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Editorial
Until a few years ago, we did not understand the pivotal role of platelets in orchestrating the process of inflammation. The discovery in 1998 that CD40 ligand is shed from activated platelets to directly initiate inflammation of the vessel wall1 was a seminal event. It led to a new understanding of the function of platelets, clarifying that, in addition to their well-established function of governance of homeostasis, platelets also have the integrated role of principal modulator of inflammation. Not only do platelets account for 90 percent of the CD40 ligand in the body, but they contain and produce key inflammatory modulators such as platelet-derived growth factor, thrombospondin, P-selectin, and interleukin precursors.2,3 Indeed, we can now conceive of platelets as a reservoir of modulators and a biologic vector of the inflammatory process. Simultaneously, we have enhanced our understanding of the adverse effect that inflammation has on clinical outcome. In patients undergoing bypass surgery, an elevated base-line C-reactive protein value has been shown to have an important relation to ischemic events, with a difference in risk by a factor of four extending into multiyear follow-up.4 But the ability to inhibit platelets and the inflammatory process in patients undergoing coronary-artery bypass grafting (CABG) has been restricted because of the known liability of aspirin. Numerous studies have emphasized that aspirin administered before surgery leads to more mediastinal blood loss, transfusion, and repeated operations.5 The most recent randomized trial indicated that aspirin use was associated with an increase by a factor of nearly four in the rate of repeated operation (6.6 percent vs. 1.7 percent).6 The consensus has been that aspirin should be avoided before surgery in order to minimize the risk of bleeding complications and particularly the need for emergency reoperation to control mediastinal bleeding. There is also widespread agreement about the vital need for long-term aspirin use after CABG to prevent closure of the graft. But the use of aspirin in the early hours after CABG has been controversial, and in many centers, it is considered taboo. In this issue of the Journal, Mangano and colleagues7 present their global registry data on the use of aspirin during the 48 hours after CABG. The findings are quite striking. Among the patients who received aspirin during the first 48 hours, the rate of death was more than 60 percent lower than that among those who did not receive aspirin during that period (1.3 percent vs. 4.0 percent), and the rates of nonfatal ischemic complications, including myocardial infarction, stroke, renal failure, and bowel infarction, were each reduced by a similar magnitude (in aggregate, from 15.4 percent to 9.4 percent). Ironically, the frequency of bleeding complications was significantly lower among the aspirin-treated patients: the rate of reoperation was reduced by 63 percent from 5.2 percent to 1.9 percent, and the frequency of gastrointestinal bleeding was reduced from 2.0 percent to 1.1 percent. Better survival, fewer major multiorgan ischemic events, and less bleeding � is this too good to be true? Perhaps so, given that the results are not derived from a randomized, controlled trial. The potential for exaggeration of the clinical benefit of a particular intervention on the basis of observational data from registries is well recognized. The use of aspirin may have been a proxy for more evidence-based practice and a general indicator of superior care. However, there are reasons to believe that the report might actually underestimate the benefit of early aspirin use. First, the deaths that occurred during the first 48 hours after CABG were not included in the analysis, and there were only 2 such deaths in the group that received aspirin but 41 in the group that did not receive aspirin.7 This large imbalance favoring aspirin appears unlikely to be due to chance and would have amplified the point estimate of the survival benefit. Second, a 48-hour window for the administration of aspirin is quite broad, and one would intuitively expect that the earliest use (within 1 to 6 hours after surgery) might yield the most important reduction in the rate of untoward events. Third, the dose of aspirin of 80 to 650 mg may have detracted from the optimal effect. Although the best dose of aspirin for patients undergoing coronary bypass surgery remains uncertain, a recent trial involving more than 12,000 patients with acute ischemic heart disease strongly suggests that lower doses of 80 to 160 mg of aspirin are preferred over a 325-mg dose because they result in a markedly lower rate of bleeding complications.8 Fourth, the current investigators did not use solely enzymatic criteria for the diagnosis of perioperative myocardial infarction. Only major events associated with clinically significant electrocardiographic changes or confirmation by autopsy were categorized as myocardial infarction. Recent studies have shown that elevated values for the MB isoenzyme of creatine kinase after CABG are a common phenomenon and that they carry a critical long-term risk of death after CABG.9 Such smaller perioperative infarctions are most likely related to embolization of atherosclerotic debris at the time of surgery, with an attendant platelet response in the microvasculature.10 In the case of nonsurgical coronary revascularization, the importance of platelet inhibition in order to reduce the risk of periprocedural myocardial infarction has been well established.10 Had Mangano et al. collated data from studies of smaller perioperative infarctions, they might well have found a considerably greater effect of suppression of myocardial infarction. From the most recent meta-analysis of 287 trials of antiplatelet therapy involving 212,000 patients, including many groups at high risk for atherothrombotic vascular events, we know that the most striking effect of aspirin is to reduce the risk of myocardial infarction (a decrease of 34 percent overall); it reduces the risk of stroke to a lesser extent (a 25 percent reduction) and the risk of death to the least extent (in aggregate, a 15 percent reduction).11 What is perhaps most intriguing about the report by Mangano et al. is the magnitude and breadth of the benefit of early aspirin after CABG in terms of survival, nonfatal ischemic events, and bleeding complications, as well as the comprehensive sweep of benefits for the heart, brain, kidneys, and bowel. Even within each organ system, there is a consistency in the magnitude and direction of the effect of aspirin � for example, its effect on the risk of encephalopathy or the need for dialysis. These findings do indeed reflect a systemic benefit of aspirin and a more profound effect than that found on platelet-mediated thrombosis. The extent and scope of the influence of aspirin are most likely a reflection of its antiinflammatory effect rather than its antithrombotic effect. The pathophysiology of many of the ischemic complications that are averted by early aspirin use does not invoke thrombosis; inflammation seems like a more probable explanation. Since these two interdependent processes are so tightly coupled, however, it is difficult to separate out the relative contributions of inflammation and thrombosis. Like the treatment effect, the true mechanism will need to be established through definitive, prospective, randomized trials. Although they are clearly needed, however, such trials of early aspirin use after CABG may never be conducted. So what do we do in the absence of trial data? The Sixth American College of Chest Physicians Consensus Conference, held in 2001, offered a guideline, recommending 325 mg of aspirin per day starting six hours after surgery.12 Although the best time for aspirin may even be as early as one hour after CABG13 and the best dose may be 80 to 160 mg,8,11 it is not certain. The findings of the current study certainly lend strong support to the recommendations of the American College of Chest Physicians. The emerging data point to an important role of platelets early after CABG, separate and distinct from their contributing role in the long-term patency of arterial conduits. Unless or until any hazard is documented, the benefits appear to be important and overriding, and early aspirin use after bypass surgery should become standard practice. We have much more to learn about the bivalent role of platelets in regulating thrombosis and inflammation, but careful study of this fundamental expansion of platelet biology will undoubtedly lead to additional therapeutic success in the future.
References
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