Correspondence Edinburgh University, The Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK

Email k.a.a.fox@ed.ac.uk

Original article

Schleinitz MD and Heidenreich PA (2005) A cost-effectiveness analysis of combination antiplatelet therapy for high-risk acute coronary syndromes: clopidogrel plus aspirin versus aspirin alone. Ann Intern Med 142: 251–259   PubMed

Synopsis

Background

Combined aspirin and clopidogrel treatment offers greater clinical benefit to patients with acute coronary syndromes (ACS) than aspirin alone, but the financial implications of combined therapy have not been fully explored. This treatment might be more economically feasible if offered to high-risk patients only.

Objectives

To evaluate cost-effectiveness of adding clopidogrel to aspirin therapy in high-risk patients with ACS, and assess the optimum therapy duration.

Design and intervention

Schleinitz and Heidenreich analyzed data from the randomized Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, which enrolled patients with non-Q-wave myocardial infarction (MI) or unstable angina and electrocardiographic changes. Patients received 325 mg aspirin daily, with or without 75 mg clopidogrel daily, for 1 year. Exclusion criteria included revascularization during the preceding 3 months, prolonged ST-segment elevation, oral anticoagulation or glycoprotein IIb/IIIa inhibition 3 days previously, and risk of heart failure or hemorrhage. A MARKOV MODEL was constructed on the basis of fatal or nonfatal occurrence of stroke, MI and revascularization, intracerebral or gastrointestinal bleeding, clopidogrel-related thrombocytopenic purpura and age-related death.

Outcome measures

The outcomes were life expectancy, measured in quality-adjusted life years (QALYs), lifetime cost of treatment and the cost-effectiveness ratio of aspirin plus clopidogrel versus aspirin alone.

Results

The model included data from 12,562 patients. Analysis of the 64-year-old base-case patient showed that life expectancy and treatment costs in patients treated with clopidogrel plus aspirin were 9.61 QALYs and US$129,300, after the initial event, compared with 9.51 QALYs and $127,700, respectively, for aspirin monotherapy. When compared with aspirin alone, the incremental cost-effectiveness ratio of combined therapy was $15,400 more per QALY. The life expectancy, effectiveness and cost-effectiveness of combined treatment were dependent on the risk of bleeding associated with clopidogrel; the cost of a QALY grew from $13,400 to $18,800 with an increase in bleeding risk of 13% to 67%. The cost-effectiveness advantage of combined therapy versus aspirin alone was simulated over a range of COST-EFFECTIVENESS THRESHOLDS. When the threshold was $0—which assumed that combined therapy was cost-saving compared with aspirin monotherapy—combined therapy was optimal in only 0.3% of the simulated situations; by contrast, at a threshold of $50,000 per QALY—a figure frequently used as the maximum that society will pay for 1 QALY—it was preferable in 97.2%. For the first month of therapy, the addition of clopidogrel was associated with an increase in survival of 0.04 QALYs at a cost of $54. For up to 1 year, each month of clopidogrel increased survival by 0.005 QALYs at a cost of $140 per month. The cost-effectiveness of clopidogrel plus aspirin began to decline after 1 year.

Conclusion

The addition of clopidogrel to aspirin for 1 year increases life expectancy by 4 weeks in high-risk patients with ACS compared with aspirin alone, and lies within acceptable cost-effectiveness limits.

Commentary

Within ACS, attention has focused on improving the outcomes of patients with ST-elevation MI. Until recently, the extent of atherothrombotic event risk following non-ST-elevation ACS was under-recognized. Robust observational studies have shown that mortality is higher among survivors of non-ST-elevation MI than in those who present with ST elevation.^{1, 2} There is an important clinical need for early and sustained antithrombotic therapy, providing the balance between risk and benefit is favorable.

By using data from the CURE trial³ of 12,562 patients with ACS, which found a 20% reduction in relative risk of death, nonfatal MI or stroke with clopidogrel,³ Schleinitz and Heidenreich performed a cost-effectiveness analysis of clopidogrel plus aspirin versus aspirin alone. The authors constructed a decision-analytic Markov model and performed sensitivity analyses. They concluded that 1 year of clopidogrel plus aspirin compared with aspirin alone achieved greater life expectancy, within the accepted limits of cost-effectiveness (incremental cost-effectiveness $15,400 per QALY). Their conclusions are supported by previous analyses of data from the Swedish hospital register of discharge and death,⁴ a Health Technology Assessment and a NICE appraisal.⁵The incremental cost-effectiveness ratio was 1,365 per life-year gained for trial-like patients and 1,009 for registry-like patients.

What are the strengths and weaknesses of these analyses? A within-trial analysis has the advantage of direct comparison, and of all data being derived from the same source. Disadvantages include the limited time span and the selection of patients for trials, who might differ in their characteristics and management from the wider population. Therefore, estimation of the treatment effect among unselected patients in the Swedish register has provided reassurance that the findings are widely applicable. Wider extrapolations beyond the trial period, however, must be viewed with caution because they assume consistency of benefit and hazard. Projections of the population effects of cost-effectiveness analyses must also be viewed cautiously, as patients who are excluded from trials have event rates and hazards that differ from patients in randomized comparisons.

Treatment duration is crucially important. As reported by Schleinitz and Heidenreich, despite the variation in risk over time, the relative efficacy of clopidogrel did not differ between the initial and subsequent months. More events are prevented in the first 3 months, however, because absolute risk is highest early after ACS. By contrast, the bleeding hazard remained relatively constant; hence the ratio of benefit to risk was lower after the acute phase of ACS.³ The main hazard was bleeding and, in the sensitivity analysis, variation in the hemorrhage probability had a marked influence on the cost-effectiveness estimates. Another crucial issue concerns aspirin dose. The cost-effectiveness analysis assumed that 325 mg was used, but, in fact, doses of 75–325 mg were used. Evidence shows that the bleeding incidence doubles for doses of aspirin over 200 mg, regardless of clopidogrel. Therefore, hazard estimates depend on aspirin dose. A CURE analysis suggested that the optimum daily dose of aspirin is 75–100 mg.⁶

Can these results be generalized to all patients with coronary disease? This will not be possible until the results of the CHARISMA trial, which includes a broad range of vascular risk patients and longer-term treatment, become available.

In conclusion, both analyses discussed here suggest that combining aspirin and clopidogrel is cost-effective when administered for 1 year following ACS, and that costs are comparable with other widely accepted therapies, such as statins or glycoprotein IIb/IIIa inhibitors.

Acknowledgments

The synopsis was written by Chloe Harman, Associate Editor, Nature Clinical Practice.

References

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4. Lindgren P et al. (2004) Cost-effectiveness of clopidogrel in acute coronary syndromes in Sweden: a long-term model based on the CURE trial. J Intern Med 255: 562–570 | Article | PubMed | ChemPort |
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Subject areas under which this article appears: Acute coronary syndromes | Public health | Therapy