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Three Part Question

In patients undergoing [urgent Coronary Arterial Bypass grafting] can surgery [with recent clopidogrel administration] be safely performed [early without excessive bleeding]

Clinical Scenario

You have been asked to perform urgent CABG on a 72 year old gentleman who has just undergone angiography for acute coronary syndrome. He had been admitted that day with chest pain at rest for 24 hours, and the Troponin T was found to be 0.95. The cardiologist has found a 30% left main stem disease and severe triple vessel disease with good LV function. He received 300mg of clopidogrel on admission. He has chest pain on minimal exertion although he has no ECG changes and his blood pressure is 140/70. The cardiologists are keen for you to get on with his surgery, but you would like to delay this gentleman's surgery 7 days, thus you decide to summarize the evidence for this decision.

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 143 papers were found. In addition all major guidelines were included and their reference lists searched. 14 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
Purkayastha et al, 2006, UK	Meta-analysis of 11 comparative studies of patients undergoing CABG from 1999 to 2004 (n = 4002). 605 patients taking clopidogrel at the time of surgery compared with 3397 patients who stopped at least seven days before surgery	Meta-analysis of cohort studies (Level 2a)	Mortality	No mortality difference. (OR 1.01 CI 0.41-2.48)	Non randomised studies were included. Studies were not matched for clopidogrel and control groups.
			Ventilation requirement	Increased in Clopidogrel group ( OR 2.81 CI 1.63 – 4.86)
			Adverse events	Increaed in Clopidogrel group ( OR 1.53 CI 1.02 – 2.32)
			Blood Loss	Weighted mean increase of 323mls in clopidogrel group
			Blood product Transfusion	Increased need for transfusion
			Re-exploration rate	Increased in Clopidogrel groups
Kapetanakis et al, 2006, USA	1572 patients undergoing isolated OFF-PUMP CABG 281 had clopidogrel within 7 days of CABG and 1291 did not have clopidogrel Risk adjusted analysis and matched pair analysis performed		Mortality	1.4% vs. 1.4%, p = 1	Retrospective single-institution analysis. The Clopidogrel group was twice as likely to be an urgent case and 10% more likely to have had an MI.
			Blood Transfusion	Increased in clopidogrel group OR = 2.6, 95% CI, 1.94 to 3.60, p <0.01
			Re-exploration	Increased in clopidogrel group OR = 5.1, 95% CI, 2.47 to 10.47, p<0.01
			Blood loss	Clopidogrel 400mls (100-3400)
Kapetanakis et al, 2005, USA	Retrospective study of 2359 patients undergoing isolated CABG 415 had clopidogrel prior to CABG surgery compared with 1944 patients who did not have clopidogrel before surgery	Cohort study (level 2b)	Mortality	Clopidogrel mortality not significantly different	Retrospective single-institution analysis Small sample size to detect mortality differences
			Re-exploration	Higher in clopidogrel group OR =4.9, 95% CI, 2.63 to 8.97, p<0.01
			Blood loss	Clopidogrel 400mls (100-2000)
			Transportation	Increased need in packed red blood cell transfusions OR = 2.2, 95% CI, 1.70 to 2.84, p <0.01
Yende et al, 2001, USA	Cohort study (Level 3b)	Retrospective analysis of 247 patients undergoing CABG at a single institution 51 patients had clopidogrel prior to CABG surgery and 194 did not	Re-exploration	Clopidogrel group 5/51 (9.8%%). Control group 3/194 1.6% p =0.01	Non randomized study. Small numbers Actual chest drainage not reported
			Need for Red blood cells	Clopidogrel group 72.6 % Control group 51.6%, p = 0.007
			Excessive chest drainage	Clopidogrel group 19.6% Control group 12.4% P=0.18
Hongo et al, 2002, USA	Prospective study of 224 consecutive patients undergoing non emergent first-time CABG. Compared those with preoperative clopidogrel exposure within seven days (n = 59) to those without exposure (n = 165).	Cohort study (Level 2b)	Bleeding	Clopidogrel group 2.51 U, Control group 1.74 U p = 0.036	Non-randomized study.
			Chest Drainage	Clopidogrel mean 1,224mls Control mean 840mls P=0.001
			Morbidity	Extubation within 8 hours clopidogrel group 54.2%. Control group 75.8%, p = 0.002 Hospital discharge 5 days Clopidogrel 33.9% Control group 46.7% p = 0.094
			Re-operation rate	Reoperation for bleeding was 10-fold higher in the clopidogrel group (6.8% vs. 0.6%, p = 0.018).
Engelberger et al, 2003, Switzerland	Analyzed the intra- and postoperative outcome of 505 consecutive patients who underwent isolated CABG Compared two groups: those with clopidogrel exposure until 72 h prior to surgery (n = 136) with those without exposition to clopidogrel (n = 369)	Cohort study (level 2b)	Blood loss	Clopidogrel group 1485mls +/-310mls. Control group 780 ml +/- 105mls P = 0.003	Observational study. preoperative characteristics, especially the rate of unstable angina and incidence of PCI prior to surgery were not similar in both groups.
			Re-exploration rate	Clopidogrel group 8pts 5.9% Control group 5pts 1.2%, P < 0:01
			Red blood cells	Clopidogrel group 4.6 +/- 2.3. Control group 1.5+/- 2.2 P=0.027
Leong et al, 2005, Australia	Prospective study of 919 patients who had isolated coronary surgery 24 patients were on clopidogrel only, 598 were on aspirin only, 61 were on both, and 236 were on neither. Clopidogrel (n = 85) versus no clopidogrel (n = 834)	Cohort study (level 2b )	Chest drainage in on pump patients	Clopidogrel 720mls(200-3,780mls) Control 615mls(50-4,500mls) P=0.02	Small number of clopidogrel patients
			Blood transfusion in on pump patients	Clopidogrel 63%, Control 52% P=0.06
			Re-exploration	Clopidogrel 2.6%, Control 1.2% P=0.28
Ascione et al, 2005, UK	All in house referrals for CABG from Jan 2001 to Jan 2002. 473 patients 91 had clopidogrel	Cohort study (level 2b)	Mortality	Clopidogrel group 7/91 (8%) Control group 4/379 (1%) P=0.0008
			Chest Drainage	Clopidogrel group 1000mls(675-1450mls) No anticoagulants 800mls(550-1100mls)
			Re-exploration	Clopidogrel group 11/91 (12%) Control group 11/379 (3%)
Karabulut et al, 2004, Turkey	1628 consecutive patients undergoing isolated CABG 48 received clopidogrel preoperatively.	Cohort study (level 2b )	Red cell transfusion	Clopidogrel 0.5±0.9. Control 0.4±0.9 P=NS.	Retrospective analysis Very small number in clopidogrel group Incredibly low re-opening rate in 1628 patients
			Chest Drainage	Clopidogrel 719±265mls. Control group 612±350mls P=NS
			Reoperation for bleeding	Clopidogrel 1patient. Control group 0 patients
Fox et al, 2004, UK	12,562 patients with acute coronary syndrome without ST elevation Clopidogrel 300 mg loading followed by 75 mg 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	Subanalysis of a Prospective Randomized controlled trial (Level 1b)	All patients cardiovascular death, myocardial infarction or stroke	Clopidogrel 14.5% vs 16.2% in aspirin group (RR, 0.89, 95%CI 0.71-1.11)	Full CURE study risk of death, MI , stroke for clopidogrel 9.3% versus 11.4%, p<0.05. Study was sponsored by Bristol-Myers-Squibb Post-operative blood loss not documented.
			Adverse events whilst awaiting CABG	Clopidogrel group 5.6% Aspirin group 6.7% P=NS
			Major Bleeding in CABG patients	Clopidogrel group 9.6% Placebo group 7.5%, RR = 1.27, 95% CI 0.96 to 1.69, p =0.095) Clopidogrel < 5 days pre surgery. 9.6% Aspirin < 5 days pre surgery 6.3% Clopidogrel > 5 days pre surgery 4.4% Aspirin > 5 days 5.3%
			Re-exploration	Clopidogrel group 4.1% Aspirin only group 2.3%, RR = 1.79, 95% CI 0.85 to 3.74
			Death, MI or stroke or major bleeding	Clopidogrel group risk is RR 0.84, 95% CI 0.76-0.94.
Steinhubl et al, 2002, USA	2116 patients who were to undergo elective PCI or deemed to have high likelihood of undergoing PCI Clopidogrel 300 mg loading 3 to 24 hours before PCI followed by 75 mg daily vs placebo in addition to aspirin (81 to 325 mg)	PRCT (Level 1a)	One-year incidence the composite of death, myocardial infarction or stroke	Clopidogrel group 8.5% Placebo group 11.5% P=0.02	No documentation of post-operative blood loss
			Major Bleed	Clopidogrel group 8.8% Placebo group 6.7% P=NS
			Procedural major bleeding	Clopidogrel group 7.7% Placebo group 5.9% P=NS
Sabatine et al, 2005, USA	3491 patients within 12 hours after the onset of an ST-elevation Myocardial infarction Clopidogrel 300 mg loading followed by 75 mg daily vs placebo.	Cohort study (Level 2b)	Composite of an occluded infarct-related artery or death or recurrent myocardial infarction	Primary endpoint was 15% in clopidogrel group and 21.7% in the placebo group	Only an observation from a randomised study. Post-operative blood loss or blood product usage not assessed
			Bleeding in 136 CABG patients who received clopidogrel within 5 days	Clopidogrel group 9.1 Placebo group 7.9%
Braunwald et al, 2002, USA	1999 Systematic review of a wide range of issues in coronary arterial bypass grafting This review updated a previous review conducted in 1991	Systematic review (level 1a) - Summary article	Antiplatelet therapy for patients undergoing elective CABG planned	In patients taking clopidogrel in whom elective CABG planned, clopidogrel should be withheld for 5 to 7 days. Level of evidence : B.	Search strategies not given Only 2 references given in support of this first recommendation
			Patients with unstable angina or NSTEMI	In hospitalized patients in whom an early non interventional approach is planned, clopidogrel should be added to ASA and continued for >1mth. Level of Evidence : B. Patients where PCI is planned should have clopidogrel started and and continued for > 1 mth. Level of Evidence : A
Mehta et al, 2001, UK	2658 patients with NSTEMI undergoing PCI in the CURE study Clopidogrel (n=1313) Placebo (N=1345)	Subanalysis of a PRCT ( level 1b)	Myocardial Infarction prior to PCI	Clopidogrel group 47/1313 (3.6%) Placebo group 68/1345 (5.1%)	Mean duration of study drug administration to PCI was 6 days
			Myocardial Infarction or refractory ischaemia before PCI	Clopidogrel group 159/1313 (12.1%) Placebo group 206/1345 (15.3%) P=0.008
			CV death, myocardial infarction 30 days after PCI	Clopidogrel group 116/1345 (8.8%) Placebo group 169/1313 (12.6%) P=0.008

Comment(s)

There are 2 issues to consider when deciding on the timing of surgery in a patient on clopidogrel: firstly does clopidogrel cause an increase in bleeding complications and their sequelae, and secondly does withholding clopidogrel in these high risk patients expose them to an increase in thrombotic complications prior to surgery? In answer to the first question, a meta-analysis of 11-cohort studies in 2004 combined papers providing data on patients who either did or did not receive clopidogrel. There was a mean increase in blood loss of 323mls, a 6-fold increase in the odds of re-exploration, an increase in adverse events and ventilation time, but no difference in hospital length-of-stay or mortality. It must be remembered that the 11-cohort studies do not take into account the fact that the clopidogrel groups are likely to be a higher risk group of patients. Since this meta-analysis many additional studies have reported. Kapetanakis[2005, 2006] compared 281 patients having clopidogrel before off-pump surgery to 1291 patients who did not have clopidogrel and also a larger group of 2359 patients having all types of coronary surgery. There were no mean differences in blood loss or mortality in either the off-pump or on-pump groups, but there was a 2-3 times increase in the odds of transfusion and a 5-times increase in the odds of re-exploration. Yende showed an increase in re-exploration rate, Hongo showed an increased re-exploration rate and a 50% increase in chest drainage, Englberger showed an increase in re-exploration, red cell usage and a doubling in chest drain output, Leong showed a modest increase in chest drainage and an increase in blood transfusion but not an increase in re-exploration. Ascione in a 1-year cohort study of in-patient referrals found that there was a 3-fold increase in the re-exploration rate, a significantly increased mortality and an increased chest drainage. In contrast to these studies Karabulut found no increase in chest drainage, re-exploration or RBC transfusion, although their study included 1628pts, but only 48 on clopidogrel. There were also many more similar small cohort studies to those above that we have not listed here, with similar findings. Thus in answer to the first part of our question, clopidogrel certainly does increase the risk of re-exploration by 2-5 times, of blood product usage and increases the chest drain blood loss by 30-100%. The second issue addresses the issue of the importance of clopidogrel in these patients. The CURE study in 2004 was a double blinded PRCT of 12,562 patients who had undergone a non-ST myocardial infarction. It showed that only 9.3% of patients randomized to clopidogrel and aspirin had either death, an MI or stroke compared to 11.4% for the aspirin alone group. They also analysed the findings of 2072 patients who subsequently underwent CABG. The overall benefits of clopidogrel were maintained by the end of the study in the CABG group. In addition there was a trend to fewer complications prior to surgery whilst awaiting the intervention(5.6%vs6.7% NNT:90). For patients continuing clopidogrel to within 5-days pre-operatively, there was a non-significant excess in re-exploration and 9.6% of clopidogrel patients versus 6.3% of placebo patients had a major bleeding event. The CURE authors recommend that it is safe for all NSTEMI patients to be started on clopidogrel and aspirin on admission, but that clopidogrel should be stopped for 5-days pre CABG. The CREDO trial showed benefits for clopidogrel loading 6-hours pre-PCI and continuing for up to 1-year in a PRCT of 2116patients. There was a high incidence of major bleeds in patients then undergoing CABG, although it was not significantly different between groups. The CLARITY-TIMI-28 trial randomized 3491patients who had suffered a Myocardial Infarction within 12-hours to clopidogrel or placebo. They showed a 7% absolute risk benefit for suffering Death, MI or stoke. A small group of 136patients who underwent CABG did not have an excess risk of bleeding although blood loss or blood product usage was not reported. The ACC/AHA guidelines of 2002 on the management of NSTEMI's and unstable angina recommend immediate administration of clopidogrel if PCI is planned. They furthermore recommend cessation of clopidogrel for 5-7 days prior to CABG, giving this a grade-B level of evidence. The PCI-CURE study provide important data when considering withholding clopidogrel for patients pre CABG. 1313 patients received clopidogrel prior to PCI with 1345 placebo controls in this double blind PRCT. The mean wait for PCI was 6-days and the incidence of an MI while waiting for their intervention was 5.1% in the placebo group but only 3.6% in the clopidogrel group (p=0.04, NNT 66 to prevent an MI pre PCI). Thus there is a clear benefit for patients suffering an MI, an NSTEMI or shortly to require PCI in commencing clopidogrel, and this therapy should not be withheld even if a possible future CABG is possible. However once it is decided that CABG is required, the AHA guidelines, the meta-analysis and multiple cohort studies would recommend cessation of clopidogrel for 5-7 days. The CURE study and its sub-analyses show that cessation of clopidogrel in these patients for this time period is associated with a 1% increase in the risk of MI.

Clinical Bottom Line

Patients requiring urgent coronary arterial bypass grafting should have their clopidogrel omitted for 5-7 days prior to their surgery if their clinical condition allows. The benefits in terms of the reduction in peri-operative blood loss, reduced risk of re-exploration and reduction of blood product usage is at the expense of a 1% increase in the risk of MI while awaiting surgery.

References

1. Purkayastha S, Athanasiou T, Malinovski V, Tekkis P, Foale R, Casula R, Glenville B, Darzi A. Does clopidogrel affect outcome after coronary artery bypass grafting? A meta-analysis. Heart 2006;92(4):531-2.
2. Kapetanakis EI, Medlam DA, Petro KR, Haile E, Hill PC, Dullum MK, Bafi AS, Boyce SW, Corso PJ. Effect of clopidogrel premedication in off-pump cardiac surgery: are we forfeiting the benefits of reduced hemorrhagic sequelae? Circulation 2006;113(13):1667-74.
3. Kapetanakis EI, Medlam DA, Boyce SW, Haile E, Hill PC, Dullum MK, Bafi AS, Petro KR, Corso PJ. Clopidogrel administration prior to coronary artery bypass grafting surgery: the cardiologist's panacea or the surgeon's headache? European Heart Journal 2005;26(6):576-83.
4. Yende S, Wunderink RG. Effect of clopidogrel on bleeding after coronary artery bypass surgery. Crit Care Med 2001;29(12):2271-5.
5. Hongo RH, Ley J, Dick SE, Yee RR. The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol 2002;40(2):231-7.
6. Englberger L, Faeh B, Berdat PA, Eberli F, Meier B, Carrel T. Impact of clopidogrel in coronary artery bypass grafting. Eur J Cardiothorac Surg 2004;26(1):96-101.
7. Leong JY, Baker RA, Shah PJ, Cherian VK, Knight JL. Clopidogrel and bleeding after coronary artery bypass graft surgery. Ann Thorac Surg 2005;80(3):928-33.
8. Ascione R, Ghosh A, Rogers C, Cohen A, Monk C, Angelini GD. In hospital Patients Exposed to Clopidogrel Before Coronary Artery Bypass Graft Surgery: A Word of Caution. Annals of Thoracic Surgery 2005;79:1210-6.
9. Karabulut H, Toraman F, Evrenkaya S, Goksel O, Tarcan S, Alhan C. Clopidogrel does not increase bleeding and allogenic blood transfusion in coronary artery surgery. Eur J Cardiothorac Surg 2004;25(3):419-23.
10. 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 revascularization for non-ST-elevation acute coronary syndrome: the CURE Trial. Circulation 2004;110(10):1202-8.
11. Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288(19):2411-20.
12. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon J, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352(12):1179-89.
13. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction--2002: summary article... Circulation 2002 October 1;106(14):1893-0.
14. Mehta SR, Yusuf S, Peters R, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H-J, Zhao F, Chrolavicius S, Copland I, Fox KA. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527-33.