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Should clopidogrel be stopped prior to urgent cardiac surgery
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     a Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK

    b Department of Cardiothoracic Surgery, Freeman Hospital, Newcastle-upon-Tyne, UK

    Abstract

    A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether clopidogrel should be stopped prior to urgent cardiac surgery. Altogether 143 papers were identified using the below mentioned search and all major international guidelines were included. Fourteen 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. We conclude that there are two issues to address when considering this topic. Firstly, whether recent clopidogrel administration causes an increase in blood loss during cardiac surgery, and secondly, whether there is a risk to the patient of withholding clopidogrel and delaying surgery. In answer to the first issue, a meta-analysis of 11 cohort studies and also many additional papers have clearly shown recent clopidogrel administration within 5–7 days of surgery is associated with an increased chest drainage of 30–100%, an increase in blood product usage, and a 2–5 times increase in the need for re-exploration. In answer to the second issue, data from the major trials that provide the basis for the current era of clopidogrel therapy also suggest that witholding clopidogrel prior to a revascularization procedure is associated with a 1% increase in the risk of myocardial infarction. Despite this small increased risk, The American College of Cardiology recommend witholding clopidogrel for 5–7 days when clinically feasible.

    Key Words: Evidence-based medicine; Clopidogrel; Thoracic surgery; Antiplatelet therapy; Reoperation; Post-operative bleeding

    1. Introduction

    A best evidence topic was constructed according to the structured protocol. This protocol is fully described in the ICVTS [1].

    2. 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 h, 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 300 mg 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 summarise the evidence for this decision.

    3. Three-part question

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

    4. 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]

    5. Search outcome

    A total of 143 papers were found. In addition all major guidelines were included and their reference lists searched. Fourteen papers were deemed to represent the best evidence on the topic and are summarised in Table 1.

    6. Discussion

    There are two 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 [2] combined papers providing data on patients who either did or did not receive clopidogrel. There was a mean increase in blood loss of 323 ml, a six-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 et al. [3, 4] 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 and Wunderink [5] showed an increase in re-exploration rate, Hongo [6] showed an increased re-exploration rate and a 50% increase in chest drainage, Englberger et al. [7] showed an increase in re-exploration, red cell usage and a doubling in chest drain output, Leong et al. [8] showed a modest increase in chest drainage and an increase in blood transfusion but not an increase in re-exploration. Ascione et al. [9] in a 1-year cohort study of in-patient referrals found that there was a three-fold increase in the re-exploration rate, a significantly increased mortality and an increased chest drainage. In contrast to these studies Karabulut et al. [10] found no increase in chest drainage, re-exploration or RBC transfusion, although their study included 1628 patients, but only 48 on clopidogrel.

    There were also many more similar small cohort studies to those presented 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 question addresses the issue of the importance of clopidogrel in these patients. The CURE [11] 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 randomised 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% vs. 6.7% 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 [12] showed benefits for clopidogrel loading 6 h pre-PCI and continuing for up to 1 year in a PRCT of 2116 patients. 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 [13] trial randomised 3491 patients who had suffered a myocardial infarction within 12 h to clopidogrel or placebo. They showed a 7% absolute risk benefit for suffering death, MI or stoke. A small group of 136 patients 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 [14] of 2002 on the management of NSTEMIs 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 [15] provides important data when considering withholding clopidogrel for patients pre CABG. Altogether 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.

    7. 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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