Durham, NC - A new comparison of CABG patients who did and did not receive clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals) within five days prior to their surgeries is challenging some of the long-held concerns about bleeding risks in CABG patients. Authors of the analysis found that clopidogrel within five days of CABG was "weakly associated" with an increased need for red blood cell transfusions, but they were no more likely to require reoperation for bleeding than people who had taken it more than five days beforehand.

What's more, many other factors, including which surgeon performed the procedure, female sex, and whether cardiopulmonary bypass was used, were all bigger determinants of bleeding risk than clopidogrel use five days or less before surgery.

According to Dr Kristin Newby (Duke Clinical Research Institute [DCRI], Durham, NC), one of the authors on the paper, the findings speak to the need to think beyond clopidogrel to minimize bleeding risk among patients who require CABG.

"We can't say there is no increased risk of giving clopidogrel; in fact, there probably is some small increase in risk, but let's think about all the other things that come into play. Some of those are things we can change; some we can't—we can't change female sex, but we can change how we use transfusions, and we can think about whether we use cardiopulmonary bypass or off-pump surgery. This study gives us reason to think about all the other things that need to be considered as we're thinking about withholding this potentially helpful drug."

The dilemma is posed in part by existing AHA/ACC guidelines, which give clopidogrel a class 1 recommendation for patients with non-ST-elevation ACS but also advise, as a class 1 recommendation, that clopidogrel be withheld for five days before CABG, if clinical circumstances permit it. Surgeons at many centers are resistant to performing what are more dangerous and technically demanding procedures when patients have recently taken clopidogrel.

Newby and colleagues' study, with first author Dr John Hyung-Jun Kim (DCRI), published in the November 2008 issue of American Heart Journal, looked at bleeding events among 4794 consecutive CABG procedures at Duke between 1999 and 2003. When the results were stratified according to whether patients had or had not received clopidogrel within five days of CABG, Kim et al found that clopidogrel <5 days was not significantly associated with the primary outcome measure of reoperation for CABG-related bleeding, nor for a secondary composite end point of reoperation, transfusion, or hematocrit drop >15%.

Clopidogrel at five days or less was significantly associated with a 40% increased need for red cell transfusion, but this association was weaker than other things assessed by the investigators. In a statistical analysis that assessed the relative statistical strength of different predictive factors, which surgeon performed the procedure was by far the strongest predictor of whether a patient required red blood cell transfusion.

Newby called this one of the "most surprising" findings of the study. "I think that knowing there is a lot of variability in how blood transfusions are used and that surgeons vary in their threshold for taking people back to the OR and for using blood products—we probably need to focus more on what thresholds are and should be for transfusion rather than focusing so much on clopidogrel and how it relates to bleeding."

Senior author on the study, Dr Christopher Granger (DCRI), agreed, adding: "We shouldn't belittle the importance of avoiding bleeding at the time of bypass surgery—that's an important objective. And all other things being equal, it's better not to have received clopidogrel in the five days prior. . . . But the more important question is how to balance the proven early benefit of thienopyridines against the risk of bleeding at bypass surgery in the small proportion who end up needing bypass surgery in that same hospitalization. And the new insight that this paper provides is that there are many other factors that are equally or more important than having received clopidogrel, and we shouldn't focus as much on the timing of clopidogrel issue as we have, and we need to continue to individualize treatment to a specific patient, and if it's a patient who will get substantial early benefit from clopidogrel, then we should more strongly consider its use."

Both Granger and Newby said their findings should reopen discussions with surgeons about when operating on a patient with recent clopidogrel should be considered and what other steps could be taken to make it safer. According to Granger, the analysis "should make us more willing to consider giving clopidogrel up front to patients with ACS, where there's proven benefit, rather than simply summarily avoiding it because of concern over the risk of bleeding at the time of bypass surgery."

Newby cautioned, however: "You have to put yourself in the shoes of the surgeon—bleeding is not a complication you want to have, so it's understandable that there is some concern and reluctance to go forward when there are two antiplatelet therapies—heparin and clopidogrel—on board."

Newby emphasized that the study is observational, from a single center, but she believes it will at least be taken into account when the AHA/ACC guidelines are reviewed. "It's not going to be a level of evidence A, but I think it will be considered, and we've had a lot of discussion about it here and it has got people thinking."

Indeed, Dr Peter Berger, who practiced at Duke before moving to Geisinger Health (Danville, PA), recalls that Dr Peter Smith, one of the coauthors on this paper and chair of cardiothoracic surgery at Duke, had previously tried—unsuccessfully—to have it considered a medical error if cardiologists administered clopidogrel upstream in ACS patients with unknown coronary anatomy. "Dr Smith ought to be credited with having kept an open mind and having helped perform this study," Berger said.

Smith, who also spoke with heartwire about the study results, acknowledged that the issue is "in transition" and that "the decision to give clopidogrel before a diagnostic cardiac catheterization has many factors involved."

But he agreed that the results have perceptibly shifted the risk/benefit equation for clopidogrel pre-CABG. "This is not, by any stretch of the imagination, a full release of Plavix as having no impact on whether or not you should do surgery. This is far from being that. It demonstrates that you can operate on patients who have had Plavix within five days safely, but that always has to be within the context of the medical necessity and urgency of the surgery. . . . The weight of the evidence is shifting a little bit more toward surgery, but it's not a carte blanche."

Smith also pointed out that these data fall short of fully reassuring surgeons, cardiologists, and patients.

"The impact of clopidogrel on surgery has not been properly investigated," he said. "I'll be frank: I think the drug manufacturers have done everyone a disservice by not investigating this. We had to do an observational trial, where the data was prospectively conducted but analyzed in retrospect, and that's a very poor way to determine what is the right thing to do, and of course it's taken us five years to get here. Meanwhile tens of thousands of patients have been randomized to find an effectiveness indication for this drug and very little has been done to assess its impact in the surgical setting."

Berger, also decrying the lack of randomized, controlled trial data for this issue, said he thinks the risk of perioperative bleeding within five days of clopidogrel is "undoubtedly higher than suggested by this confounded observational study."

The true value of this study, says Berger, is in identifying factors unrelated to clopidogrel that affect rates of perioperative bleeding and transfusion. "This study provides additional evidence that we need to develop appropriate guidelines for transfusion of all blood products among patients undergoing cardiac surgery, whether or not they are on clopidogrel," he said.

In terms of what the appropriate delay period should be pre-CABG in patients taking clopidogrel, Berger believes Kim et al's study "doesn't come close" to suggesting that the five- to seven-day recommendation be changed, although it does support a policy of not delaying surgery in ACS patients at high risk of suffering an MI during the waiting period.

The issue is not purely academic, Berger emphasized. "At the AHA meeting, a number of colleagues from around the country and from Canada told me about patients they had cared for who had died while waiting for surgery that was being delayed to let clopidogrel wear off; their surgeons could not be persuaded to operate under any circumstances."