Interact CardioVasc Thorac Surg 2006;5:755-760. doi:10.1510/icvts.2006.143156
© 2006 European Association of Cardio-Thoracic Surgery
Best evidence topic - Coronary |
Should high risk patients receive clopidogrel as well as aspirin post coronary arterial bypass grafting?
Babu Kunadiana,
Andrew R. Thornleya,
Thotala N. Babub and
Joel Dunninga,*
a Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK
b Department of Cardiology, Lincoln Medical Health Center, New York, USA
Received 31 August 2006;
accepted 1 September 2006
*Corresponding author. Tel./fax: +44-780-1548122.
E-mail address: joeldunning{at}doctors.org.uk (J. Dunning).
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Abstract
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A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether clopidogrel should be given in addition to aspirin in high risk patients after coronary bypass surgery to reduce thrombotic complications. High risk patients would include patients recently post MI or patients with a patent stent in situ. Altogether 511 papers were identified using the below mentioned search and all major international guidelines were included. Eleven presented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group, relevant outcomes and weaknesses were tabulated. The 2004 American College of Chest Physicians (ACCP) guidelines recommend 9–12 months of clopidogrel in addition to aspirin for patients undergoing coronary arterial bypass grafting (CABG) for non-ST segment elevation acute coronary syndrome (grade 1C). This is based on subanalyses of the CURE and CAPRIE studies that showed significant reductions in the incidence of death, myocardial infarction and stroke in patients who had CABG during these trials. A randomised trial is currently underway to investigate this further. Thus, patients post CABG who have had a recent NSTEMI or have a stent not covered by a graft should have clopidogrel in addition to aspirin for 9–12 months.
Key Words: Clopidogrel; Cardiac surgical procedures; Antiplatelet therapy
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1. Introduction
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A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
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2. Clinical scenario
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You are reviewing a 55-year-old patient in the clinic who underwent coronary bypass grafts 6-weeks ago after he suffered a non-ST segment myocardial infarction (NSTEMI) the week before. You notice that the cardiologist saw him last week and restarted his clopidogrel in addition to the aspirin you gave him. The cardiologist wrote in his letter that he recommenced this on the basis of the 2004 ACCP guidelines. You resolve to investigate this further.
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3. Three-part question
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In patients post [urgent coronary arterial bypass grafting] should [clopidogrel be given in addition to aspirin] to reduce the chance of [thrombotic complications].
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4. Search strategy
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Medline 1966–May 2006
[Exp Thoracic surgery/OR thoracic surgery.mp OR CABG. mp OR coronary art$ bypass.mp OR heart surgery.mp OR cardiac surgery.mp OR exp Cardiac surgical Procedures/OR cardiac operation.mp OR heart operation.mp] AND [clopidogrel.mp or Plavix.mp].
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5. Search outcome
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A total of 511 papers were found. In addition, all major guidelines were included and their reference lists searched. Of note, this topic updates a previous related BET [2]. Eleven papers were deemed to represent the best evidence on the topic and are summarized in Table 1.
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6. Discussion
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The American College of Chest Physicians (ACCP) seventh conference on antithrombotic and thrombolytic therapy published their guidelines in 2004 [3]. For patients who undergo CABG for non-ST segment elevation ACS, they recommend that clopidogrel should be started in addition to aspirin post-surgery and continued for 9–12 months. This recommendation is based on the CAPRIE study and the CURE study.
The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study reported an 8.7% relative risk reduction in the primary composite endpoint (first occurrence of ischaemic stroke, myocardial infarction or vascular death) favour of clopidogrel (75 mg/day) over aspirin (325 mg/day) in a multicentre RCT of 19,185 patients with a history of recent ischaemic stroke, recent myocardial infarction or symptomatic peripheral arterial disease [4]. A sub-analysis of the CAPRIE database showed that in 1480 patients with a previous history of cardiac surgery, clopidogrel was associated with a relative risk reduction of 39% for vascular death, 38% for myocardial infarction, 25% for all-cause rehospitalisation, and 27% for rehospitalisation for ischaemia or bleeding. A major drawback of this study is the lack of information about the type of cardiac surgery previously performed in these patients.
The CURE (Clopidogrel in Unstable angina to prevent Recurrent Events trial) randomised patients with acute coronary syndromes (n=12,562) to treatment with clopidogrel (300 mg then 75 mg/day) or placebo in addition to aspirin (75–325 mg/day). The antiplatelet combination resulted in a 20% risk reduction relative to aspirin alone (9.3% vs. 11.4%, P<0.001) in the primary endpoint of cardiovascular death, myocardial infarction or stroke over a mean nine-month treatment period [5]. The antiplatelet combination produced a 19.0% reduction relative to aspirin alone in the risk of cardiovascular death, myocardial infarction or stroke among those patients who underwent CABG surgery during the initial hospitalisation and an 11.0% relative risk reduction among patients who underwent CABG surgery at any time during the treatment period. The clinical benefits of aspirin plus clopidogrel were mainly evident during the preoperative period with 18% relative risk reductions in the primary endpoint seen before CABG surgery compared to 3% relative risk reduction following CABG surgery relative to aspirin alone [6]. The main pitfall of the study is that patients who did not take the drug after surgery were still included in the clopidogrel group and the effect of clopidogrel was not adjusted for other risk factors.
The Clopidogrel for the Reduction of Events During Observation (CREDO) trial evaluated the short-term benefits of combined aspirin and clopidogrel pre-treatment and the long-term benefits of sustained therapy in the setting of percutaneous coronary intervention (PCI) in an RCT of 2116 patients. After one year of treatment, patients receiving clopidogrel (75 mg/day) plus aspirin (81–325 mg/day) had a significant 26.9% relative risk reduction in the combined endpoint of death, myocardial infarction or stroke [7]. A subgroup analysis of patients who underwent CABG without PCI had a modest reduction of 1-year events (RRR 16.7%) with clopidogrel [8]. But this was a post hoc analysis and the number of patients in this group was small.
The recent observational study by Gurbuz et al. [9] showed that clopidogrel therapy with aspirin was independently associated with decreased symptom recurrence and adverse cardiac events following OPCAB. However, extending clopidogrel use beyond 30 days did not have a significant effect on defined end points.
In order to provide convincing evidence of combination of clopidogrel and aspirin versus aspirin alone on saphenous vein graft disease after CABG, a double-blinded, randomised control is currently underway. The CASCADE (Clopidogrel After Surgery for Coronary Artery Disease) is randomising 100 patients to clopidogrel or placebo in addition to 162 mg of aspirin post CABG, with one year angiography as the primary outcome measure [10].
With regard to the other high risk group of patients, namely patients post percutaneous intervention (PCI) having CABG, we found no studies that looked at the outcome of stent patency post-CABG. The ACCP guidelines [11] recommend clopidogrel in addition to aspirin for all patients post PCI for 9–12 months (Grade 1A). A small study by Kaluza et al. [12] demonstrated that there was an instent thrombosis rate of around 20% with a similar mortality in patients having surgery of any type shortly post PCI. Therefore, if the stent is not covered by a graft intraoperatively then it would seem reasonable to follow the ACCP guideline with 9–12 months of clopidogrel. However, if the stent is covered by a graft more distally, there is no evidence to support continuation of clopidogrel.
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7. Clinical bottom line
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The 2004 ACCP guidelines recommend 9–12 months of clopidogrel in addition to aspirin for patients undergoing CABG for non-ST segment elevation ACS. This is based on subanalyses of the CURE and CAPRIE studies that showed significant reductions in the incidence of death, myocardial infarction and stroke in patients who had coronary bypass grafting (CABG) during these trials. A randomised trial is currently underway to investigate this further. Patients post CABG who have had a recent NSTEMI or have a stent not covered by a graft should have clopidogrel in addition to aspirin for 9–12 months.
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References
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- Stein PD, Schunemann HJ, Dalen JE, Gutterman D. Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126:600S–608S.
- Bhatt DL, Chew DP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 2001; 103:363–368.
- 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; 345:494–502.[Abstract/Free Full Text]
- Fox KA, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ, Yusuf S. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularisation for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004; 110:1202–1208.
- Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, De Lago A, Wilmer C, Topol EJ. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomised controlled trial. J Am Med Assoc 2002; 288:2411–2420.[Abstract/Free Full Text]
- Saw J, Topol EJ, Steinhubl SR, Brennan D, Berger PB, Moliterno DJ. CREDO Investigators. Comparison of long-term usefulness of clopidogrel therapy after the first percutaneous coronary intervention or coronary artery bypass grafting versus that after the second or repeat intervention. Am J Cardiol 2004; 94:623–625.[CrossRef][Medline]
- Gurbuz AT, Zia AA, Vuran AC, Cui H, Aytac A. Postoperative clopidogrel improves mid-term outcome after off-pump coronary artery bypass graft surgery: a prospective study. Eur J Cardiothorac Surg 2006; 29:190–195.[Abstract/Free Full Text]
- Kulik A, Le May M, Wells GA, Mesana TG, Ruel M. The clopidogrel after surgery for coronary artery disease (CASCADE) randomised controlled trial: clopidogrel and aspirin versus aspirin alone after coronary bypass surgery [NCT00228423]. Curr Control Trials Cardiovasc Med 2005; 6:15.
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Abstract
1. Introduction