Clopidogrel versus aspirin for secondary prophylaxis of vascular events: a cost-effectiveness analysis☆

Article Outline

• Abstract
• Methods
  • Model structure
  • Model inputs
• Results
  • Base case analysis
  • Sensitivity analyses
• Discussion
• References
• Copyright

Abstract 

Purpose

Clopidogrel is more effective than aspirin in preventing recurrent vascular events, but concerns about its cost-effectiveness have limited its use. We evaluated the cost-effectiveness of clopidogrel and aspirin as secondary prevention in patients with a prior myocardial infarction, a prior stroke, or peripheral arterial disease.

Methods

We constructed Markov models assuming a societal perspective, and based analyses on the lifetime treatment of a 63-year-old patient facing event probabilities derived from the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial as the base case. Outcome measures included costs, life expectancy in quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios, and events averted.

Results

In patients with peripheral arterial disease, clopidogrel increased life expectancy by 0.55 QALYs at an incremental cost-effectiveness ratio of $25,100 per QALY, as compared with aspirin. In poststroke patients, clopidogrel increased life expectancy by 0.17 QALYs at a cost of $31,200 per QALY. Aspirin was both less expensive and more effective than clopidogrel in post–myocardial infarction patients. In probabilistic sensitivity analyses, our evaluation for patients with peripheral vascular disease was robust. Evaluations of stroke and myocardial infarction patients were sensitive predominantly to the cost and efficacy of clopidogrel, with aspirin therapy more effective and less expensive in 153 of 1000 simulations (15.3%) in poststroke patients and clopidogrel more effective in 119 of 1000 simulations (11.9%) in the myocardial infarction sample.

CONCLUSION

Clopidogrel provides a substantial increase in quality-adjusted life expectancy at a cost that is within traditional societal limits for patients with either peripheral arterial disease or a recent stroke. Current evidence does not support increased efficacy with clopidogrel relative to aspirin in patients following myocardial infarction.

Atherosclerotic vascular disease is a major contributor to morbidity, mortality, and medical costs in the United States, where approximately 1.5 million acute ischemic vascular events were reported in 1995 (1) and the total annual cost in 1997 was estimated at $259 billion (2). The mainstay of prophylaxis has been aspirin, which has been shown to be effective, particularly in patients at high risk due to known prior events (3).

Other antiplatelet drugs have more recently become available, including ticlopidine and clopidogrel, inhibitors of adenosine diphosphate–dependent platelet activation 4, 5. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial demonstrated an 8.7% relative risk reduction in the combined endpoint of stroke, myocardial infarction, and vascular death in patients with a recent myocardial infarction, a recent stroke, or peripheral vascular disease who were treated with clopidogrel (6). In particular, patients with peripheral arterial disease experienced a large advantage with clopidogrel, whereas those with a previous stroke benefited less substantially. The point estimate for post–myocardial infarction patients favored aspirin but did not reach statistical significance. The only notable difference in major side effects between the two treatments was a decrease in gastrointestinal bleeding in the clopidogrel group.

Despite this advantage, adoption of clopidogrel for this indication has been limited by concerns regarding its cost-effectiveness 2, 5, 7, 8, 9, 10. While some studies have evaluated the cost-effectiveness of clopidogrel for the secondary prophylaxis of stroke 8, 11, 12 or coronary artery disease (10), the effects of clopidogrel in different patient samples limits the generalizability of these studies. Therefore, we designed decision-analytic models to evaluate the cost-effectiveness of clopidogrel relative to aspirin in patients with peripheral arterial disease, a recent stroke, or a recent myocardial infarction.

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Methods 

The cost-effectiveness analysis used decision-analytic Markov models (13) (TreeAge, version 3.5; TreeAge Software, Inc. Williamstown, Massachusetts), one for each subgroup in the CAPRIE trial: peripheral arterial disease, defined as symptomatic claudication in a patient with an ankle-brachial index of less than 0.85; stroke in the previous 6 months; and myocardial infarction in the previous 35 days. As recommended by the Panel on Cost-Effectiveness in Health and Medicine, we analyzed a base case assuming a societal perspective (14), discounting costs and utilities at an annual rate of 3% (15). We calculated costs, life expectancy in quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios, and events averted.

The target patient group was all patients with peripheral arterial disease, a previous nonhemorrhagic stroke, or a previous myocardial infarction. We included myocardial infarction, despite the negative point estimate for efficacy versus aspirin in CAPRIE, because many patients experience more than one of these conditions. To mirror patients in the trial, we considered a 63-year-old patient as the base case, and compared treatment costs and clinical outcomes for two alternatives of antiplatelet therapy: aspirin, 325 mg orally per day, and clopidogrel, 75 mg orally per day. We considered 50- and 75-year-old patients in the sensitivity analysis.

Model structure 

We considered events that are directly related to the disease process: stroke, myocardial infarction, vascular death, and amputation. The first two events could be potentially fatal and include any stroke of varying severity. We also modeled gastrointestinal and intracerebral hemorrhagic events, as well as clopidogrel-associated thrombotic thrombocytopenic purpura.

Separate Markov states were created for any event that durably altered quality of life, health care costs, or the probability of subsequent events (Figure 1). Exceptions were gastrointestinal bleeding and thrombotic thrombocytopenic purpura, for which a utility toll was assessed. We also modeled Markov states for each combination of two events to account for the possibility of multiple events within a given monthly cycle. When more than two events occurred, we used the Markov state that combined the two events with the lowest utility.

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• Figure 1. 

  Schematic representation of the decision model. The square node on the left depicts the treatment decision. The Markov states are outlined. In each monthly cycle, patients face the risk of one or several vascular events (myocardial infarction, stroke, amputation, or vascular death), one or several hemorrhagic events (gastrointestinal bleeding or intracranial hemorrhage), or another side effect (thrombotic thrombocytopenic purpura). At the completion of each cycle, patients return to the Markov state appropriate for both the Markov state in which they began the cycle and the events occurring during the cycle. Triangles depict transition to the “dead” Markov state. Not shown is the risk of age-related mortality, which is present in each cycle.

Model inputs 

Event rates were obtained from CAPRIE (6). Although the trial did not assess the severity of stroke, we included this variable because of its effects on quality of life and costs. We assumed that clopidogrel did not alter the distribution of severity, based on studies of other antiplatelet therapies (16). We assumed that the rate of amputation correlated with the prevalence of peripheral arterial disease, and derived rates for each subgroup. We obtained age-specific mortality from life tables and adjusted for events explicitly included in our models (17).

We calculated the rate of hemorrhagic events for all CAPRIE patients. The rate of thrombotic thrombocytopenic purpura associated with clopidogrel was derived from an observational study 18, 19; most patients who experienced this disorder did so within the first month of treatment. We overestimated subsequent cases by assuming that the subsequent 2 cases per 3 million patients were monthly rather than lifetime. We converted rates to probabilities using standard equations (13) (Table 1).

Table 1. Annual Event Probabilities and Efficacy*

As CAPRIE results were heterogeneous for the three subgroups, we used the estimates and 95% confidence intervals for the efficacy of clopidogrel for each subgroup rather than the primary study estimate. We varied the efficacy of clopidogrel in reducing hemorrhagic side effects by a factor of 0.5 to 2 (Table 1).

We included published, population-based values for utilities, representing either time trade-off or standard gamble techniques. For Markov states representing multiple events, we combined utilities by multiplication (Table 2).

Table 2. Model Inputs

QALY = quality-adjusted life-year; VA = Veterans Affairs.

We derived costs for each event and for the chronic care of disabled patients using the literature as well as from Medicare diagnostic-related group data (20). We used the average U.S. wholesale price for medications (42) and based the ranges on prices negotiated by a large-volume purchaser. For states depicting survival after a severe stroke or intracerebral hemorrhage and another event, we included 20% of the chronic cost of the other condition to account for overlapping therapy. We accounted for other health care costs, including costs for cardiovascular procedures not explicitly modeled, by using age-adjusted annual health expenditures (41). We converted costs to 2002 values using a gross domestic product deflator (54).

Clopidogrel remained efficacious throughout the 3 years of the CAPRIE study. The duration of effectiveness is unknown. We considered two alternatives. In the base case, we presumed that the efficacy of clopidogrel was constant. In the sensitivity analysis, we assumed that after 3 years the efficacy of clopidogrel was identical to that of aspirin, but maintained its advantage in the number of hemorrhagic events.

In a supplementary analysis, we determined the events prevented by using clopidogrel rather than aspirin in a hypothetical cohort of 250,000 patients treated for their respective lifetimes. For each model, we compared both the types and total number of events.

We performed one-way sensitivity analysis by re-evaluating each model at the extremes of the 95% confidence interval for each model input. In evaluating patients of different ages, we adjusted both age-related mortality and annual health care costs accordingly. We considered our analysis sensitive to variables for which variation changed the incremental cost-effectiveness ratio substantially.

We performed probabilistic sensitivity analysis using Monte Carlo simulations (55). In each of 1000 simulations, the value for each of the model inputs was selected at random from its distribution. We constructed cost-effectiveness acceptability curves by calculating the average net monetary benefit for each strategy in each simulation over a range of potential cost-effectiveness thresholds, from no additional expenditure relative to the less expensive therapy, to $100,000 for each QALY gained. We determined the proportion of the 1000 simulations for which clopidogrel resulted in the greatest net monetary benefit at each cost-effectiveness threshold.

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Results 

Base case analysis 

For patients with peripheral arterial disease, treatment with clopidogrel resulted in a 0.55 QALY increase in life expectancy at a cost of $25,100 per QALY compared with aspirin therapy (Table 3). In patients with a prior stroke, clopidogrel improved life expectancy by 0.17 QALYs relative to aspirin and increased costs by $31,200 per QALY. For patients treated following a myocardial infarction, life expectancy on clopidogrel was 0.26 QALYs shorter than with aspirin and also more costly.

Table 3. Base Case Results

QALY = quality-adjusted life-year.

Assessments of the events expected in a hypothetical cohort of 250,000 patients were most informative for post–myocardial infarction patients (Table 4). While clopidogrel treatment resulted in decreases in almost all event types, as well as the total number of events, this benefit was negated both in terms of effectiveness and cost-effectiveness by the increased rate of nonspecified vascular death.

Table 4. Expected Numbers of Events in a Hypothetical Cohort of 250,000 Patients with Peripheral Arterial Disease, a Prior Stroke, or a Prior Myocardial Infarction, by Indicated Therapy

Sensitivity analyses 

Our evaluations were more sensitive to the efficacy and cost of clopidogrel than to other variables (Figure 2). For patients with peripheral arterial disease, the lower bound for efficacy resulted in a cost-effectiveness ratio of $86,400 per QALY, which improved to $13,500 per QALY at the upper bound. For poststroke patients, the cost-effectiveness ratio for clopidogrel at the upper bound of the 95% confidence interval for efficacy was $6300 per QALY. At the lower bound, clopidogrel was both more expensive and less effective than aspirin. In post–myocardial infarction patients, for whom aspirin was more effective and cheaper in the base case, the cost-effectiveness ratio improved to $42,000 per QALY at the best estimate for efficacy.

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• Figure 2. 

  One-way sensitivity analysis for patients with peripheral arterial disease. Bars depict the effect of varying the indicated parameter through the specified range on the cost-effectiveness ratio of clopidogrel relative to aspirin. The values for each parameter are shown in parentheses. Variation in the efficacy of clopidogrel in both the stroke and myocardial infarction models resulted in cost-effectiveness ratios approaching both negative and positive infinity. QALY = quality-adjusted life-year; RRR = relative risk reduction.

The daily cost of clopidogrel was the second most critical model input. In peripheral vascular patients, variation in the cost of clopidogrel from $1.80 to $7.10 per day changed the cost-effectiveness ratio from a minimum of $14,900 per QALY to a maximum of $41,800 per QALY. This difference was greater in stroke patients for whom clopidogrel therapy was less expensive than aspirin when clopidogrel cost $1.80. At a daily cost of $7.10, the cost-effectiveness ratio for clopidogrel was $85,500 per QALY.

Long-term efficacy was constant in the base case. When we considered an efficacy of zero relative to aspirin after 3 years, the incremental cost-effectiveness ratio rose from $25,100 to $53,600 per QALY for patients with peripheral vascular disease. The poststroke analysis was more sensitive to the duration of efficacy, with an increase to $111,800 per QALY from the base case value of $31,200 per QALY.

In probabilistic sensitivity analyses (Figure 3), the cost-effectiveness thresholds at which clopidogrel was optimal in 50% of simulations were $25,600 per QALY for patients with peripheral vascular disease and $30,300 per QALY for those with a recent stroke. In patients warranting therapy for peripheral arterial disease, clopidogrel was optimal at a cost-effectiveness threshold of $10,000 per QALY in 55 of 1000 simulations (5.5%), and in 971 of 1000 simulations (97.1%) at $100,000 per QALY. In patients with an initial stroke, clopidogrel was both more effective and less expensive than aspirin in 127 of 1000 trials (12.7%), and was optimal in 271 of 1000 simulations (27.1%) at a cost-effectiveness threshold of $10,000 per QALY, and in 714 of 1000 simulations (71.4%) at $100,000 per QALY. In patients with a prior myocardial infarction, clopidogrel therapy resulted in greater quality-adjusted life expectancy in 119 of 1000 simulations (11.9%).

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• Figure 3. 

  Results of probabilistic sensitivity analysis. Cost-effectiveness acceptability curves are shown for each subgroup, each the result of a 1000-simulation Monte Carlo analysis. The horizontal axis depicts potential cost-effectiveness thresholds, while the vertical axis depicts the proportion of simulations for which clopidogrel resulted in a greater net monetary benefit than did aspirin at the indicated threshold. QALY = quality-adjusted life-year.

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Discussion 

We found that in patients with peripheral vascular disease or a prior stroke, secondary prophylaxis with clopidogrel was within traditional limits of societal cost-effectiveness. In patients with peripheral arterial disease, the increase in quality-adjusted life expectancy with clopidogrel as compared with aspirin was 0.55 QALYs, almost 7 months, at a cost of $25,100 per QALY. Stroke patients benefited less substantially from clopidogrel therapy, gaining 0.17 QALYs, just over 2 months, at a cost of $31,200 per QALY. Although aspirin was both cheaper and more effective in post–myocardial infarction patients, this finding was driven by the increased rate of vascular death in clopidogrel-treated patients in CAPRIE.

Although the cost of clopidogrel has been featured prominently in the literature 2, 5, 7, 8, 9, clopidogrel remained relatively cost-effective for patients with either peripheral vascular disease or a previous stroke, even at a daily cost that was almost twice the average wholesale cost. More impressive were the cost-effectiveness ratios resulting from prices negotiated by large purchasers. At a daily cost of $1.80, clopidogrel cost $14,900 per QALY gained in patients with peripheral vascular disease, whereas in patients with a recent stroke, clopidogrel therapy was less expensive than aspirin. This raises an interesting distinction between these analyses. For patients with peripheral arterial disease, both the additional medical costs incurred during the prolonged lifetime, as well as the price of clopidogrel, contribute to the cost discrepancy between clopidogrel and aspirin. In stroke patients, for whom the gain in life expectancy is less substantial, only the price of clopidogrel accounts for the difference in cost between the two therapies.

Our findings were most sensitive to the efficacy of clopidogrel. In the poststroke subgroup, it was only in the lower range of the efficacy estimate, when clopidogrel was equal or less efficacious than aspirin, that it became financially unattractive. However, as ticlopidine, which has a similar mechanism of action to clopidogrel, has been shown to be superior to aspirin in this group of patients 56, 57, we believe that this extreme is unlikely. In the post–myocardial infarction sample, our results were almost entirely driven by the increased rate of vascular death in clopidogrel-treated patients. Given that this increased rate was not seen in another trial (58), there may be a potential for benefit, and further analysis in this group of patients is warranted.

It is useful to consider the origin of these disparate outcomes. We might expect that patients at greatest risk of adverse events would benefit the most from improved platelet inhibition. This was not the case, however, as the group with the lowest event rate, peripheral arterial disease patients, benefited more than did stroke patients, who had the greatest risk. Post–myocardial infarction patients experienced event rates comparable with patients with peripheral vascular disease but were least helped by clopidogrel. This heterogeneity may be due to a difference in disease process, although the accepted pathophysiologic mechanism and previous antiplatelet trials argue against this. More likely, undertreatment of risk factors in patients with peripheral vascular disease may make improved antiplatelet therapy more advantageous for these patients than for those with a recent stroke or myocardial infarction for whom there is already aggressive risk factor modification.

The question remains of how to treat patients who have characteristics of two of these conditions, particularly if one is a myocardial infarction. A post hoc analysis in the CAPRIE study combined patients with myocardial infarction as their qualifying event with the 2144 patients who were included because of a recent stroke or peripheral vascular disease and a remote history of myocardial infarction. In this larger cohort, clopidogrel was associated with a reduction in risk of 7.4%, suggesting that clopidogrel does remain cost-effective in patients who have had a previous myocardial infarction.

Our study also demonstrated the importance of side effects. While not as substantial as gains due to reduced vascular events, avoidance of hemorrhage contributed to the cost-effectiveness of clopidogrel in all patient groups. Thrombotic thrombocytopenic purpura was uncommon and did not markedly affect the cost-effectiveness of clopidogrel.

Our study has limitations. Our analysis was based on a predominantly white, largely male sample and considered three patient ages. We did not explicitly model other events and interventions, such as coronary artery bypass grafting, percutaneous coronary interventions, carotid endarterectomy, peripheral arterial bypass, and hospital admissions for unstable angina or heart failure. CAPRIE patients who were treated with clopidogrel were hospitalized less frequently than those treated with aspirin, and hospitalizations were not subdivided by diagnosis or subgroup (59). We assessed equal, age-adjusted health care costs, including costs for cardiovascular procedures and hospitalizations that were not explicitly modeled, for both clopidogrel and aspirin. The conservative assumption that these events occur equally with either therapy penalized the clopidogrel arm of our model.

We also assumed a constant probability of events over time, which was a conservative assumption because the occurrence of fewer events favored the aspirin arm of the model. Another characteristic of the analysis that favored aspirin was that the number of concurrent chronic conditions was limited to two. These biases suggest that the true cost-effectiveness ratio for clopidogrel in each subgroup studied may be lower than the base case.

Other authors have discussed how cost might affect the use of clopidogrel 2, 8, 9. In four cost-effectiveness analyses of clopidogrel versus aspirin for either secondary stroke prevention 8, 11, 12 or secondary prophylaxis of coronary artery disease (10), two considered a narrow time horizon, which may underestimate the long-term benefits seen with prophylactic therapy for conditions with potential long-term disability 8, 12. Further, the units used (dollars per event averted) limit comparison with other treatments. Although our analysis differs from that of Sarasin and colleagues (11) for secondary stroke prophylaxis, our results support one another. The results of Gaspoz and colleagues (10), who studied a slightly different sample, are qualitatively similar to our findings in patients with a prior myocardial infarction. Our study broadens this work to include all three groups of patients.

The CAPRIE study demonstrated that clopidogrel provided a clear benefit for patients with peripheral vascular disease. Our findings indicate that this benefit may be achieved at a cost that is within traditional societal limits. In patients with a recent stroke, the benefit from clopidogrel therapy is less substantial but still acceptable from a cost standpoint. This treatment decision may be made more difficult by the presence of a similarly cost-effective therapy in the form of the aspirin/dipyridamole combination (11). Our analyses indicate that clopidogrel is cost-effective in patients with peripheral arterial disease, a recent stroke, or either of these in combination with a prior myocardial infarction. Still, the effectiveness, and therefore cost-effectiveness, of clopidogrel in patients whose sole indication for therapy is a recent myocardial infarction warrants further evaluation.

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