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Should clopidogrel be stopped prior to urgent cardiac surgery?

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 OR OR coronary art$ OR heart OR cardiac OR exp Cardiac surgical Procedures/ OR cardiac OR heart] AND [ or]

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,
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 surgeryMeta-analysis of cohort studies (Level 2a)MortalityNo 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 requirementIncreased in Clopidogrel group ( OR 2.81 CI 1.63 – 4.86)
Adverse eventsIncreaed in Clopidogrel group ( OR 1.53 CI 1.02 – 2.32)
Blood LossWeighted mean increase of 323mls in clopidogrel group
Blood product TransfusionIncreased need for transfusion
Re-exploration rateIncreased in Clopidogrel groups
Kapetanakis et al,
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 performedMortality1.4% vs. 1.4%, p = 1Retrospective 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 TransfusionIncreased in clopidogrel group OR = 2.6, 95% CI, 1.94 to 3.60, p <0.01
Re-explorationIncreased in clopidogrel group OR = 5.1, 95% CI, 2.47 to 10.47, p<0.01
Blood lossClopidogrel 400mls (100-3400)
Kapetanakis et al,
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 surgeryCohort study (level 2b)MortalityClopidogrel mortality not significantly differentRetrospective single-institution analysis Small sample size to detect mortality differences
Re-explorationHigher in clopidogrel group OR =4.9, 95% CI, 2.63 to 8.97, p<0.01
Blood lossClopidogrel 400mls (100-2000)
TransportationIncreased need in packed red blood cell transfusions OR = 2.2, 95% CI, 1.70 to 2.84, p <0.01
Yende et al,
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 notRe-explorationClopidogrel group 5/51 (9.8%%). Control group 3/194 1.6% p =0.01Non randomized study. Small numbers Actual chest drainage not reported
Need for Red blood cellsClopidogrel group 72.6 % Control group 51.6%, p = 0.007
Excessive chest drainageClopidogrel group 19.6% Control group 12.4% P=0.18
Hongo et al,
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)BleedingClopidogrel group 2.51 U, Control group 1.74 U p = 0.036Non-randomized study.
Chest DrainageClopidogrel mean 1,224mls Control mean 840mls P=0.001
MorbidityExtubation 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 rateReoperation for bleeding was 10-fold higher in the clopidogrel group (6.8% vs. 0.6%, p = 0.018).
Engelberger et al,
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 lossClopidogrel group 1485mls +/-310mls. Control group 780 ml +/- 105mls P = 0.003Observational study. preoperative characteristics, especially the rate of unstable angina and incidence of PCI prior to surgery were not similar in both groups.
Re-exploration rateClopidogrel group 8pts 5.9% Control group 5pts 1.2%, P < 0:01
Red blood cellsClopidogrel group 4.6 +/- 2.3. Control group 1.5+/- 2.2 P=0.027
Leong et al,
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 patientsClopidogrel 720mls(200-3,780mls) Control 615mls(50-4,500mls) P=0.02Small number of clopidogrel patients
Blood transfusion in on pump patientsClopidogrel 63%, Control 52% P=0.06
Re-explorationClopidogrel 2.6%, Control 1.2% P=0.28
Ascione et al,
All in house referrals for CABG from Jan 2001 to Jan 2002. 473 patients 91 had clopidogrelCohort study (level 2b)MortalityClopidogrel group 7/91 (8%) Control group 4/379 (1%) P=0.0008
Chest DrainageClopidogrel group 1000mls(675-1450mls) No anticoagulants 800mls(550-1100mls)
Re-explorationClopidogrel group 11/91 (12%) Control group 11/379 (3%)
Karabulut et al,
1628 consecutive patients undergoing isolated CABG 48 received clopidogrel preoperatively.Cohort study (level 2b )Red cell transfusionClopidogrel 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 DrainageClopidogrel 719±265mls. Control group 612±350mls P=NS
Reoperation for bleedingClopidogrel 1patient. Control group 0 patients
Fox et al,
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 therapySubanalysis of a Prospective Randomized controlled trial (Level 1b)All patients cardiovascular death, myocardial infarction or strokeClopidogrel 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 CABGClopidogrel group 5.6% Aspirin group 6.7% P=NS
Major Bleeding in CABG patientsClopidogrel 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-explorationClopidogrel group 4.1% Aspirin only group 2.3%, RR = 1.79, 95% CI 0.85 to 3.74
Death, MI or stroke or major bleedingClopidogrel group risk is RR 0.84, 95% CI 0.76-0.94.
Steinhubl et al,
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 strokeClopidogrel group 8.5% Placebo group 11.5% P=0.02No documentation of post-operative blood loss
Major BleedClopidogrel group 8.8% Placebo group 6.7% P=NS
Procedural major bleedingClopidogrel group 7.7% Placebo group 5.9% P=NS
Sabatine et al,
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 infarctionPrimary endpoint was 15% in clopidogrel group and 21.7% in the placebo groupOnly 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 daysClopidogrel group 9.1 Placebo group 7.9%
Braunwald et al,
1999 Systematic review of a wide range of issues in coronary arterial bypass grafting This review updated a previous review conducted in 1991Systematic review (level 1a) - Summary articleAntiplatelet therapy for patients undergoing elective CABG plannedIn 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 NSTEMIIn 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,
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 PCIClopidogrel 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 PCIClopidogrel group 159/1313 (12.1%) Placebo group 206/1345 (15.3%) P=0.008
CV death, myocardial infarction 30 days after PCIClopidogrel group 116/1345 (8.8%) Placebo group 169/1313 (12.6%) P=0.008


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.


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  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.
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  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.
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