Cochrane for Clinicians

Putting Evidence into Practice

Aspirin Combined With Clopidogrel (Plavix) Decreases Cardiovascular Events in Patients with Acute Coronary Syndrome

Am Fam Physician. 2007 Dec 1;76(11):1643-1645.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). See CME Quiz on page 1611.

Clinical Scenario

A 65-year-old man with a history of myocardial infarction is on low-dose aspirin. His peripheral vascular disease has worsened over the past year.

Clinical Question

Should physicians combine aspirin with clopidogrel (Plavix) in patients with a high risk of cardiovascular disease or in patients with acute coronary syndrome?

Evidence-Based Answer

A combination of aspirin and clopidogrel decreased cardiovascular events in patients at high risk of cardiovascular disease and in those with acute coronary syndrome. However, the risk of major bleeding events outweighed the benefits in all high-risk patients except those with acute coronary syndrome.1

Practice Pointers

Cardiovascular disease affects more than 79 million Americans and is the leading cause of mortality in the United States.2 Nearly 700,000 Americans die from heart disease each year, which accounts for 29 percent of all deaths in the United States.3 Standard risk reduction measures, including lipid lowering, blood pressure control, and aspirin therapy, reduce morbidity and mortality in patients at higher risk of cardiovascular disease. Compared with placebo, low-dose aspirin reduces the risk of nonfatal stroke by 25 percent in patients at high risk of occlusive vascular events, such as those with acute or previous vascular disease or other predisposing conditions.4 Clopidogrel improves outcomes in patients with recent coronary artery stent placement.5 Prior to this study, it was unclear whether combination therapy with aspirin and clopidogrel was superior to aspirin alone in high-risk groups.

The Cochrane reviewers included two large randomized controlled trials with a total of 28,165 patients. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial included patients at high risk of cardiovascular events, which is defined as clinically evident cardiovascular disease or multiple risk factors. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial enrolled patients who had a recent non-ST segment elevation acute coronary syndrome. The patients were given aspirin plus clopidogrel or aspirin plus placebo. Primary outcomes included mortality (from myocardial infarction, stroke, cardiovascular causes, all-causes), nonfatal myocardial infarction, nonfatal stroke, unstable angina, heart failure, revascularizations, major and minor bleeding, and all adverse events. Analysis was by intention-to-treat.

When evaluating data from both studies, the review showed that patients who were given aspirin plus clopidogrel had a lower risk of cardiovascular events compared with those given aspirin alone. However, they also had a higher risk of major bleeding, and there was an unacceptable rate of major bleeding in patients who had a higher risk of cardiovascular disease but who did not have acute coronary syndrome.6

Aspirin combined with clopidogrel has been shown to decrease the risk of cardiovascular events in patients at higher risk of cardiovascular disease, as well as in those with acute coronary syndrome. The risk of major bleeding in these patient populations is also increased; therefore, therapy with aspirin and clopidogrel is recommended only for patients with acute coronary syndrome who have demonstrated a positive risk-benefit ratio.7 Patients with a higher risk of cardiovascular disease, but without acute coronary syndrome, should remain on low-dose aspirin therapy unless they present with acute coronary syndrome in the appropriate clinical setting.8 This review excluded studies that followed or treated patients for less than 30 days. Although the optimal treatment length is unknown, the National Institute for Health and Clinical Excellence recommends 12 months of treatment with clopidogrel plus aspirin for patients following non-ST segment acute coronary syndromes.9

Cochrane Abstract

Background: Aspirin is the prophylactic antiplatelet drug of choice for persons with cardiovascular disease. However, protection with anti-platelet therapy in persons with a high risk of cardiovascular disease is unsatisfactory in absolute terms. Adding a second antiplatelet drug to aspirin may produce additional benefit for those at high risk and those with established cardiovascular disease.

Objectives: To quantify the effects (both benefit and harm) of adding clopidogrel (Plavix) to standard long-term aspirin therapy for preventing cardiovascular events in persons at high risk of cardiovascular disease and those with established cardiovascular disease.

Search Strategy: Central (Issue 2, 2006), Medline (2002 to May 2006), and Embase (2002 to May 2006) were searched. Online registers of ongoing trials and reference lists from original articles and reviews were checked.

Selection Criteria: All randomized controlled trials comparing long-term (more than 30 days') use of aspirin plus clopidogrel, with aspirin plus placebo, or with aspirin alone in patients with coronary disease, ischemic cerebrovascular disease, or peripheral arterial disease, or in patients at high risk of atherothrombotic disease (with data for at least one of the outcomes) were included.

Data Collection and Analysis: Data were collected on the following outcomes and analyzed where appropriate: mortality (from myocardial infarction, stroke, cardiovascular causes, all-causes), nonfatal myocardial infarction, nonfatal stroke, unstable angina, heart failure, revascularizations, major and minor bleeding, and all adverse events. Quantitative analysis of outcome was based on an intention-to-treat principle. The overall treatment effect was estimated by the pooled odds ratio (OR) with 95% confidence interval (CI) using a fixed-effect model (Mantel-Haenszel).

Main Results: Two randomized controlled trials were found. Patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study were at high risk of cardiovascular events, with or without an established cardiovascular disease. Patients enrolled in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study had a recent non-ST segment elevation acute coronary syndrome. The use of clopidogrel plus aspirin, compared with placebo plus aspirin, was associated with a lower risk of cardiovascular events (OR = 0.87; 95% CI, 0.81 to 0.94; P < 0.01) and a higher risk of major bleeding (OR = 1.34; 95% CI, 1.14 to 1.57; P < 0.01). Overall, we would expect 13 cardiovascular events to be prevented for every 1,000 patients treated with the combination, but six major bleeds would be caused. Treatment effects differed in the two trials.

The CURE trial, confined to persons with acute non-ST segment coronary syndromes, showed definite evidence of benefit from treatment. For every 1,000 persons treated for an average of nine months, 23 events would be avoided and 10 major bleeds would be caused.

In the CHARISMA trial that randomized persons at high cardiovascular risk defined in terms of pre-existing cardiovascular diseases or risk factors, the effects of treatment were less marked and were consistent with the play of chance. For every 1,000 persons treated for an average of 28 months, five cardiovascular events would be avoided and three major bleeds would be caused.

Authors' Conclusions: The available evidence demonstrates that the use of clopidogrel plus aspirin is associated with a reduction in the risk of cardiovascular events compared with aspirin alone in patients with acute non-ST coronary syndrome. In patients at high risk of cardiovascular disease, but who are not presenting acutely, there is only weak evidence of benefit, and hazards of treatment almost match any benefit obtained.


These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).

Address correspondence to Christopher W. Walker, MAJ, USAF, MC, at Christopher.Walker1@travis.af.mil. Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Air Force Medical Department or the U.S. Air Force service at large.

REFERENCES

1. Keller TT, Squizzato A, Middeldorp S. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease. Cochrane Database Syst Rev. 2007;(3):CD005158.

2. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, et al., for the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee [Published correction appears in Circulation 2007;115:e172]. Circulation. 2007;115:e69–171.

3. Centers for Disease Control and Prevention. Heart disease, 2007. Accessed October 24, 2007, at: http://www.cdc.gov/HeartDisease/.

4. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients [Published correction appears in BMJ 2002;324:141]. BMJ. 2002;324:71–86.

5. Galla JM, Lincoff AM. The role of clopidogrel in the management of ischemic heart disease. Curr Opin Cardiol. 2007;22:273–9.

6. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706–17.

7. Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL, et al. Effects of aspirin dose when used along 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.

8. Campbell CJ, Smyth S, Montalescot G, Steinhubl SR. Aspirin dose for the prevention of cardiovascular disease: a systematic review. JAMA. 2007;297:2018–24.

9. Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al. A rapid and systematic review on clinical effectiveness and cost-effectiveness of clopidogrel used in combination with aspirin compared to aspirin alone in the treatment of non-ST-segment-elevation acute coronary syndromes (ACS) (Assessment Report). National Institute for Clinical Excellence on behalf of the National Health Service, United Kingdom, 2004. Accessed October 24, 2007, at: http://guidance.nice.org.uk/download.aspx?o=110467.

The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Drs. Walker, Dawley, and Fletcher present a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/ab005158.html.

The series coordinator for AFP is Clarissa Kripke, MD, Department of Family and Community Medicine, University of California, San Francisco.


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