The process of platelet adhesion, activation and aggregation plays a pivotal role in the pathogenesis of coronary thrombosis after atherosclerotic plaque rupture, and pharmacological inhibition of platelet function forms the cornerstone of treatment for acute coronary syndromes (ACS).1 The thienopyridines (clopidogrel and ticlopidine), a class of antiplatelet drugs that reduce adenosine diphosphate-mediated platelet activation,2 have been shown to provide significant clinical benefit in the initial treatment and secondary prevention of ACS. Compared with aspirin alone, dual antiplatelet therapy with aspirin plus clopidogrel or ticlopidine reduces the risk of vessel thrombosis and recurrent ischemic events in patients undergoing percutaneous coronary interventions,3,4 and is a valuable adjunct to coronary artery stenting.5–8 Moreover, in the setting of coronary artery bypass graft (CABG) surgery, combination aspirin and ticlopidine therapy initiated in the immediate post-operative period improves both immediate and late (one-year) aorto-coronary bypass graft patency.9,10 However, the most important limitation to the use of dual antiplatelet therapy is the increased bleeding risk that accompanies the enhanced antiplatelet effect. In common with aspirin, clopidogrel irreversibly inhibits platelet function for the lifetime of the individual platelet,11,12 with the maximal antiplatelet effect occurring 3 to 5 days after initiation of treatment.13 Recent reports of an increased risk of procedural bleeding arising from administration of dual aspirin and clopidogrel therapy immediately prior to CABG surgery14–16 raise the question of whether, despite its clinical benefits, clopidogrel should be routinely given on hospital admission to patients presenting with ACS. In light of the current American College of Cardiology/ American Heart Association recommendation to discontinue clopidogrel for at least 5 days prior to elective CABG surgery,17,18 the emergency room physician may be inclined to avoid clopidogrel use out of concern that the patient may potentially require urgent cardiac surgery. The latest figures from the Global Registry of Acute Coronary Events indicate that 4% of patients presenting with ST-segment elevation myocardial infarction, 6% of those with unstable angina and 7% of those with non-ST-segment elevation myocardial infarction undergo CABG surgery during the initial hospitalization.19 To delay initiation of clopidogrel therapy until coronary revascularization has been performed would potentially deprive the majority of patients of the early benefits of the drug. The following article is a summary of a roundtable discussion that took place in New York on January 30, 2004 on strategies for the use of antiplatelet therapy in patients requiring surgical revascularization. The participants were Deepak L. Bhatt, MD, from the Cleveland Clinic Foundation, Cleveland, Ohio, who served as the moderator, Sary Aranki, MD, from Brigham & Women’s Hospital, Boston, Massachusetts, John Byrne, MD, from Vanderbilt University Medical Center, Nashville, Tennessee, Devinder Bhatia, MD, from the University of Texas, Houston, Texas, Shamir Mehta, MD, from McMaster University, Hamilton, Ontario, Canada, and Roger Mills, MD, from Henry Ford Hospital, Detroit, Michigan. Benefits and Risks Associated with Clopidogrel Use in ACS Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study. The CAPRIE study, a 3-year study comparing aspirin versus clopidogrel monotherapy in the general atherothrombosis population, is the single largest trial of antiplatelet therapy that has been performed to date (n = 19,185).20 Compared with aspirin, clopidogrel achieved a significant 8.7% relative risk reduction (RRR) in the combined endpoint of myocardial infarction (MI)/ischemic stroke/vascular death. The efficacy advantage shown by clopidogrel over aspirin was amplified in the subset of CAPRIE patients who had undergone prior CABG surgery (36% RRR in the combined endpoint of MI/ischemic stroke/vascular death). Clopidogrel showed a highly clinically relevant risk reduction in CABG patients, and there was a suggestion of a greater degree of benefit with more prolonged durations of therapy.21 Clopidogrel for the Reduction of Events During Observation (CREDO) study. The CREDO study assessed the short-term and long-term benefits of dual antiplatelet therapy in patients undergoing (mainly elective) angioplasty and stenting — a fairly stable coronary disease population.4 CREDO specifically addressed the question of (i) whether 12 months of dual antiplatelet (aspirin + clopidogrel) therapy is better than the (then) standard 1 month of dual antiplatelet therapy followed by aspirin monotherapy post-stenting; and (ii) whether the addition of clopidogrel to aspirin treatment prior to percutaneous coronary intervention (PCI) is beneficial. Standard care (then and now) is to give aspirin pre-angioplasty/stenting and to continue it indefinitely thereafter. Clopidogrel pre-treatment (>= 6 hours pre-procedure) produced a substantial reduction (38.6% RRR) in ischemic events in the first 28 days post-procedure; overall, there was a 27% RRR favoring long-term (12 months) dual antiplatelet therapy. Thus, the data support the use of clopidogrel pre-treatment and long-term clopidogrel maintenance therapy: most of the benefit is derived over the long term, but there is also additional short-term benefit from pre-treatment. While there was a tendency for an increased incidence of major bleeding with clopidogrel, this was largely driven by surgical (predominantly CABG) bleeding; clopidogrel had no significant effect on non-procedural or minor bleeding. Thus, from the interventional cardiologist’s perspective, there are no disadvantages to dual antiplatelet therapy and opinion is nearly unanimous that clopidogrel and aspirin should be given prior to angioplasty/stenting and continued over the long term. As regards the pyramid of risk post-revascularization, the real risk for the patient undergoing PCI or surgery is the ongoing risk of future major cardiac events — not so much from the stented culprit lesion or the bypassed artery as from recurrent ischemic events in the coronary/cerebral/peripheral arterial beds. Currently there is near unanimity among interventional cardiologists about the advantages to be gained from aspirin and clopidogrel pre-treatment in patients undergoing interventional revascularization procedures. Opinion among U.S. interventional cardiologists is shifting toward the use of a 600 mg loading dose of clopidogrel (current standard practice is to use a 300 mg loading dose) in order to achieve an adequate level of platelet inhibition more rapidly. Intracoronary Stenting and Antithrombotic Regimen —Rapid Early Action for Coronary Treatment (ISAR-REACT) study. In the recent ISAR-REACT study, low-risk patients undergoing elective PCI for stable angina received clopidogrel 600 mg >= 2 hours pre-procedure and were randomized to abciximab or placebo post-procedure.22 The high loading dose of clopidogrel not only provided similar efficacy to abciximab, but also less thrombocytopenia, lower transfusion requirements and less bleeding. Thus, adequate pre-treatment with an oral antiplatelet agent (clopidogrel) obviates the need for an intravenous (and costly) glycoprotein IIb/IIIa inhibitor in patients undergoing low-risk elective coronary stenting. The ongoing Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) study is designed to assess whether clopidogrel 75 mg/day plus aspirin offers superior long-term efficacy to aspirin alone in a broad range of low-risk atherosclerosis patients.23 If the study results prove positive for clopidogrel, its use is likely to expand to cover the whole spectrum of secondary prevention patients and high-risk primary prevention patients (e.g., diabetic patients). Consequently, it is likely that in the future increasing numbers of patients will be referred to cardiac surgery while receiving clopidogrel therapy. Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study. In the CURE study, ACS patients presenting within 24 hours of symptom onset were randomized to receive a loading dose of clopidogrel 300 mg or placebo and were maintained on clopidogrel 75 mg/day or placebo (in addition to aspirin) for 24 Overall, there was a 20% RRR in the combined endpoint of MI/ischemic stroke/vascular death: this comprised both an early benefit (21% RRR at 30 days) and a late benefit (18% RRR at 1–12 months). The event curves began to diverge as early as 2 hours after the loading dose; at 24 hours there was a ~33% RRR in MI/ischemic/stroke/severe ischemia/vascular death. Thus, the CURE study effectively validated the concept of dual antiplatelet therapy in patients with ACS, and indicated that the earlier clopidogrel can be administered, the sooner the benefits will be realized. In this study, clopidogrel significantly increased the incidence of major bleeding (3.7% vs. 2.7%) and minor bleeding (5.1% vs. 2.4%) but not that of life-threatening bleeding (2.2% vs. 1.8%). The biggest determinant of bleeding rate was the dose of aspirin: low-dose (= 200 mg) = 3.7%. Importantly the bleeding rate with low-dose aspirin + clopidogrel (3.0%) was lower than that with high-dose aspirin alone (3.7%). In the CURE study, 2,072 ACS patients underwent CABG surgery, making it also the largest randomized trial of antiplatelet therapy conducted in the CABG population. Clopidogrel showed consistent benefit in the CABG and non-CABG groups. For patients undergoing CABG surgery during the initial hospitalization, there was a 22% RRR in the combined endpoint of MI/ischemic stroke/vascular death with clopidogrel, which is quantitatively similar to the effect obtained with clopidogrel in non-CABG patients (RRR 20%). Most of the benefit of clopidogrel was seen in the period prior to CABG surgery (44% RRR), so there is a clear advantage in maintaining patients on clopidogrel prior to CABG surgery. The risk of major bleeding in the 7-day post-operative period was not significantly affected by clopidogrel pre-treatment: incidences of major bleeding in the clopidogrel plus aspirin (4.4%) and aspirin (5.3%) treatment arms were similar.23 There was a higher incidence of life-threatening bleeding with the clopidogrel plus aspirin combination (absolute excess 2.8%) in those patients who underwent CABG surgery 5 days prior to surgery.25 Likewise, re-operation rates for bleeding in the acute post-operative period tended to be higher with clopidogrel + aspirin than with aspirin alone (4.1% vs. 2.3%) for those patients undergoing CABG surgery 5 days prior to surgery.25 Even if clopidogrel was maintained until the day of surgery, there was only a 1.6-fold increase in bleeding risk (i.e. less than a doubling of risk). However, there was a substantial increase in bleeding risk in CABG patients on switching from low-dose to high-dose aspirin. The message for surgeons is that clopidogrel increases the risk of bleeding in CABG surgery, but it is not a catastrophic increase. Based on findings from the CURE study, clopidogrel pre-treatment in the CABG setting effectively prevents approximately 12 ischemic events (MI/ischemic stroke/vascular death) in the first 30 days post-operatively at the expense of 3 additional bleeds per 1,000 patients.24 Long-term clopidogrel therapy prevents 10 ischemic events at the expense of 1 additional bleed per 1,000 patients. Thus the benefit:risk ratio for clopidogrel is highly favorable, both in the short- and long-term. PCI-CURE study. The PCI-CURE study, conducted in a subset of CURE patients in the CURE trial who had undergone PCI, addressed the questions (i) whether clopidogrel treatment prior to PCI is of benefit post-PCI; and (ii) whether long-term clopidogrel therapy is beneficial.3 All patients received thienopyridines for 30 days post-PCI since the vast majority underwent coronary stenting. Clopidogrel pre-treatment led to a 44% RRR in the combined endpoint of MI/ischemic stroke/vascular death in the 30 days post-PCI, and produced no appreciable increase in risk of bleeding (major, life-threatening or minor) during this period. Overall, there was a 31% RRR from randomization to the end of 12 months’ follow-up, no appreciable increase in major or life-threatening bleeding and a modest increase in minor bleeding (3.5% vs. 2.1%). Antiplatelet Therapy — The Clinical Cardiologist’s Perspective An overview of antiplatelet therapy from the perspective of a clinician managing pre-operative and post-operative CABG patients was provided by Dr. Roger Mills. In CABG surgery, the etiology of saphenous vein graft (SVG) loss changes with time: in the first year technical problems and poor distal vessel flow largely account for loss of graft patency; in years 1–3, intimal proliferation leads to graft loss; from year 3 onward, atherosclerotic plaque is largely responsible for graft loss.26 Similarly, graft closure rates alter with time: 15–20% of patients lose a graft within the first year; annual graft closure rates are ~2% in years 1–6 and ~4% in years 6–11.26 Thus, at 10 years post-CABG surgery, approximately 50% of SVGs are closed and 50% of the remaining patent grafts show significant atherosclerosis. Aspirin reduces the 1-year occlusion rate in SVGs from ~22–16%, and its benefit is overwhelmingly confined to anastomoses to smaller vessels.25 Coronary disease is a local manifestation of systemic atherosclerosis, thus long-term antiplatelet therapy should provide more benefit than simply maintaining graft patency — as evidenced by the effect of clopidogrel in reducing not only cardiac events, but stroke and hospitalization as well. Revascularization (whether percutaneous or surgical) is not the end of the treatment process, but rather a marker of the need for more intensive therapy. However, cardiac surgeons are reluctant to discharge every post-CABG patient on dual antiplatelet therapy. The policy I use in my practice is to administer aspirin monotherapy to those CABG patients (the minority) with all-arterial grafts, good distal target vessels, and no other overt evidence of atherosclerosis; to use clopidogrel monotherapy in aspirin-intolerant/resistant patients; and dual aspirin + clopidogrel therapy in patients with poor distal vessels, insulin-dependent diabetics and patients with signs of generalized atherosclerotic disease. In addition to antiplatelet drugs, post-CABG patients should receive concomitant statin, beta-blocker and ACE inhibitor/angiotensin receptor blocker therapy. Use of Clopidogrel Therapy in Private Cardiac Surgery Practice — A Personal Perspective Dr Devinder Bhatia described his personal approach to the use of clopidogrel therapy in his private cardiac surgery practice. The use of antiplatelet agents is becoming more prevalent in patients presenting for surgery, and cardiac surgeons can expect to encounter increasing numbers of such patients in the future. In Dr. Bhatia’s opinion, cardiac surgeons’ hesitancy to operate on clopidogrel-treated patients is largely based on uncertainty and fear of the unknown. Off-pump CABG is becoming increasingly common: in Dr. Bhatia’s practice (Houston), some 35–40% of CABG operations are performed off-pump, and the re-exploration rate is ~3.5%. In order to prevent early thrombosis, a loading dose of clopidogrel (150 mg) is administered to patients going to the operating room for off-pump CABG surgery. The timing of clopidogrel administration prior to surgery is typically not a major issue: where feasible, steps are taken to avoid using the cardiopulmonary bypass machine, as this has a significant impact on the incidence of post-operative bleeding. In light of the CURE trial findings,24 for patients undergoing elective CABG pre-existing clopidogrel therapy is discontinued approximately 4–5 days prior to surgery. However, for patients presenting with ACS (even if stable), no 4- to 5-day clopidogrel washout period is instituted before proceeding with surgical revascularization (urgent or emergent CABG surgery). Clopidogrel is routinely included on the post-operation and discharge orders and long-term treatment is maintained for 6–9 months or longer. It is Dr. Bhatia’s view that antiplatelet therapy (preferably dual aspirin + clopidogrel) should be used not just for CABG patients, but also for those with peripheral vascular disease, carotid disease, and iliac stents. Open Forum Discussion Pre-operative Use of Clopidogrel Dr. Sary Aranki: At Brigham & Womens’ Hospital (Boston) our approach toward elective CABG patients presenting on dual antiplatelet therapy is generally to continue aspirin until the day of surgery, with the aim of improving graft patency. However, the question arises: Should we discontinue aspirin (because of the bleeding risk) and continue clopidogrel instead? Having discontinued clopidogrel, many cardiac surgeons forget to reinitiate clopidogrel treatment following CABG surgery. In addition, off-pump CABG patients should be on dual antiplatelet therapy post-CABG since, by avoiding cardiopulmonary bypass, the low-grade coagulopathy associated with the pump is avoided, and the patient is therefore at increased risk of early graft failure. Dr. Shamir Mehta: Our approach at McMaster University (Canada) is to discontinue clopidogrel several days prior to CABG surgery if the patient is stable; we rarely delay CABG surgery for the full 5 days. Patients who have been on clopidogrel prior to CABG surgery show more oozing (although this is not unmanageable) and increased use of blood products (cryoprecipitate, fresh frozen plasma, red blood cells and platelet transfusions), but this is mostly for prophylactic purposes — we have not seen an excess of re-operations for bleeding in clopidogrel-pre-treated patients. We also routinely use aprotinin prior to the procedure, which appears to reduce bleeding and oozing substantially. Dr. John Byrne: I would suspect that the predominant feeling among cardiac surgeons nationwide toward operating on clopidogrel-pre-treated patients is fairly negative. Typically, they would insist that the medically stable patient is taken off clopidogrel for 4 to 5 days before they operate (other than in rare cases of catheter laboratory emergency). However, it’s clearly unacceptable for patients to be kept in hospital for 4 to 5 days waiting for clopidogrel washout. Dr. Deepak L. Bhatt: In reality, the emergency room physician is reluctant to give clopidogrel for fear that the patient will require cardiac surgery; likewise the clinical cardiologist is also hesitant to give clopidogrel pre-treatment. For this reason, patients fail to receive clopidogrel from the outset of hospitalization. Although the emergency room physician, the interventional cardiologist and the clinical cardiologist would all favor pre-treating the ACS patient with clopidogrel in the emergency room, the majority do not do this out of concern that the patient might proceed to surgery. Dr. Shamir Mehta: The CABG surgery population is a relatively small proportion of the total ACS patient population; if you withhold clopidogrel, the majority of ACS patients (i.e. the non-surgery patients) are denied the benefits of pre-treatment with the drug. However, many hospitals have adopted this approach. The CURE and PCI-CURE studies indicated that detectable benefit starts within a couple of hours of clopidogrel administration; thus, the patient loses out if the decision to initiate clopidogrel is not taken until coronary angiography is performed. Post-revascularization Use of Clopidogrel Dr. Shamir Mehta: There is no protocol stipulating what to do after 12 months of clopidogrel therapy post-revascularization. For higher-risk ACS patients (CABG or non-CABG treated), I continue clopidogrel beyond 12 months. Dr. John Byrne: The vast majority of CABG surgery patients only receive aspirin as antiplatelet therapy post-procedure. In our institution, it’s only extreme ACS cases such as coronary endarterectomy that receive long-term dual antiplatelet therapy (usually for 6 months). Dr. Deepak L. Bhatt: My approach is to continue long-term clopidogrel therapy indefinitely post-stenting because there is no reason to believe that the drug’s benefit ceases at 12 months. As is seen with the statins, ACE inhibitors, etc., the Kaplan-Meier curves for clopidogrel consistently show that the longer the duration of therapy, the greater the clinical benefit. It may be possible to extrapolate this approach (i.e., indefinite clopidogrel therapy) to the post-CABG setting, although this is speculation. CABG Bleeding Dr. John Byrne: Bleeding (chest tube output) is a quantitative measure of bleeding, whereas transfusion requirements are surgeon/nurse-biased and more subjective. The same definitions of bleeding cannot be applied to CABG surgery and PCI. Dr. Sary Aranki: Transfusion requirements are not necessarily related to bleeding, and are dictated not only by the use of antiplatelet therapy, but also by factors such as hematocrit and patient age. Those surgeons who are dubious about operating on clopidogrel-treated patients should be taking into account these additional factors. Dr. Roger Mills: Re-operation for bleeding after CABG surgery is a hard endpoint — it means a longer time in the intensive care unit, re-intubation and an increased risk of infection. The incremental risk of re-operation for bleeding is ~1 patient per 1,000 patients, which is a modest and probably acceptable increment. In those CABG cases where re-operation for bleeding is required, 9 times out of 10, it’s due to technical reasons rather than coagulopathy. Dr. Deepak L. Bhatt: A prospective registry of data on bleeding in CABG surgery patients (and other surgery patients) would provide a useful snapshot of surgical practice across the country, but would be subject to potential bias. Clopidogrel-treated patients would probably do worse than non-clopidogrel-treated patients, who are more likely to have less severe (stable) disease and positive stress tests. A similar bias might be expected to apply to bleeding, with surgeons having a lower threshold for resorting to transfusion in clopidogrel-treated patients. Hybrid Revascularization Dr. John Byrne: Hybrid revascularization (surgical revascularization/valve surgery and the use of coated stents) represents the future of coronary surgery. I perform combined valve surgery and PCI in clopidogrel-pre-treated patients. Dr. Deepak L. Bhatt: The concept of hybrid revascularization is excellent, but the main impediment to its adoption is the clopidogrel issue — most interventional cardiologists are unwilling to interrupt clopidogrel therapy and most cardiac surgeons are unwilling to operate on clopidogrel-treated patients. Dr. Sary Aranki: Dual aspirin plus clopidogrel therapy is particularly important for preventing stent thrombosis, so it would be a risky strategy to stent and then discontinue clopidogrel prematurely in order to perform CABG or valve replacement surgery. It would be simpler to continue clopidogrel therapy and take the patient to surgery immediately after stenting (i.e. on the same day). Alternatively, it would probably be better to perform CABG first, give a loading dose of clopidogrel either immediately before or during CABG surgery, and then transfer the patient to the catheterization laboratory for stenting. Dr. Deepak L. Bhatt: For the patient requiring CABG surgery on non-culprit lesions after stenting, premature discontinuation of clopidogrel (because of impending CABG surgery) would increase the risk of acute stent thrombosis.28 Platelet Transfusion and Clopidogrel Dr. Deepak L. Bhatt: In the same way that platelet transfusion reverses the bleeding effect of aspirin, so it should reverse the action of clopidogrel, since both agents are irreversible platelet antagonists and remain bound to the platelet until it is removed from the circulation. Thus, the antiplatelet effect of clopidogrel should be overcome by transfusion of sufficient numbers of new platelets.
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