhat over time, it is never made up. The clinical results of COURAGE were converted to a difference in life expectancy and a difference in quality-adjusted life expectancy. The cost difference between the PCI group and the optimal medical therapy group may then be divided by the difference in life expectancy or quality-adjusted life expectancy to offer an incremental cost-effectiveness ratio. The incremental cost-effectiveness ratios were calculated in-trial and with a lifetime extension, using differences in life expectancy and quality-adjusted life expectancy, and were in the range of $200 000. Statistical techniques that evaluated the play of chance and additional sensitivity analyses of other sources of variability showed that it is unlikely that the cost per life-year saved or quality-adjusted life-year saved is less than the common benchmarks of $50 000 or $100 000, respectively. Consistent with the clinical results, the COURAGE trial did not find PCI to be a cost-effective initial management strategy for the treatment of chronic coronary artery disease.
Guest Editor for this article was Eric D. Peterson, MD.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00007657.
The online-only Data Supplement is available with this article at http://circoutcomes.ahajournals.org/cgi/content/full/1/1/12/DC1.