EDITORIAL COMMENT
Acute Coronary SyndromesDon't Bypass the Clopidogrel*
Colin M. Barker, MD and
H. Vernon Anderson, MD ,*
Scripps Clinic, La Jolla, California
University of Texas Health Science Center, Houston, Texas
* Reprint requests and correspondence: Dr. H. Vernon Anderson, Cardiology Division, University of Texas Health Science Center, 6431 Fannin, Suite 1.246, Houston, Texas 77030 (Email: h.v.anderson{at}uth.tmc.edu).
Key Words: coronary artery bypass surgery • clopidogrel • acute coronary syndromes
The thienopyridine agent clopidogrel, added to aspirin and antithrombin therapies, benefits patients with non–ST-segment elevation acute coronary syndromes (ACS). The efficacy of clopidogrel compared with placebo in these patients was firmly established first in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, in which there was an absolute reduction in the primary end point (cardiovascular death, myocardial infarction, and stroke) of 2.1% (1). The relative risk of clopidogrel compared with placebo was 0.80. This risk reduction was equally present in patients treated either medically or, very importantly, with revascularization. Clopidogrel reduced the risk overall of ischemic vascular events, with effects noticeable within 24 h of initiation of treatment and continuing for up to 12 months (2). Thus, the current American College of Cardiology/American Heart Association (ACC/AHA) guidelines for managing patients with ACS include a Class I recommendation (Level of Evidence: A) for early dual antiplatelet therapy with aspirin and either clopidogrel or, alternatively, a glycoprotein IIb/IIIa inhibitor (3). The emphasis here is on the word "early."
Effective platelet inhibition comes with a potential cost of increased bleeding. In the CURE trial, dual antiplatelet therapy compared with aspirin alone was associated with significant increases in major bleeding (3.7% vs. 2.7%) and minor bleeding (5.1% vs. 2.4%), but not in life-threatening bleeding events (2.2% vs. 1.8%). Bleeding was more common in the patients requiring coronary artery bypass surgery (CABG) for their coronary disease, but only when clopidogrel was discontinued <5 days before surgery (1). Other reports have confirmed this. In the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines) registry, patients who underwent CABG within 5 days of discontinuing clopidogrel had a significant increase in blood transfusions (65% vs. 57%) (4). In contrast, if CABG was delayed  5 days after stopping clopidogrel, bleeding was similar to that in those patients who had not received it. A multicenter, retrospective cohort analysis of 596 randomly selected ACS patients requiring CABG showed that discontinuing clopidogrel within 5 days before surgery increased risks for reoperation, major bleeding, and longer length of stay (5). Thus, the ACC/AHA guidelines also contain the recommendation to withhold clopidogrel for 5 to 7 days before CABG (3). Yet somehow, despite the guideline recommendations and the data behind them, some centers do not routinely administer early, upfront clopidogrel to all ACS patients. Ostensibly the reasoning for this is the increased bleeding risk that may arise if the ACS patients were to need CABG. This concern prevails, although only 10% to 15% of ACS patients will require CABG during their hospitalization (1,4,6).
In this issue of the Journal, Ebrahimi et al. (7) present data from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial on this topic. In this large, prospective, randomized study of ACS patients undergoing early invasive management, the timing of clopidogrel initiation was left to investigator discretion, but was carefully recorded in the case report forms. A 5-day delay before CABG was recommended for patients who received clopidogrel. In this trial, 1,539 (11.1%) of the patients underwent CABG before discharge, and 50.9% had received clopidogrel before surgery. The patients exposed to clopidogrel had a longer median duration of hospitalization, but lower rates of composite ischemic events (death, myocardial infarction, or unplanned revascularization) at 30 days, primarily because of fewer myocardial infarctions in the clopidogrel-treated patients. By multivariate analysis, clopidogrel exposure before CABG was an independent predictor of freedom from composite ischemia at 30 days (odds ratio: 0.67, 95% confidence interval: 0.48 to 0.92, p = 0.001). Furthermore, there was no association between clopidogrel exposure and both non-CABG and post-CABG major bleeding. Regarding the timing of clopidogrel exposure, those who received the drug and underwent CABG within 5 days had comparable rates of ischemia at 30 days and 1 year, with no difference in bleeding before or after surgery, when compared with those who never received clopidogrel. Interestingly, those exposed to clopidogrel who went for surgery 5 days after the last dose had significantly lower rates of 30-day (8.8% vs. 17.3%, p = 0.001) and 1-year (14.9% vs. 21.4%, p = 0.02) composite ischemia and less transfusions compared with those not exposed. Finally, when tabulated as net adverse clinical events to account for both types of unwanted outcomes, including composite ischemia or non-CABG major bleeding, the results favored early clopidogrel administration followed by 5-day delay for those patients needing CABG; this group had the lowest net adverse clinical events of all 3. This is precisely the position of the ACC/AHA guidelines (3).
This study has several limitations, but the data clearly support the current guidelines both in the recommendation of early clopidogrel in all ACS patients as well as waiting 5 days in the minority of patients who will undergo CABG. The primary limitation of this work is the lack of robustness inherent in a retrospective analysis of an unblinded, nonrandomized cohort. Second, the trial was not powered for the cohort of patients undergoing CABG. Perhaps the greatest limitation and confounder is the lack of data on clopidogrel use after the initial hospitalization, because this might explain some of the ischemia benefit. The data show a strong association between pre-operative exposure to clopidogrel and being discharged on the drug, as well as between never receiving clopidogrel and not being discharged on the drug. Specifically, 65.6% exposed were discharged on clopidogrel and only 14.7% not exposed were discharged on the drug (p < 0.0001). Further studies would be necessary to determine whether some of the ischemia benefit is from the pre-CABG exposure or the treatment after being discharged.
Individualized care is rapidly evolving with new discoveries and innovations that go beyond traditional risk factors. In cardiology, this is especially apparent in antiplatelet therapy. Point-of-care platelet function assays may eventually enable physicians to tailor antiplatelet therapy to the individual patient. A small study on healthy volunteers evaluated platelet reactivity using the VerifyNow P2Y12 assay (Accumetrics, San Diego, California) after a loading dose of 600 mg clopidogrel. The data suggest that early platelet inhibition with clopidogrel varies widely among individuals, and recovery of platelet function depends less on the number of days after the exposure and more on the magnitude of the initial inhibition (8). If they can be validated in clinical use, point-of-care assays may help tailor the management of ACS patients who go on to receive CABG by identifying those at low risk for surgical bleeding. Additionally, recent advances in pharmacogenomics and the mechanism of clopidogrel metabolism have generated interest in applying a patient's genetic information to antiplatelet therapy. Carriers of certain alleles in the cytochrome P450 system (especially CYP 2C19*2) have lower concentrations of the active metabolite of clopidogrel and a greater number of ischemic events (9,10). Whether this information can be translated into clinical medicine and improve patient care remains to be seen, but it is very exciting and appears promising.
In conclusion, even with very specific guidelines to help standardize and improve the care of patients with ACS, much remains in the hands of the treating physicians and the institutions where they work. Despite the known benefits of early clopidogrel administration, even on initial hospital presentation and before coronary angiography, this practice is far from universal. The data presented by Ebrahimi et al. (7) support the current ACC/AHA guideline recommendations, and hopefully this may sway those who continue to withhold early clopidogrel despite its safety and proven efficacy.
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Footnotes
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Dr. Anderson has received honoraria for speaking engagements from Bristol-Myers Squibb, Sanofi-Aventis, Daiichi Sankyo, PDL Biopharma, and The Medicines Company.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST segment elevation N Engl J Med 2001;345:495-502.2. Yusuf S, Mehta SR, Zhao F, et al. Early and late effects of clopidogrel in patients with acute coronary syndromes Circulation 2003;107:966-972.[Abstract/Free Full Text] 3. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons J Am Coll Cardiol 2007;50:e1-e157.[Free Full Text] 4. Mehta RH, Roe MT, Mulgund J, et al. Acute clopidogrel use and outcomes in patients with non–ST-segment elevation acute coronary syndromes undergoing coronary artery bypass surgery J Am Coll Cardiol 2006;48:281-286.[Abstract/Free Full Text] 5. Berger JS, Frye CB, Harshaw Q, Edwards FH, Steinhubl SR, Becker RC. Impact of clopidogrel in patients with acute coronary syndromes requiring coronary artery bypass surgery J Am Coll Cardiol 2008;52:1693-1701.[Abstract/Free Full Text] 6. Mehta RH, Chen AY, Pollack CV, et al. Challenges in predicting the need for coronary artery bypass grafting at presentation in patients with non–ST-segment elevation acute coronary syndromes Am J Cardiol 2006;98:624-627.[CrossRef][Web of Science][Medline] 7. Ebrahimi R, Dyke C, Mehran R, et al. Outcomes following pre-operative clopidogrel administration in patients with acute coronary syndromes undergoing coronary artery bypass surgery: the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial J Am Coll Cardiol 2009;53:1965-1972.[Abstract/Free Full Text] 8. Price MJ, Teirstein PS. Dynamics of platelet functional recovery following a clopidogrel loading dose in healthy volunteers Am J Cardiol 2008;102:790-795.[CrossRef][Web of Science][Medline] 9. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel N Engl J Med 2009;360:354-362.[CrossRef][Web of Science][Medline] 10. Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents J Am Coll Cardiol 2008;51:1925-1934.[Abstract/Free Full Text]
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