Meta-analysis Demonstrates Mixed Evidence on CABG in ACS Patients Taking Clopidogrel

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Many ACS patients may safely undergo CABG while on clopidogrel therapy or after recent discontinuation, despite guideline recommendations to the contrary. But data for this strategy are limited, and many factors, including case urgency and surgeon skill, should play into the decision, according to a large meta-analysis published online May 24, 2011, ahead of print in the European Heart Journal.

Current guidelines suggest discontinuing clopidogrel 5 days before CABG. But according to the paper, much of the literature focuses on elective, stable cases rather than ACS patients, who are both more likely to be operated on with recent clopidogrel exposure and at elevated risk of further death and MI without the drug.

Sukhjinder S. Nijjer, BSc, MB ChB, MCRP, of the Imperial College Healthcare NHS Trust (London, United Kingdom), and colleagues conducted a meta-analysis of 34 studies involving 22,584 patients that examined clopidogrel use in patients undergoing CABG. Most studies were not blinded, and 29 observed local experiences, 17 retrospectively and 12 prospectively. Three were subgroup analyses from larger randomized controlled trials of ACS, while 2 were small randomized studies of clopidogrel exposure prior to surgery. Moreover, inclusion and exclusion criteria were not uniformly reported. Only 12 studies specified that they included at least some ACS patients.

Patients with recent clopidogrel exposure were compared with those who were either clopidogrel naïve or had undergone a drug-free washout period. In the entire cohort, which included patients with and without ACS, recent clopidogrel exposure increased the likelihood of mortality (OR 1.6; 95% CI 1.30-1.96; P < 0.00001), but there was no difference in risk of MACE, defined as MI, stroke, and death (OR 1.10; 95% CI 0.87-1.41; P = 0.43).

However, mortality risk was influenced by ACS status. There was no elevated risk of mortality, postoperative MI, stroke, or reoperation among the ACS population (table 1).

Table 1. Outcomes in ACS Patients: Recent vs. No Clopidogrel

Importantly, reoperation risk in patients with recent clopidogrel exposure seemed to decrease over the course of the study period. Early cases (1999-2002) were most likely to require reoperation, while midterm (2003-2006) and recent cases (2007-2009) showed more favorable results as surgical experience grew (table 2).

Table 2. Reoperation Risk Over Time: Recent vs. No Clopidogrel

“This meta-analysis demonstrates that present guidelines are based on limited evidence which do not definitively determine the safety of continuing clopidogrel until CABG in ACS patients,” the investigators write, pointing out that many studies compared ACS patients on dual antiplatelet therapy against more stable patients who received no antiplatelet medications. No studies have considered the effects of higher loading doses or glycoprotein IIb/IIIa inhibitor use, they add.

A randomized controlled trial in ACS patients looking at various clopidogrel discontinuation times before CABG is needed to settle this issue, Dr. Nijjer and colleagues conclude. “In the meantime, the data do demonstrate that many patients have undergone CABG safely with recent clopidogrel exposure,” they say, “and this practice can continue in expert hands in ACS patients who need to continue clopidogrel.”

Increasing Comfort But with Reservations

In a telephone interview with TCTMD, Ajay S. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), said that the meta-analysis looks at an important clinical issue that he encounters regularly as an interventionalist.

“In our lab, we actually give patients clopidogrel before the diagnostic cath. So then in those cases that need to go to surgery, you either have to wait 5 days or you take them to the OR,” he noted. “In the past, there were surgeons who were really reluctant to do that, because there’s no question that it increases bleeding, but now some of the surgeons are more used to dealing with it and they will go ahead.”

Dr. Nijjer told TCTMD in an e-mail communication that adherence to the 5-day guideline varies among centers and countries as well as by clinical urgency.

“In the United States, there may be a financial imperative to operate early, which means patients undergo surgery without delay. . . . In some major UK cardiac centers, the pressure to move patients through their journey quickly (and thus free beds for waiting patients elsewhere) does mean many also get operated on without a 5-day wait. However, in contrast to this practice, the majority of UK patients may wait a long period before surgery, with waits around 12 days being typical,” he said, adding that the delay in that country can be even longer if patients are first admitted to a nonsurgical center. “The concern is that often these patients are waiting for surgery without clopidogrel on board and therefore at increased risk of further ACS during this time.”

In the past, surgeons were also reluctant to operate on patients taking aspirin, Dr. Kirtane reported, but they became more comfortable as research demonstrated that aspirin use can improve acute graft patency and reduce closure. Although there are signs that clopidogrel may carry similar benefits, the drug “is more potent, and there are going to be [new agents] more potent than that,” so surgeons may have reservations, he explained. “But I think that is why the topic is relevant.”

Dr. Kirtane cautioned, however, that the study results do not endorse shortening the delay between clopidogrel and CABG because the 44% mortality increase in ACS patients, though only a trend, approached significance. “To say that there’s no difference is statistically correct, but it is something important to highlight,” especially given that most studies were not randomized and could introduce confounders, he said, suggesting that patients who proceeded to CABG despite clopidogrel use may have been lower risk than those whom surgeons decided were worth the wait.

Also interesting is the finding that reoperation rates decreased over time as surgeons became more accustomed to operating in ACS patients on clopidogrel, Dr. Kirtane added. Even today, though, “surgeons are often going to wait [if possible] just to reduce the bleeding issues, because there has been increasing recognition that bleeding complications are associated with late [adverse] outcomes.”

Experience, Attention Matter

Asked what skills make for ‘expert hands’ in clinicians who choose to perform CABG in ACS patients on clopidogrel, Dr. Nijjer replied that volume matters greatly for cardiothoracic surgeons.

“Rigorous attention to hemostasis throughout the procedure is required, together with precise wound closure. Those performing fewer procedures and more junior teams are less likely to be comfortable with operating on clopidogrel,” he specified. “Perfusionists and anesthetists all have to be closely involved as well as the [intensive therapy unit] physicians, so that any bleeding problems can be detected earlier. The use of blood products should follow protocols.”

Case urgency might also alter outcomes, the paper notes, although details were hard to tease out from the available datasets.

Despite this lack of clarity, said Dr. Nijjer, “[o]ur feeling is that urgency must affect mortality as the patient cohort is simply different than elective cases. Cases are done whilst on intra-aortic balloon pumps, close after [abciximab] infusions and maximum anticoagulation, often without full preoperative workup. Patients may have undetected carotid and lung disease as there is no time to do the scans before the urgent or emergent operation. This will undoubtedly confound the apparent effect of clopidogrel exposure.”

 

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Source:
Nijjer SS, Watson G, Athanasiou T, Malik IS. Safety of clopidogrel being continued until the time of coronary artery bypass grafting in patients with acute coronary syndrome: A meta-analysis of 34 studies. Eur Heart J 2011;Epub ahead of print.

 

 

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