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A Cost-Effectiveness Analysis of Combination Antiplatelet Therapy for High-Risk Acute Coronary Syndromes: Clopidogrel plus Aspirin versus Aspirin Alone

Mark D. Schleinitz, MD, MS; and Paul A. Heidenreich, MD, MS
[+] Article and Author Information

From Brown University and Rhode Island Hospital, Providence, Rhode Island; and Stanford University Medical Center and VA Palo Alto Healthcare System, Palo Alto, California.


Grant Support: Dr. Schleinitz was supported in part by a Building Interdisciplinary Research Careers in Women's Health (BIRCWH) career development grant (HD43447) from the National Institutes of Health Office of Research on Women's Health, administered through Women and Infants' Hospital, Providence, Rhode Island. Dr. Heidenreich was supported by a Career Development Award from the Veterans Administration Health Services Research and Development Service (CD98326).

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Mark D. Schleinitz, MD, MS, Division of General Internal Medicine, Brown University and Rhode Island Hospital, 593 Eddy Street, MPB-1, Providence, RI 02903; e-mail, Mark_Schleinitz@Brown.edu.

Current Author Addresses: Dr. Schleinitz: Brown University and Rhode Island Hospital, Division of General Internal Medicine, 593 Eddy Street, MPB-1, Providence, RI 02903.

Dr. Heidenreich: VA Palo Alto Healthcare System, 3801 Miranda Avenue, Palo Alto, CA 94304.

Author Contributions: Conception and design: M.D. Schleinitz, P.A. Heidenreich.

Analysis and interpretation of the data: M.D. Schleinitz, P.A. Heidenreich.

Drafting of the article: M.D. Schleinitz.

Critical revision of the article for important intellectual content: M.D. Schleinitz, P.A. Heidenreich.

Final approval of the article: M.D. Schleinitz, P.A. Heidenreich.

Statistical expertise: M.D. Schleinitz.

Collection and assembly of data: M.D. Schleinitz.


Ann Intern Med. 2005;142(4):251-259. doi:10.7326/0003-4819-142-4-200502150-00007
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We performed a cost-effectiveness analysis using a Markov model (4)(DATA 4.0, TreeAge Software, Inc., Williamstown, Massachusetts). We analyzed a reference case assuming a societal perspective (5) and a lifetime time horizon (6). Our analysis was based on the CURE trial, a randomized comparison of 3 to 12 months of therapy with clopidogrel plus aspirin or aspirin alone to prevent cardiovascular death, myocardial infarction, or stroke in 12 562 patients with an acute coronary syndrome (1). We discounted costs and utilities at 3% annually and determined lifetime costs, quality-adjusted life expectancy, and the incremental cost-effectiveness ratio. Sensitivity analyses included 1-way analyses on all data inputs; probabilistic sensitivity analysis; evaluation of varying duration of combination therapy, including potential loss of efficacy over time; and consideration of populations with varying risk.

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Figures

Grahic Jump Location
Figure 1.
Schematic representation of the decision model.

The rectangular node depicts the treatment decision. Representative Markov states are outlined. The remaining 3 subtrees, 1 each for thrombotic events, hemorrhagic events, and side effect, make up the monthly cycle of the model. Multiple events, including multiple events within a subtree, are possible. 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. Not shown is the risk for age-related mortality, present in each cycle.

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Figure 2.
Results of probabilistic sensitivity analysis.

Shown are the results of a 1000-simulation Monte Carlo analysis comparing 1 year of therapy with clopidogrel plus aspirin followed by aspirin alone with aspirin monotherapy. The y-axis depicts the proportion of trials for which clopidogrel with aspirin resulted in a greater net monetary benefit than aspirin alone. QALY = quality-adjusted life-year.

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Figure 3.
Sensitivity analysis on duration of therapy.

Shown are the results of lifetime treatment with aspirin and the results of varying duration of combination therapy with clopidogrel plus aspirin followed by aspirin alone. Lines depict the incremental cost-effectiveness ratio for the next longer duration. Quality-adjusted life expectancy was greatest with 5 years of combination therapy. QALY = quality-adjusted life-year.

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Figure 4.
Two-way sensitivity analysis on annual event rate and the proportion of events attributable to cerebrovascular accidents.

The black circle indicates the base case. QALY = quality-adjusted life-year.

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Comments

Submit a Comment
Clopidogrel plus Aspirin. Can the Cost-Effectiveness Improve?
Posted on February 26, 2005
Enrique J. Sánchez-Delgado
Hospital Metropolitano Vivian Pellas, Managua, Nicaragua
Conflict of Interest: None Declared

The analysis of Schleinitz and Heidenreich should be balanced against two important facts: first, as they state, the first month of combined therapy provides 43% of the potential gain, but only less than 4% of the incremental costs. Clopidogrel is much more expensive than aspirin, and increments the costs significantly. I will show that it is possible to reduce the cost of clopidogrel in up to fifty percent, and still maintain the protective effects and maybe reduce the adverse reactions.

Second, this study apparently did not include the results of the MATCH study (1), which found that life-threatening bleedings, including cerebral bleedings, were higher in the group receiving aspirin and clopidogrel versus clopidogrel alone (2.6% vs 1.3%). This emphasizes the importance to find a way of keeping the positive effects of the combination, minimizing the adverse effects.

Two years ago (2), I proposed to give the combination of aspirin and clopidogrel during the first 30 days. Beyond 30 days, these medications could be given on alternate days, one day aspirin and the other day clopidogrel. That would reduce the cost, probably not affecting the efficacy and maybe reducing the risk of life-threatening bleeds.

With this approach, in the Study CURE (3), the main effect would be reached in the first 30 days (4.3% versus 5.4%), when one needs to treat 91 patients to prevent one event. Beyond 30 days, the events would rise only 0.9% in total (5.2% versus 6.3%), the relative risk reduction would remain 18%, and the absolute risk reduction would then be only 0.16%, resulting in a "number needed to treat" of 625 to prevent an event. It is also important to remember that the effects of aspirin, and of clopidogrel, are irreversible, so they would be active on the day off, and the new, unaffected platelets, would then be inhibited by the other drug. A study to confirm this hypothesis should be done. This strategy could be very useful for the patients (and doctors) with limited economic resources. It could also be useful in cases of aspirin resistance.

References: 1.- Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht HJ; MATCH investigators. Lancet. 2004 Jul 24;364(9431):331-7

2.- Sánchez-Delgado E. Circulation. 2003 Aug 26;108(8):e56

3.- Yusuf S, Mehta SR, Zhao F, et al. Circulation. 2003; 107: 966"“972

Conflict of Interest:

None declared

Cost-Effectiveness of Extended Clopidogrel Therapy for High-Risk Acute Coronary Syndrome ? Some Addi
Posted on March 1, 2005
Peter Eriksson
Interventional Heart Laboratory, Heart Centre, Umea Uniersity, Sweden
Conflict of Interest: None Declared

Sir, - I read with interest the article by Schleinitz and Heidenreich in the February 15, 2005 issue of Annals. However, I am concerned about the author's conclusion, "In patients with high-risk acute coronary syndromes, 1 year of therapy with clopidogrel plus aspiring results in greater life expectancy than aspirin alone, at a cost within the traditional limits of cost-effectiveness". There are evidently better ways to be cost-effective.

In the CURE trial (2) patients with an acute coronary syndrome without ST-segment elevation received clopidogrel or placebo, in addition to aspirin, for a mean of 9 months. Nonetheless, most ischemic events (cardiovascular death, myocardial infarction or stroke) occurred early, and there was basically no difference in the rates of events between the clopidogrel and placebo groups after the first 3 months. Around 85 % of the total benefit achieved after 1 year with clopidogrel was observed already by 3 months (2, 3). The excess risk of bleedings with dual antiplatelet therapy is constant, however, which unfavourably changes the risk-benefit ratio when clopidogrel is given long-term (4). By using clopidogrel for 3 months rather than 1 year, most of the gain of the drug would be achieved, while bleeding hazards as well as costs of therapy would be reduced by approximately 75 %. This would be a judicious compromise between clinical efficiency, side effects and economy.

There is an even more provoking interpretation of the CURE study. The investigators showed that there was no advantage of clopidogrel over placebo at all when the dose of aspirin was 101 to 199 mg (relative risk 0.97; 95 % confidence interval, 0.77 to 1.22, n = 3 109) (5). Obviously, this observation has to be confirmed in a prospective study.

Author: Peter Eriksson, MD, PhD Interventional Cardiology Laboratory Heart Centre University Hospital SE-901 85 Umea Sweden peter.eriksson@medicin.umu.se Fax: +46-90-13 76 33 Conflicts of Interest: I have no conflicts of interest to declare Word count: 298.

References

1. Schleinitz MD, Heidenreich PA. A cost-effectiveness analysis of combination antiplatelet therapy for high-risk acute coronary syndromes: clopidogrel plus aspirin versus aspirin alone. Ann Intern Med 2005; 142: 251-9. {PMID: 15710958}

2. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST- segment elevation (erratum in N Engl J Med 2001; 345: 1716, N Engl J Med 2001; 345: 1506). N Engl J Med 2001; 345: 494-502. {PMID: 11519503}

3. Yusuf S, Mehta SR, Zhao F, Gersh BJ, Commerford PJ, Blumenthal M, et al; Clopidogrel in Unstable angina to prevent Recurrent Events Trial Investigators. Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation 2003; 107: 966-72. {PMID: 12600908}

4. Harding SA, Boon NA, Flapan AD. Antiplatelet treatment in unstable angina: aspirin, clopidogrel, glycoprotein IIb/IIIa antagonist, or all three? Heart 2002; 88: 11-4. {PMID: 12067932}

5. Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL, et al. Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Trial Investigators. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003; 108: 1682-7. [PMID: 14504182}

Effectiveness assumption could overestimate the cost-effectiveness of clopidogrel
Posted on March 14, 2005
Michael B Rothberg
Baystate Medical Center
Conflict of Interest: None Declared

As Schleinitz and Heidenrich point out, their finding that combination antiplatelet therapy with clopidogrel and aspirin in the first year following an acute coronary syndrome "represents good value according to traditional limits of cost-effectiveness" has serious economic implications if adopted into practice.(1) Although decision analytic models offer valuable insight into treatment decisions, such as the observation that the first month of treatment is much more cost-effective than subsequent months, the simplifying assumptions required for modeling can lead to biased conclusions when comparing the cost-effectiveness of an intervention to an external benchmark. Before making treatment or policy decisions based on a decision model, it is important to examine the key assumptions. In this analysis, the authors apply the 20% reduction in overall vascular events seen in the CURE trial(2) equally to non-fatal myocardial infarctions, strokes and death from cardiovascular causes. Although patients randomized to clopidogrel did experience a 23% reduction in non-fatal myocardial infarction, the reductions in stroke (14%) and cardiac deaths (7%) did not reach statistical significance. This finding parallels observations of warfarin in acute coronary syndromes.(3, 4) In CURE, the 95% confidence interval for the relative risk of cardiac death extended from 0.79 to 1.08, making a 20% reduction unlikely. The authors did perform sensitivity analysis, but the minimum risk reduction considered was 10%, greater than the 7% reduction in cardiovascular mortality seen in the trial.

Because there was no long-term quality adjustment for myocardial infarction, any gain in quality-adjusted life years had to come from decreasing rates of stroke and cardiac death. As neither of these outcomes alone nor the combination of the two showed statistically significant decreases with clopidogrel, more data is needed to know the true cost-effectiveness of the treatment. In the meantime, a Monte Carlo analysis using a different relative risk reduction for each outcome based on its 95% confidence interval would offer a truer estimate of the cost- effectiveness of clopidogrel than what has been presented.

References

1. Schleinitz MD, Heidenreich PA. A Cost-Effectiveness Analysis of Combination Antiplatelet Therapy for High-Risk Acute Coronary Syndromes: Clopidogrel plus Aspirin versus Aspirin Alone. Ann Intern Med. 2005;142(4):251-259. 2. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation. N Engl J Med. 2001;345(7):494-502. 3. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347(13):969-74. 4. Anonymous. Effects of long-term, moderate-intensity oral anticoagulation in addition to aspirin in unstable angina. The Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators. Journal of the American College of Cardiology. 2001;37(2):475-84.

Conflict of Interest:

None declared

Authors' Response
Posted on April 15, 2005
Mark D. Schleinitz
Brown University
Conflict of Interest: None Declared

Dr. Rothberg suggests that our analysis would have been stronger had we used outcome specific estimates of the efficacy of clopidogrel when added to aspirin. We agree in theory, and have used this approach in an analysis of clopidogrel monotherapy (1). The CURE trial (2), however, did not report the numbers of each type of event that comprised the composite outcomes. The cardiovascular death rate cited by Rothberg, for example, is itself a composite of deaths due to stroke, myocardial infarction and other cardiovascular causes. We felt that the potential to introduce bias by estimating event rates on aspirin monotherapy as well as combination therapy and using these calculations to approximate outcome specific efficacy was too great to justify this method.

Dr. Eriksson emphasizes our point that the balance of protection from thrombotic events with the risk of hemorrhage is critical in determining the benefit of adding clopidogrel to aspirin, and thereby its cost- effectiveness. Assuming constant relative efficacy of combination therapy, we found that the diminishing absolute benefit in thrombotic event rates is negated by the constant risk of hemorrhage after 5 years. Cost may help specify the "ideal" duration of therapy in one of two ways: at the average individual level, as reflected by the incremental cost- effectiveness ratio (ICER), or at the societal budgetary level, a function of both the ICER as well as the size of the affected population. Variation in both societal preference and available resources means that this "ideal" duration may differ between countries.

Eriksson also notes that in a post-hoc evaluation the efficacy estimate of adding clopidogrel to aspirin varied with the dose of aspirin (3). Aspirin dose was at the physician's discretion. We have shown that efficacy estimates of anti-platelet therapies derived from non-randomized studies may be statistically distinct from results of randomized comparisons (4), and agree that a randomized comparison is warranted to clarify the optimal dose of aspirin for combination therapy.

1. Schleinitz M, Weiss J, Owens D. Clopidogrel versus aspirin for secondary prophylaxis of vascular events: a cost-effectiveness analysis. Am J Med. 2004;116(12):797-806.

2. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.

3. Peters RJ, Mehta SR, Fox KA, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003;108(14):1682- 7.

4. Schleinitz MD, Olkin I, Heidenreich PA. Cilostazol, clopidogrel or ticlopidine to prevent sub-acute stent thrombosis: a meta-analysis of randomized trials. Am Heart J. 2004;148(6):990-7.

Conflict of Interest:

None declared

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Summary for Patients

Is It Cost-Effective To Treat High-Risk Cardiac Patients with Clopidogrel plus Aspirin as Opposed to Aspirin Alone?

The summary below is from the full report titled “A Cost-Effectiveness Analysis of Combination Antiplatelet Therapy for High-Risk Acute Coronary Syndromes: Clopidogrel plus Aspirin versus Aspirin Alone.” It is in the 15 February 2005 issue of Annals of Internal Medicine (volume 142, pages 251-259). The authors are M.D. Schleinitz and P.A. Heidenreich.

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