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Three Part Question

In patients post [urgent coronary arterial bypass grafting] should [clopidogrel be given in addition to aspirin] to reduce the chance of [thrombotic complications].

Clinical Scenario

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.

Search Strategy

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].

Search Outcome

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 [1292]. Eleven papers were deemed to represent the best evidence on the topic and are summarized in the table

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Stein et al, 2004, USA	American College of Chest Physicians: Guidelines on antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts	Systematic Review (level 1a)	Recommendation for patients who undergo CABG post non-ST-segment elevation ACS	Clopidogrel, 75mg/d, for 9-12 months following the procedure in addition to treatment with aspirin (Grade 1C) Underlying values and preferences: This recommendation places a relatively high value on avoiding myocardial infarction and a relatively low value on avoiding bleeding complications	Search strategies not given Systematic review not performed on this topic Recommendation based largely on findings from CAPRIE and CURE
			Aspirin allergy patients	For patients with coronary artery disease undergoing CABG who are allergic to aspirin, we recommend clopidogrel, 300mg, as a loading dose 6 h after operation followed by 75mg/d po (Grade 1C)
Bhatt et al, 2001, USA	19,185 patients with recent ischaemic stroke, recent MI or symptomatic peripheral arterial disease subgroup analysis of 1480 patients with recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease with previous history of surgery Clopidogrel 75mg daily (n=775) vs aspirin 325 mg/day (n=705)	Cohort study (level 2b)	Composite of vascular death, myocardial infarction, first occurrence of ischaemic stroke	Clopidogrel 5.32% vs. 5.83% events rate per year, P=0.043 (8.7% RR, 95% CI, 0.3–16.1).	Only an observation from a randomised study Exact date of previous cardiac surgery unknown Proportion of patients receiving venous or arterial grafts unknown
			Vascular death	39% Relative risk reductions with clopidogrel relative to aspirin (Clopidogrel 2% vs. 3.3%, P=0.03)
			Myocardial infarction	38% Relative risk reductions with clopidogrel relative to aspirin (Clopidogrel 2.4% vs. 3.9%, P=0.037)
			All cause rehospitalisation	25% Relative risk reductions with clopidogrel relative to aspirin (Clopidogrel 35.8% vs. 47.5%, P=0.002)
			Rehospitalisation for ischaemia or bleeding	27% Relative risk reductions with clopidogrel relative to aspirin (Clopidogrel 10.6% vs. 14.6%, P=0.015)
Fox et al, 2004, UK	12,562 patients with acute coronary syndrome without ST elevation Clopidogrel 300mg loading followed by 75mg daily vs placebo in addition to aspirin for both groups Subgroup analysis of 2,072 patients who underwent CABG surgery after randomisation to oral antiplatelet therapy	Sub analysis of a prospective randomised controlled trial (level 1b)	All patients cardiovascular death, myocardial infarction or stroke 9-month treatment period	Antiplatelet combination resulted in 20% risk reduction relative to aspirin alone (9.3% vs.11.4%, P<0.001)	Study was sponsored by Bristol-Myers-Squibb Clopidogrel was stopped for a median of 10 days after surgery and was restarted in 75.3% of patients who stopped before surgery 24.7% who did not take the drug were included severity of CAD, type of CABG not reported effect of clopidogrel was not adjusted with other risk factors
			Patients undergoing CABG before surgery	Antiplatelet combination resulted in 18% relative risk reduction compared to aspirin (Clopidogrel 5.6% vs. 6.7% in placebo group, RR, 0.82; 95% CI, 0.58–1.16)
			Patients undergoing CABG after surgery	Antiplatelet combination resulted in 3% relative risk reduction relative to aspirin (Clopidogrel 103 vs. 112 in placebo group, RR, 0.97; 95% CI, 0.74–1.26)
			Patients undergoing CABG at any time during the treatment period	Antiplatelet combination resulted in 11% relative risk reduction relative to aspirin Clopidogrel 14.5% vs. 16.2% in aspirin group (RR, 0.89, 95% CI, 0.71–1.11)
			Patients undergoing CABG at any time during intial hospitalisation n=1013	Antiplatelet combination resulted in 19% relative risk reduction relative to aspirin (Clopidogrel 13.4% vs. 16.4% in aspirin group, RR, 0.81, 95% CI, 0.59–1.12)
			Bleeding risk	Clopidogrel 1.3% vs. placebo 1.1% (relative risk, 1.26; 95% CI, 0.93 to 1.71).
Saw et al, 2004, USA	2116 patients who were to undergo elective PCI or deemed to have a high likelihood of undergoing PCI Clopidogrel 300mg loading 3-24 hrs before PCI followed by 75mg daily vs placebo in addition to aspirin (81 to 325mg) 83 patients underwent initial CABG without index PCI 320 patients underwent repeat CABG or PCI after index PCI	Sub-analysis of a prospective randomised controlled trial (level 1b)	One-year incidence the composite of death, MI or stroke	26.9% relative risk reduction in the composite endpoint (Clopidogrel group 8.5%, Placebo group 11.5%, P=0.02)	Post hoc analysis of CREDO trial Observation from randomised study Small size in the CABG group
			Composite of death, MI or stroke	16.7% relative risk reduction (Clopidogrel 12.2% vs. 14.3%, P=0.78) 42.4% relative risk reduction (Clopidogrel 15.4% vs. 24.1%, P=0.05)
Gurbuz et al, 2005, USA	591 OPCAB patients 2000-2004 (mean 37.7±13.4 months) 186 patients clopidogrel for 30 days 139 received clopidogrel for (mean 33.6±12 months) in addition to aspirin	Cohort study (level 2b)	Angina, recurrence, MI, coronary artery intervention, death and sudden death	Clopidogrel receivers had significantly lower angina recurrence (1.8% vs 8.6% P<0.0001), myocardial infarction (0% vs 3.4%, P<0.001), coronary artery intervention (0.6% vs 6.8%, P<0.0001), death (2.2% vs 8.3%, P<0.0001), and sudden death group (0% vs 1.9%, P<0.013) Clopidogrel decreased symptom recurrence (P<0.0001, OR 0.3 (0.15-0.99; 95% CI) and adverse cardiac events (P<0.0001, OR 0.2 [0.10-0.45]; 95% CI)	No preoperative use of clopidogrel small sample size observational study
			Adverse events as short-term and long-term	There was no difference in the incidence of endpoints between short-term (30 days) and long-term receivers of clopidogrel
Kulik et al, 2005, Canada	100 patients undergoing multi-vessel CABG and in whom 2 vein grafts will be used with or without cardiopulmonary bypass Clopidogrel 75mg daily vs placebo in addition to aspirin 162mg, for both groups	Randomised controlled trial (level 1b)	Reduction in intimal hyperplasia, in saphenous vein grafts 12 months after CABG, as assessed by IVUS Vein graft patency and area of stenosis at 1 year Major adverse coronary events (MI, CVA, angina, mortality, need for coronary intervention, hospitilisation for coronary ischaemia) and bleeding complications	Ongoing study-results awaited	Exclusion of patients with preoperative use of clopidogrel
Popma et al, 2004, USA	Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Antithrombotic Therapy during Percutaneous Coronary Intervention	Systematic review (level 1a)	Clopidogrel after PCI	After PCI, we recommend, in addition to aspirin, clopidogrel (75mg/d) for at least 9-12 months (Grade 1A)
Kaluza et al, 2000, USA	40 patients who underwent coronary stent placement less than six weeks before noncardiac surgery requiring general anaesthesia were included in the study (1-39 days average: 13 days). 1996-1998 at a single centre Records searched for adverse events	Retrospective cohort study (level 3b)	Deaths	8/40 patients died (6 MIs and 2 bleeds). 6 of these patients had all antiplatelets withdrawn pre-operatively	All deaths and MIs occurred in patients <14 days post PCI
			Myocardial infarctions	7 MIs (Type of MI compatible with stent thrombosis in all cases)
			Bleeding episodes	11 Bleeding episodes
Braunwald et al, 2002, USA	Systematic review of a wide range of issues in coronary arterial bypass grafting This review updated a previous review conducted in 1999	Systematic review (level 1a)	Antiplatelet therapy for pts undergoing elective CABG planned pts with unstable angina of NSTEMI	In patients taking clopidogrel in whom elective CABG planned, clopidogrel should be withheld for 5-7 days. Level of evidence:B In hospitalised patients in whom an early non-interventional approach is planned, clopidogrel should be added to ASA and continued for 1 month. Level of evidence:B Patients where PCI is planned should have clopidogrel started and continued for 1 month. Level of evidence:A	Search strategies not given

Comment(s)

The American College of Chest Physicians (ACCP) seventh conference on antithrombotic and thrombolytic therapy published their guidelines in 2004 [Stein]. 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 [Bhatt]. 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 [Yusef]. 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 [fox]. 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 [Steinhubl]. A subgroup analysis of patients who underwent CABG without PCI had a modest reduction of 1-year events (RRR 16.7%) with clopidogrel [Saw]. 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. 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 [Kulik] 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 recommend clopidogrel in addition to aspirin for all patients post PCI for 9–12 months (Grade 1A). A small study by Kaluza et al. 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.

Clinical Bottom Line

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.

References

1. 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.
2. 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.
3. 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.
4. 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 CURE trial. Circulation 2004; 110:1202–1208.
5. 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.
6. 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.
7. 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.
8. 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. Curr Control Trials Cardiovasc Med 2005; 6:15.
9. Popma JJ, Berger P, Ohman EM, Harrington RA, Grines C, Weitz JI. Antithrombotic therapy during percutaneous coronary intervention: Seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126:576–599.
10. Kaluza GL, Joseph J, Lee JR, Raizner ME, Raizner AE. Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol 2000; 35:1288–1294.
11. Braunwald E, Antman EM, Beasley JW et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—2002: summary article Circulation 2002; 106:1893–1900.