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Economic effects of prolonged clopidogrel therapy after percutaneous coronary intervention |
Cowper P A, Udayakumar K, Sketch M H, Peterson E D |
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Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology The prolongation of clopidogrel therapy from one month to one year after percutaneous coronary intervention (PCI) in unselected patients was examined.
Economic study type Cost-effectiveness analysis.
Study population The study population comprised a hypothetical, unselected, heterogeneous cohort of patients treated in the era of bare-metal stents. The patients had undergone PCI. Patients were included if they:
were over 21 years of age;
did not have significant left main coronary artery disease;
did not undergo percutaneous revascularisation in the 2 weeks before the index PCI;
did not have a "staged procedure" (two planned procedures in the same admission);
did not receive intracoronary radiation therapy for in-stent restenosis; and
were treated with no more than one month of clopidogrel after the procedure.
Setting The setting was secondary care and a hospital. The economic study was carried out in the USA.
Dates to which data relate The effectiveness data came from studies published between 2000 and 2002 and from a database covering the period January 1999 to December 2001. No dates for the resource use data were explicitly reported. The costs came from sources published between 2000 and 2004. The price year was 2000.
Source of effectiveness data The effectiveness evidence was derived from a synthesis of completed studies and a hospital database.
Modelling A decision tree model was constructed to compare the outcomes and costs of prolonging clopidogrel therapy from one month to one year after PCI with the alternative strategy of discontinuing therapy after one month of peri-procedural clopidogrel. The model included myocardial infarction (MI), revascularisation (coronary artery bypass grafting versus PCI), major bleeding and death. Events that were rare (e.g. stroke) or had minimal economic consequences (e.g. minor bleeding) were excluded. The structure of the tree was reported. A time horizon of one year was adopted.
Outcomes assessed in the review The outcomes estimated from the literature were:
the rate of major events (MI, death, repeat vascularisation) after PCI (given one month of therapy);
the rates of major bleeding;
the effect of clopidogrel (prolonged therapy) on rates of MI, major bleeding (relative risk compared with one month of therapy);
repeat vascularisation;
death; and
life expectancy.
Study designs and other criteria for inclusion in the review It would appear that the primary studies were identified selectively and a systematic review of the literature was not undertaken. The relative risk of MI for prolonged clopidogrel therapy in comparison with one month of therapy came from a clinical trial, (Clopidogrel for the Reduction of Events During Observation, CREDO, trial). Other clinical data came from two longitudinal studies and the Duke Information System for Cardiovascular Care (DISCC) database (Duke Medical Center, Durham, NC, USA), which gathered data on patients receiving one month of clopidogrel. Patients characteristics for the CREDO trial and DISCC were reported. In the CREDO trial, the mean age of the patients was 62 (+/- 11) years and 29% were women. In the DISCC database, the mean age was 62 (+/- 12) years and 35% were women. The two patient population were similar, but DISCC patients were more likely to be female, non-white, and have a history of diabetes, MI or a recent MI.
Sources searched to identify primary studies Criteria used to ensure the validity of primary studies Methods used to judge relevance and validity, and for extracting data Number of primary studies included Three primary studies and a hospital database provided the clinical evidence.
Methods of combining primary studies A narrative method appears to have been used to combine the primary estimates.
Investigation of differences between primary studies Results of the review Without clopidogrel (i.e. clopidogrel therapy only for 1 month):
the rate of death was 1.4% in the CREDO trial and 4.2% using the DISCC database,
the rate of MI was 3.2% in the CREDO trial and 5.8% using the DISCC database,
the rate of revascularisation was 15.2% in the CREDO trial and 14.3% using the DISCC database, and
the rate of major bleeds was 3% in the CREDO trial.
The rate of MI with clopidogrel was 1.4% in the CREDO study and 3.2% in the hospital database.
The absolute risk reduction of MI was 1.4% in the CREDO study and 2.6% in the hospital database.
The expected survival of patients in the hospital database was 13.2 years (undiscounted). The estimated reduction in life expectancy of patients surviving 6 months after acute MI was approximately 2 years (undiscounted). Thus, the estimated life expectancy for patients surviving an MI was 11.2 years (undiscounted).
Measure of benefits used in the economic analysis The summary benefit measures used were the rate of MI and life expectancy, which was discounted at an annual rate of 3%. The death rate was also reported. All measures were estimated using a modelling approach.
Direct costs The costs were not discounted since a time horizon of one year was adopted. The unit costs were presented for some items but there was limited information on the quantities of resources used. The economic evaluation considered the costs of hospitalisation for major clinical events and event combinations, physicians' fees, revascularisation procedures and clopidogrel (including a monthly dispensing fee). The cost of death was also included as the difference of Diagnosis Related Group (DRG) payments for MI with and without death. The cost/resource boundary of the third-party payer appears to have been adopted. The costs were estimated using Medicare fee schedules and reimbursement rates. The drug costs came from average wholesale prices. Some resource use was based on average lengths of stay reported for DRGs; the sources of other resources were unclear. All the costs were inflated to 2000 values using the average Producer Price Index for general medical and surgical hospitals.
Statistical analysis of costs The costs were treated deterministically.
Indirect Costs The indirect costs were not included in the economic evaluation, although the authors stated that a societal perspective was adopted.
Sensitivity analysis Univariate and multivariate sensitivity analyses were performed to examine the robustness of the cost-effectiveness ratios to variations in model inputs and assumptions. The parameters varied were the relative risk reduction for MI, the cost of MI, the rate and cost of major bleeds, the price of clopidogrel, medication compliance and the reduction in life expectancy due to MI. Alternative ranges of values appear to have been either set by the authors or derived from the literature. The analysis was further carried out in sub-groups of patients (high- versus low-risk groups).
Estimated benefits used in the economic analysis The rate of death from one month to one year was 3.92% with clopidogrel and 4.15% without clopidogrel (difference 0.23%).
The rate of MI from one month to one year was 3.24% with clopidogrel and 5.80% without clopidogrel (difference 2.56%).
The discounted life expectancy was 10.43 years with clopidogrel and 10.37 years without clopidogrel (difference 0.056 years).
In the sub-group of high-risk patients, the difference between clopidogrel and no clopidogrel was 0.29% in terms of rate of death, 3.54% for rate of MI and 0.075 years in life expectancy.
In the sub-group of low-risk patients, the difference between clopidogrel and no clopidogrel was 0.16% in terms of rate of death, 1.64% for rate of MI and 0.037 years in life expectancy.
Cost results The total costs were $3,715 with clopidogrel and $2,819 without clopidogrel (difference $896).
The incremental cost of clopidogrel was $775 per patient in the sub-group of high-risk patients, and $983 per patient in the sub-group of low-risk patients.
Synthesis of costs and benefits An incremental cost-effectiveness ratio was calculated to combine the costs and benefits of the two clopidogrel strategies.
The incremental cost per MI avoided with clopidogrel over no clopidogrel was $34,336 ($21,893 in the high-risk group and $59,939 in the low-risk group).
The incremental cost per life-year saved with clopidogrel over no clopidogrel was $15,696 ($10,333 in the high-risk group and $26,568 in the low-risk group).
The sensitivity analysis also showed that the cost-effectiveness of clopidogrel therapy was relatively robust to moderate reductions in the effect of clopidogrel on the rate of MI, whereas it was sensitive to variations in the price of the drug. For example, a decrease of one third in the price of clopidogrel would result in a cost per year of life saved of only $9,250 ($5,520 in the high-risk group).
If all patients were compliant with drug therapy and the effectiveness of clopidogrel increased in proportion to the improvement in compliance, the cost per year of life saved would improve to $10,622.
As the cost of hospitalisation for MI increased, the financial attractiveness of clopidogrel therapy improved because savings from avoided hospitalisations increased.
The results were relatively insensitive to variations in the effect of clopidogrel on the incidence of major bleeds and in the cost of bleeds, owing to the low baseline risk of major bleeding. If the baseline estimate of years of life lost over a lifetime due to an MI were reduced by 50%, the cost-effectiveness ratio would be $21,975.
Authors' conclusions Continuing clopidogrel therapy after percutaneous coronary intervention (PCI) beyond one month was relatively cost-effective, especially in patients at high risk of myocardial infarction (MI).
CRD COMMENTARY - Selection of comparators The selection of the comparator (i.e. clopidogrel limited to one month after PCI) was appropriate as it reflected standard care for unselected patients. You should decide whether this is a valid comparator in your own setting.
Validity of estimate of measure of effectiveness The effectiveness evidence came from published studies that appear to have been identified selectively. Thus, a review of the literature was not undertaken. Extensive details of the characteristics of the primary studies were provided. The authors noted some differences between the two main sources of data (the hospital database and the CREDO study) in terms of the baseline patient characteristics. The primary estimates were combined using a narrative approach.
Validity of estimate of measure of benefit Both generalisable and disease-specific summary benefit measures were used in the analysis. The use of life-years saved helps comparisons with the benefits of other health care interventions. Discounting was applied as US guidelines for economic evaluation recommend.
Validity of estimate of costs The categories of costs considered in the economic study appear to have been consistent with the perspective of a third-party payer, although the authors stated that a societal perspective was adopted. The source of the data was reported. The unit costs were presented, although a detailed breakdown of the items was not. In fact, some costs were presented as macro-categories. The costs were treated deterministically and only some key economic items were varied in the sensitivity analysis. The price year was reported, which aids reflation exercises in other time periods. The authors noted that the unit costs were obtained from secondary sources.
Other issues The authors compared their findings with those from a recently published study and stated that their results were less favourable than those published already. The issue of the generalisability of the study results to other settings was not explicitly addressed, but several sensitivity analyses were carried out. These enhance, in part, the external validity of the analysis. The authors noted some limitations of their study. First, the model was based on one year of data and lifetime survival was extrapolated using available external estimates. Second, clopidogrel therapy was modelled for one year, and the extent to which the relative benefits of clopidogrel continue to accrue beyond one year is unknown. Third, the possibility that the pre-procedural loading dose contributed to the observed effect of prolonged treatment could not be ruled out. Fourth, the time horizon for the cost analysis was restricted to one year, while lifetime benefits were estimated. Finally, the study was based on data collected before the introduction of drug-eluting stents, which affect typical recommendations for clopidogrel use.
Implications of the study The authors stated "the therapy is most worthwhile in high-risk patients. However, without comprehensive medication coverage, the cost of the therapy would be borne primarily by patients already facing significant medication expenses".
Source of funding Supported by a grant from the Agency for Healthcare Research and Quality, US Department of Health and Human Services.
Bibliographic details Cowper P A, Udayakumar K, Sketch M H, Peterson E D. Economic effects of prolonged clopidogrel therapy after percutaneous coronary intervention. Journal of the American College of Cardiology 2005; 45(3): 369-376 Other publications of related interest Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-20.
Lindgren P, Jonsson B. Cost-effectiveness of clopidogrel in acute coronary syndromes in Sweden: a long-term model based on the cure trial. Journal of Internal Medicine 2004;255:562-70.
Eriksson P. Long-term clopidogrel therapy after percutaneous coronary intervention in PCI-CURE and CREDO: the 'Emperor's New Clothes' revisited. European Heart Journal 2004;25:720-2.
Indexing Status Subject indexing assigned by NLM MeSH Aged; Angioplasty, Balloon, Coronary; Cost-Benefit Analysis; Decision Support Techniques; Drug Administration Schedule; Female; Follow-Up Studies; Health Care Costs; Humans; Male; Middle Aged; Myocardial Infarction /economics /prevention & Platelet Aggregation Inhibitors /administration & Retrospective Studies; Ticlopidine /administration & Time Factors; Treatment Outcome; control; derivatives /economics; dosage /analogs & dosage /economics AccessionNumber 22005000257 Date bibliographic record published 30/11/2005 Date abstract record published 30/11/2005 |
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