Why Don’t We Practice Evidence-based Medicine?

Despite several studies showing an advantage of early treatment with clopidogrel in the patient presenting with acute coronary syndrome, or prior to percutaneous coronary intervention (PCI),^1–6 this treatment is frequently not given early enough to achieve maximum benefit. In the United States, PCI is usually applied as an ad hoc procedure at the same time as the cardiac catheterization. Due to concerns regarding increased bleeding risk from clopidogrel at the time of possible coronary artery bypass graft surgery, it is often not administered early, but is witheld until after the coronary anatomy is clarified in case the patient ends up being referred for surgery. Whether this possible bleeding risk justifies withholding clopidogrel prior to cardiac catheterization (with attendant ad hoc angioplasty) remains controversial. Current recommendations by the AHA/ACC guidelines committee for acute coronary syndrome address, but do not resolve, these conflicts.⁷ Clopidogrel, in addition to aspirin, is given a class 1 indication, but only for those patients who are not felt to require coronary artery bypass surgery. Unfortunately, it is quite difficult to predict which patients will require coronary artery bypass graft surgery before the results of coronary anatomy are known, especially since only a minority of patients will end up being referred to surgery. For example, in over 65,000 patients in the CRUSADE Initiative, bypass surgery was performed in only 11.5% of patients presenting with acute coronary syndrome.⁸ Because of the prominent role of ad hoc angioplasty and fear for bleeding complications at the time of surgery, the ACC/AHA recommendations end up supporting the strategy of withholding clopidogrel prior to cardiac catheterization, effectively limiting its proven benefit prior to PCI. Data on the surgical bleeding risk due to clopidogrel come from the randomized CURE trial involving patients presenting with acute coronary syndromes, and from retrospective and prospective registries.^1,9–13 In the CURE trial, there was an overall increase in major bleeding of 1% over a nine-month period, with a specifically increased risk in patients undergoing coronary artery bypass graft surgery.¹ This major bleeding primarily consisted of the need for blood transfusions. This bleeding risk, however, is counterbalanced by the anti-ischemic efficacy of clopidogrel seen even prior to coronary artery bypass graft surgery.⁹ Patients undergoing bypass graft surgery in CURE who received clopidogrel had a 22% relative risk reduction in the primary endpoint (cardiovascular death, myocardial infarction or stroke over a median follow-up of nine months), similar to the risk reduction found in the overall CURE population.¹ Interestingly, although a particularly strong benefit of clopidogrel was seen in the CAPRIE study in patients with a prior history of coronary artery bypass graft surgery,¹⁴ the reduction of ischemic events due to clopidogrel in the surgical cohort of CURE was due to pre-surgical reduction in ischemic events.⁹ Furthermore, anti-ischemic benefits in CURE were seen within the first 24 hours, thus reducing the need for urgent surgery in an unstable patient, leading to a lower risk surgical procedure.¹ In the CURE study, patients undergoing coronary artery bypass surgery and randomized to clopidogrel needed more blood transfusions and required longer times in the operating room, but were not more likely to need to go back to the operating room for bleeding or to spend more time on bypass (personal communication, Salim Yusuf). This is in contradistinction to some (but not all) registry data which did associate the use of clopidogrel with significant increases in returns to the operating room for bleeding.^11–13 However, the conclusions arising from each of the registries are limited due to the differences in baseline characteristics between the groups undergoing surgery who were not on clopidogrel. Patients undergoing surgery on clopidogrel in these studies were more unstable prior to surgery due to ischemia, and were more likely to need adjunctive therapy such as intra-aortic balloon pumps, or to require emergent surgery. (The study by Kuchalakanti et al. in this issue of the Journal of Invasive Cardiology shares the problem of comparing a lower risk to a higher risk group¹⁵). Despite these high-risk characteristics, patients on clopidogrel prior to surgery tended to have less post-operative ischemic events.^12,13,15 Interestingly, this potential benefit of clopidogrel has often been under-emphasized in these papers. One paper even excluded two patients from their analysis because they died from causes other than bleeding, reflecting a bias on the parts of the authors in this arbitrary exclusion.¹¹ Because there were only eight adverse events reported in this small study, the inclusion of these patients might have significantly altered their conclusions. The next question addresses the importance of early treatment with clopidogrel in patients presenting with an acute coronary syndrome who do not require bypass graft surgery. As noted above, only a small proportion (approximately 10%) of patients presenting with acute coronary syndrome are treated with coronary artery bypass graft surgery. The benefit of clopidogrel was seen in patients treated medically (which still accounts for nearly half of patients with acute coronary syndrome in the United States), and in particular those treated with PCI.^1,3 Multiple studies have consistently supported a benefit to pre-treatment with a thienopyridine prior to PCI, even when contemporary antithrombotic agents are used.^2–5 In the CREDO trial of patients undergoing PCI, a benefit of pre-treatment with clopidogrel was not seen unless the patient was given the therapy at least 15 hours prior to the angioplasty procedure.¹⁶ A patient receiving a clopidogrel load of 300 mg at the time of presentation with an acute coronary syndrome would be therefore adequately pre-treated if referred the following day for coronary arteriography and an ad hoc angioplasty procedure. For interventional cardiologists this strategy would be preferable to withholding thienopyridines until the coronary anatomy is known. One may ask why has the bleeding risk at surgery for a minority of patients been perceived as more important than the anti-ischemic benefits seen in a larger population? The key word may be perception. Surgical bleeding is more visibly apparent and immediate than the prevention of myocardial infarctions or ischemia. Even though major surgical bleeding remains the exception, minor, nuisance bleeding is quite obviously increased in the peri-operative period when patients are on clopidogrel. To surgeons, the increased bleeding has personal and political implications. First, the surgeon needs to expend extra time and effort controlling not only the major, but also the increase in minor bleeding associated with clopidogrel use. As interventional cardiologists are becoming increasingly more aggressive in their use of percutaneous approaches to revascularization, cardiac surgeons are finding themselves with an increasingly greater percentage of high-risk patients being referred for surgical coronary artery revascularization. Having to spend additional time and effort on these patients due to the use of clopidogrel exacerbates this situation. Additionally, the surgical community is exposed to a great deal of scrutiny from national, state and local oversight organizations. A marker frequently used to assess quality of care with surgery is the need for blood transfusions. Therefore, taking a patient to surgery who has recently been on clopidogrel is likely to lead to an increased need for blood transfusions, which will be counted as a “demerit” to the surgeon and the surgical program, and thus is a disincentive. For all of these reasons, many cardiac surgeons will not agree to operate unless a patient has been off clopidogrel for seven days, as suggested in the package insert. However, finger-pointing should not be directed at these cardiac surgeons, even if one argues that their logic is flawed. After all, it is not cardiac surgeons who make the decision regarding the medications to prescribe for the patient who initially presents with an acute coronary syndrome — it is the cardiologists, hospitals and other primary care deliverers. The prolonged in-hospital management of patients awaiting surgery is frustrating to many non-surgeon clinicians, increases the expense of caring for these patients and ties up needed hospital beds. These disincentives to cardiac surgeons and general cardiologists have led many programs to withhold therapy despite proven efficacy, resulting in an inability to translate evidence-based medicine into clinical practice. This retrospective review by Kuchulakanti et al (see pages 5–7) offers a different strategy, allowing for the early administration of clopidogrel. They propose administering clopidogrel upon presentation, but discharging stabilized patients who require bypass surgery, allowing the clopidogrel effects to wear off before surgery. It is difficult to draw any conclusions from this study due to its retrospective nature and the differences in risk between the groups. However, it does suggest an alternative approach, while allowing for the benefits of early clopidogrel administration. Interventional cardiologists are often poorly positioned to provide pre-procedure input regarding the patient who presents with an acute coronary syndrome, since such patients are often managed by others until the patient arrives at the cardiac catheterization laboratory for a coronary arteriogram. As interventional cardiologists, we are in a position to educate our colleagues. Some time in the not-so-distant past, aspirin was routinely discontinued prior to coronary bypass graft surgery. This practice is much less common today because surgeons and non-surgeons were educated on the anti-ischemic benefits of aspirin as a reasonable counterbalance to the increased bleeding risk. Today, it is not only the surgeon who should perhaps reconsider the risk/benefit ratio of antiplatelet therapy, it is also the non-surgeon managing the patient in the hospital. Even if a surgeon insists on delaying surgery to allow the effect of clopidogrel to wear off, the evidence would suggest that this is preferable to altogether avoiding early administration of this agent. It is a therapy with proven efficacy, albeit occasionally inconvenient.

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