Should clopidogrel be stopped prior to urgent cardiac surgery?

September 18, 2006

September 18, 2006

Babu Kunadian, Andrew R. Thornley, Marios Tanos, Cardiothoracic Registrars (Department of Cardiothoracic Surgery, James Cook University Hospital and Freeman Hospital, Newcastle-upon-Tyne)

Joel Dunning, Department of Cardiothoracic Surgery, James Cook University Hospital and Freeman Hospital, Newcastle-upon-Tyne

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

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.

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]

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

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.

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.

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.
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?
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?
4. Yende S, Wunderink RG.. Effect of clopidogrel on bleeding after coronary artery bypass surgery.
5. Hongo RH, Ley J, Dick SE, Yee RR.. The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting.
6. Englberger L, Faeh B, Berdat PA, Eberli F, Meier B, Carrel T.. Impact of clopidogrel in coronary artery bypass grafting.
7. Leong JY, Baker RA, Shah PJ, Cherian VK, Knight JL.. Clopidogrel and bleeding after coronary artery bypass graft surgery.
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.
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.
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.
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.
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.
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...
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.