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Review

Aspirin in coronary artery bypass surgery: new aspects of and alternatives for an old antithrombotic agent

^a Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, D-53175 Bonn, Germany
^b Heinrich-Heine – University, Department of Thoracic and Cardiovascular Surgery, Moorenstrasse 5, D-40225 Duesseldorf, Germany
^c Heinrich-Heine – University, Department of Pharmacology and Clinical Pharmacology, Moorenstrasse 5, D-40225 Duesseldorf, Germany

Received 14 February 2008; received in revised form 10 March 2008; accepted 19 March 2008.

^_* Corresponding author. Tel.: +49 228 207 3136; fax: +49 228 207 3558. (Email: nzimmermann{at}bfarm.de).

	Abstract

Top Abstract 1. Introduction 2. Aortocoronary vein graft... 3. Antiplatelet effect of... 4. Aspirin resistance 5. Therapeutic approaches of... 6. Future perspectives and... References

 
The success of coronary artery bypass graft surgery (CABG) depends mainly on the patency of the graft vessels. Aortocoronary vein graft disease is comprised of three distinct but interrelated pathological processes: thrombosis, intimal hyperplasia and atherosclerosis. Early thrombosis is a major cause of vein graft attrition during the first month after CABG, while during the remainder of the first year, intimal hyperplasia forms a template for subsequent atherogenesis, which thereafter predominates. Platelets play a crucial role in the pathophysiology of graft thrombosis and aspirin is the primary antiplatelet drug that has been shown to improve vein graft patency within the first year after CABG. Nevertheless, a significant number of grafts still occlude in the early postoperative period despite ‘appropriate’ aspirin treatment. Moreover, laboratory investigations showed that the expected inhibition of platelet function is not always achieved. This has been called ‘aspirin nonresponse’ or ‘aspirin resistance’, although a uniform definition is lacking. The finding that a considerable number of patients show an impaired antiplatelet effect of aspirin after CABG brought new insight into the discussion concerning poor patency rates of bypass grafts: the early period after CABG shows a coincidence of an increased risk for bypass thrombosis (amongst others, due to platelet activation and endothelial cell disruption of the graft) and an increased prevalence of aspirin resistance. Hitherto, the underlying mechanisms of aspirin resistance are uncertain and largely hypothetical; amongst others, increased platelet turnover, enhanced platelet reactivity, systemic inflammation, and drug–drug interaction are discussed. Up to now available data concerning the clinical outcome of aspirin resistant CABG patients are limited, and there is evidence that platelets of patients with graft thrombosis are more likely to be resistant to aspirin compared with patients without thrombotic events. Many publications concerning aspirin resistance are available today, but reports addressing this topic in CABG patients are sparse. This review summarises recent insights into the antiplatelet treatment after CABG and describes the clinical benefit, but also the therapeutic failure of the well-established drug aspirin. Moreover, possible pharmacological approaches to improve antithrombotic therapy in aspirin nonresponders among CABG patients are discussed.

Abbreviations: ACS = acute coronary syndrome • ADP = adenosine diphosphate • ASA = aspirin • bid = twice daily (dosing) • CABG = coronary artery bypass graft surgery • CAD = coronary artery disease • CAPRIE = clopidogrel versus aspirin in patients at risk of ischaemic events • CHARISMA = clopidogrel for high atherothrombotic risk and ischaemic stabilisation, management and avoidance • CI = confidence interval • Clo = clopidogrel • COX = cyclooxygenase • CPB = cardiopulmonary bypass • CREDO = clopidogrel for the reduction of events during observation • CURE = clopidogrel in unstable angina to prevent recurrent ischaemic events • e.g. = for example (Latin abbreviation for exempli gratia) • HR = hazard ratio • i.e. = that is (Latin abbreviation for id est) • IMA = internal mammary artery • LTA = light transmission aggregation (turbidimetry) • MI = myocardial infarction • n.a. = not available • n.s. = not significant • NSAID = nonsteroidal anti-inflammatory drug • OPCAB = off-pump coronary artery bypass surgery • OR = odds ratio • qd = once daily (dosing) • PAD = peripheral arterial disease • PCI = percutaneous coronary intervention • PFA-100 = platelet function analyser • RR = relative risk • STEMI = ST-elevation myocardial infarction • SVG = saphenous vein graft • TIA = transient ischaemic attack • tid = three times daily (dosing) • TX = thromboxane • VK-A = vitamin K-antagonist

Key Words: Coronary artery bypass grafting • Platelet function • Antithrombotic therapy • Aspirin resistance • Aspirin nonresponse • Clinical outcome

	1. Introduction

Top Abstract 1. Introduction 2. Aortocoronary vein graft... 3. Antiplatelet effect of... 4. Aspirin resistance 5. Therapeutic approaches of... 6. Future perspectives and... References

 
Coronary artery bypass graft surgery (CABG) is an important therapeutic approach in coronary artery disease. CABG is the most frequent cardiac surgery procedure, with nearly 1 million operations conducted per year worldwide. However, with demonstration of the dramatic benefits obtainable by CABG came recognition of the ultimately palliative nature of this operation. Indeed, the long-term success after CABG depends on the patency of the bypass vessels that is mainly influenced by the type of the graft used, but also by the quality of the distal vessel into which the graft is placed. Moreover, bypass patency can also be improved with platelet inhibitory therapy.

Since platelets play a crucial role in the pathogenesis of thrombosis, antiplatelet drugs, and of these especially acetylsalicylic acid (aspirin), are broadly used in order to reduce serious vascular events. In general, there is broad consensus about the value of long-term aspirin therapy in reducing the risk of death, myocardial infarction, and stroke in patients at high risk of occlusive disease [1,2]. Nevertheless, the meta-analysis of the antiplatelet trialists’ collaboration revealed a proportional risk reduction for vascular events among patients who underwent CABG of only 4% (standard error 14%) with a wide confidence interval including a risk reduction of one quarter, and the trialists discuss that ‘the apparent lack of effect of antiplatelet therapy on vascular events immediately after coronary artery bypass surgery may – given the clear evidence of benefit among other patients with coronary artery disease – be largely or wholly due to chance.’

A beneficial effect of aspirin on vein graft patency has been shown during the first year after CABG, but not beyond this period [3–5]. Moreover, there is evidence that not all individuals respond comparably to antiplatelet therapy but suffer from thromboembolic events in spite of continuous antiplatelet therapy. This therapy failure has been called ‘nonresponse’ or ‘aspirin resistance’. Especially early after CABG, a high incidence of aspirin resistance has been described affecting more than two thirds of the patients [6]. The Society of Thoracic Surgeons guideline on ‘aspirin and other antiplatelet agents during operative coronary revascularization’ mentions this special feature only in brief and recommends ‘continue or increase dose of aspirin in nonresponders’ [7]. The coincidence of aspirin resistance and the high risk of acute thrombotic occlusion within the early period after surgery is of special importance and raises the question whether graft patency rates can be improved.

Nonresponse to antiplatelet therapy has become a special area of interest in the treatment of patients suffering from atherosclerotic diseases. In the meantime, many publications concerning aspirin resistance are available, especially with regard to percutaneous coronary interventions (PCI) [8–10], but reviews covering this topic in patients undergoing CABG are lacking, though both groups of patients face the same problem, i.e. postprocedural vessel occlusion. Hence, this review focuses on new insights into aspirin as an antiplatelet agent in the treatment of CABG patients.

After a short overview regarding aortocoronary vein graft disease (Section 2) and clinical studies investigating aspirin in CABG patients, trials that were mostly performed in the 80s and 90s of the last century (Section 3), incidence and clinical impact of aspirin resistance after CABG are discussed in detail (Section 4). Furthermore, possible therapeutic approaches (Section 5), future perspectives and clinical recommendations are presented (Section 6).

	2. Aortocoronary vein graft disease

Top Abstract 1. Introduction 2. Aortocoronary vein graft... 3. Antiplatelet effect of... 4. Aspirin resistance 5. Therapeutic approaches of... 6. Future perspectives and... References

 
On the basis of clinical trials and experimental studies, three consecutive phases of aortocoronary artery bypass vein graft disease have been shown: an early phase of platelet thrombotic occlusion during the first month after CABG, an intermediate phase of intimal hyperplasia between month 1 and 1 year, and a late phase of atherosclerotic obstruction beyond the first year after surgery [11].

Early occlusion due to thrombus formation occurs in 8% to 18% of all vein grafts within the first postoperative month [12,13]. From month 2 to 12 a further 10–15% of vein grafts occlude, primarily due to luminal narrowing which occurs as a consequence of smooth-muscle cell hyperplasia in the vein intima. After 1 year the attrition rate is approximately 1–4% per annum, as a result of intimal hyperplasia and progressive atherosclerotic obstruction. Occlusion after 5 years is usually secondary to atherosclerosis with the net result that by 10 years, only 50% of all vein grafts are patent [11]. Vein graft disease (diagnosed angiographically) appears by 1 year after CABG and the rate accelerates by 2.5 years, involving nearly half of vein grafts at 5 years and more than 80% at 15 years or later [14].

Moreover, vein graft patency and disease have been shown to be closely related to long-term survival after CABG [14].

Among other factors influencing the risk of vein graft occlusion, the technique of harvesting has special importance. Endothelial cell disruption due to instrumentation, pressurisation (during the leak testing) or stripping of the graft has an unfavourable impact on vein graft reactivity and patency [15–17], but angiographic and histologic appearance of saphenous vein grafts harvested endoscopically are similar to those harvested with an open, conventional technique [18–20] and vein source (thigh vs calf) is not predictive either [15]. On the other hand, vein graft patency is affected by a size mismatch between the bypass and the coronary target, the diameter of the grafted native coronary vessel, the distal artery run-off (intrinsic disease in the outflow bed), ‘abnormal’ anastomotic angle and whether or not an associated endarterectomy has been performed [3,4,21,22]. Moreover, statin therapy improves vein graft patency as well as perioperative and long-term survival rates [23–26]. But detailed discussion of these important issues is beyond the scope of this review.

	3. Antiplatelet effect of aspirin

Top Abstract 1. Introduction 2. Aortocoronary vein graft... 3. Antiplatelet effect of... 4. Aspirin resistance 5. Therapeutic approaches of... 6. Future perspectives and... References

 
Aspirin, first synthesised in its impure form in 1853 by Charles-Frédéric Gerhardt and rediscovered by Felix Hofmann in 1897, is one of the oldest commercialised drugs still in use [27]. Since 1904, stamped tablets of aspirin are used as an analgesic and anti-inflammatory compound. In 1950 aspirin earned a place in the Guinness Book of Records as the most popular painkiller in the world. In the same year, Craven published his experiences with aspirin (in the dosage of 250–750 mg) in the prophylaxis of coronary thrombosis in male patients at the age of 40–65 years [28]. The (main) mechanism of action, the irreversible acetylation of a specific serine residue (ser529) in the platelet cyclooxygenase, was first reported by Vane in 1971 [29]. In the meantime, aspirin is the most widely studied antiplatelet drug and has been the mainstay in antiplatelet therapy for several decades [1].

3.1 Mechanism of action
The target for aspirin is cyclooxygenase (COX), of which there are two isoforms, COX-1 and COX-2. COX-1 is ubiquitously expressed and is the only isoform relevant for platelet aggregation, where it generates thromboxane (TXA₂). COX-1 is also expressed in vascular endothelium, where it generates prostacyclin (PGI₂), the major cyclooxygenase product of these cells. COX-2 is an inducible enzyme that is found at sites of inflammation and in many cancers [30].

TXA₂, that is released from stimulated platelets in large amounts, activates a surface membrane G-protein-coupled receptor, the TP-receptor. Activation of the TP receptor induces further platelet activation, amplifying the original stimulus and reinforcing the platelet aggregation.

Since aspirin transfers its acetyl group selectively to the catalytic subunit of COX-1, platelet thromboxane formation is inhibited irreversibly [29,31]. Aspirin-induced inhibition lasts for the lifetime of the platelet (about 10 days), because the anucleate platelets lack the synthetic machinery to generate relevant amounts of new COX-1, and so new platelets must be generated to restore cyclooxygenase activity [32]. Thus, following a single 100 mg dose of aspirin, the ability of whole blood to generate TXA₂ recovers in parallel with the appearance of new platelets and achieves pretreatment levels at 8–10 days. Maintenance of the antiplatelet effect requires only a small dose of aspirin, as low as 40 mg daily. Despite its short half-life of about 20 min [33], aspirin has a long-term effect on platelets that can be maintained by just once-a-day administration [34].

3.2 Antithrombotic effect of aspirin after CABG and current clinical use
Multiple CABG studies show that aspirin reduces the frequency of saphenous vein graft occlusion. Compared to CABG patients treated with aspirin, angiographically detected vein graft occlusion is up to five times more frequent in the placebo group (Table 1 ). Results from different trials may be difficult to compare because they are confounded by variables such as varying inclusion and exclusion criteria, the timing of the start of aspirin treatment, the dose given, whether grafts or anastomosis are being counted, the diameter of the grafted artery, the adequacy of its run-off, surgical techniques (e.g. whether or not endarterectomy was undertaken), and different times, when vein graft patency was assessed. For this reason, the ratio of the occlusion rates of untreated versus (vs) aspirin-treated patients within each trial was calculated and is given in Fig. 1 . It is striking that these ratios decline in time, a finding that is in line with the decreasing impact of thrombosis on vein graft occlusion. Moreover, an aspirin dose effect cannot be identified.

View larger version (8K): [in this window] [in a new window]   Fig. 1. Ratio of occlusions rates (placebo/aspirin) after CABG. Due to differences in patient populations and aspirin regimens a comparison between the single studies seems inappropriate. Thus, the ratio of the occlusion rates in placebo vs aspirin-treated patients (see data in Table 1) within each study has been calculated. The ratios are blotted indicating the duration of follow-up and the daily dose of aspirin. Abbreviations: qd: once daily (dosing); tid: three times daily (dosing).

After a median time from surgery to catheterisation of 9 days, early vein graft occlusion rates were significantly higher in the placebo group (14.8%, n = 153), compared with 6.5% (p = 0.008) and 7.7% (p = 0.036) in patients treated with 325 mg of aspirin once (n = 154) and three times (n = 155) per day, respectively [3]. The diameter of the recipient vessel was an important determinant of vein graft patency; only in vessels with a diameter of less than 1.5 mm, aspirin improved vein graft patency significantly.

At 1 year, patients taking 325 mg of aspirin once (n = 340) and three times a day (n = 315) had a lower occlusion rate (13.2% and 16.8%) compared with placebo (22.6%, n = 345), but the level of significance (p < 0.05) was only reached for the group receiving aspirin once daily [4]. Again, the diameter of the recipient vessel had an important impact. In vein grafts placed to vessels less than or equal to 2.0 mm in diameter (804 distal sites), the vein graft occlusion rate in all of the aspirin groups was 20.1% compared with 32.3% for the placebo group (p = 0.008), whereas in vein grafts placed to vessels greater than 2.0 mm in diameter (511 distal sites), there was no difference in the occlusion rates between aspirin and placebo treatment at 1 year (8.7% vs 9.0%, p = 0.918). The patency rates of the internal mammary artery (IMA) grafts were excellent, irrespective of treatment (placebo 100.0%, aspirin 92.1%; p = 0.385) [42].

After receiving aspirin 325 mg per day for 1 year after CABG and undergoing a 1-year postoperative cardiac catheterisation, patients were randomised to receive either aspirin (325 mg) or placebo for 2 additional years [5]. For saphenous vein grafts that were patent at 1 year, the occlusion rate at 3 years was 4.8% (15 of 313) for patients treated with aspirin compared with 4.2% (13 of 310) for patients who received placebo (p = 0.757). On the other hand, IMA graft patency was not significantly affected by aspirin treatment. At 3 years, the IMA graft occlusion rate was 10.3% (8 of 78) for patients treated with aspirin compared with 7.9% (7 of 89) for patients treated with placebo (p = 0.0594).

As shown in Table 1, the results of controlled trials investigating the antithrombotic effect of aspirin show a wide range of patency rates and only about half of these studies revealed statistically significant differences between aspirin-treated and untreated patients. On the other hand, no similar benefit was conferred when only IMA grafting was used for CABG [43].

3.2.1 Dosage of aspirin
In order to prevent thromboembolic events, aspirin doses of 75 mg or below daily have been suggested to be more effective than higher doses because such low doses may ‘spare’ prostacyclin (a platelet antiaggregant and vasodilator) and cause less gastrointestinal toxicity [44]. However, aspirin doses <75 mg have been rarely assessed in patients undergoing CABG. Among the trials of higher daily doses of aspirin, no particular dose range was preferable for the prevention of vein graft thrombosis. On the other hand, there are no clinical studies that directly compared low, medium, and high-dose aspirin regimens. Lim et al. [45] evaluated the efficacy of low-dose aspirin (75–150 mg) in comparison to medium dose therapy (300–325 mg) on vein graft patency after CABG using indirect comparison meta-analysis. The pooled relative risk reduction for graft occlusion was 45% in the medium dose trials (0.55, 95% CI 0.41–0.73) compared with 26% in the low-dose trials (0.74, 95% CI 0.60–0.91), with a relative risk ratio of 0.74 (0.52–1.06; p = 0.10), indicating no statistical difference in vein graft occlusion rates between medium and low-dose aspirin. However, this analysis was per vein and thus includes patients more than once, so that the results are over precise.

Accordingly, the meta-analysis of the antiplatelet trialists’ collaboration showed a pooled odds reduction for graft occlusion of 44% in five trials that compared low-dose aspirin (75–325 mg per day), and of 50% in nine trials that compared high-dose aspirin (500–1500 mg per day) with placebo or control group, with no statistical difference in occlusion rates between low-dose and high-dose aspirin [1]. While there is no convincing evidence showing that the antithrombotic effect of aspirin is dose related, there is a close relationship between dosage and adverse effects [46].

In accordance, the current guideline of the American College of Chest Physicians recommends for patients undergoing CABG aspirin 75–162 mg per day [43].

3.2.2 Onset of aspirin therapy
The mural thrombi that form in vein graft probably do so within a few hours of surgery. Moreover, endothelial cell disruption of vein grafts (resulting from the harvesting procedure) begins to heal within 2–3 days [47], suggesting some recovery from vein graft injury within this early timeframe. Thus antithrombotic measures should be initiated early in the perioperative period.

Indeed, most of the trials which have failed to demonstrate any advantage in early patency with aspirin therapy have been those where treatment was delayed until the third postoperative day or later (Table 1) [39–41]. This suggestion is endorsed by a prospective cohort study of Mangano [48] that investigated the early treatment with aspirin in 5065 patients undergoing CABG. Among patients who received aspirin (up to 650 mg) within 48 h after revascularisation, subsequent mortality was 1.3% (40 of 2999 patients), as compared with 4.0% among those who did not receive aspirin during this period (81 of 2023, p < 0.001). Aspirin therapy was associated with a 48% reduction in the incidence of myocardial infarction (2.8% vs 5.4%, p < 0.001), a 50% reduction in the incidence of stroke (1.3% vs 2.6%, p = 0.01), a 74% reduction in the incidence of renal failure (0.9% vs 3.4%, p < 0.001), and a 62% reduction in the incidence of bowel infarction (0.3% vs 0.8%, p = 0.01). Multivariate analysis showed that no other factor or medication was independently associated with reduced rates of these outcomes. No aspirin dose effect was found for either fatal or nonfatal outcomes with total doses of 75 mg, 81 mg, 100 mg, 150 mg, 162 mg, 250 mg, or 325 mg. Nevertheless, 4.3% (128 of 2999) of patients treated with aspirin showed ischaemic events (myocardial infarction, stroke, and gastrointestinal ischaemia or infarction) raising the questions (i) whether (at least some of) these subjects were aspirin nonresponders and (ii) whether the rate of adverse events could have been reduced by an altered antiplatelet regimen.

The question whether aspirin should be administered before CABG leads to the ‘aspirin-dilemma’; on the one hand, a sufficient antiplatelet effect of aspirin is beneficial by improving graft patency, but on the other hand, postoperative bleeding might be promoted. A report of the Society of Thoracic Surgeons cites five randomised controlled trials (including a total of 1812 patients) showing an increased postoperative bleeding, but only one small randomised controlled trial in 36 patients that did not illustrate increased bleeding. Moreover, nine observational/descriptive trials (3121 patients) found no increased postoperative bleeding whereas six observational/descriptive trials (3400 patients) did so [7]. A meta-analysis of 10 randomised and nonrandomised studies reporting comparisons between preoperative aspirin and control involving 1748 CABG patients (913 aspirin, 835 placebo) showed a significant increase in blood loss and transfusion of red blood cells and fresh frozen plasma in the aspirin group (p < 0.05) [49]. There was no significant difference between the two groups in the rate of platelet transfusion or the incidence of re-exploration (p > 0.05).

In this context, not only bleeding complications, but also the outcome after surgery has to be discussed.

Goldman et al. [50] compared the effects of aspirin therapy started before CABG with aspirin started 6 h after operation on early (7–10 days) graft patency. Patients were randomised to receive either aspirin 325 mg or placebo the night before surgery; after operation, all patients received aspirin 325 mg daily, with the first dose administered 6 h after operation. Saphenous vein graft patency (351 patients) and IMA graft patency (246 patients) were investigated 8 days after surgery (mean) using angiography. In the patients given preoperative aspirin, the vein graft occlusion rate was 7.4 ± 1.3% compared with 7.8 ± 1.5% in those who received preoperative placebo (p = 0.871). The IMA occlusion rate was 0.0% (0 of 131) in the aspirin group compared with 2.4 ± 1.4% (3 of 125) in the placebo group (p = 0.081). Patients in the aspirin group received more transfusions than those in the placebo group (900 ml vs 725 ml; p = 0.006), had a higher chest tube drainage within the first 6 h after operation (500 ml vs 448 ml; p = 0.011) and a higher reoperation rate for bleeding (6.3% vs 2.4%; p = 0.036). Thus, preoperative aspirin was associated with increased bleeding complications and offered no additional benefit in early vein graft patency compared with starting aspirin therapy 6 h after operation.

In contrast, a study performed by Bybee et al. [51] in 1636 CABG patients showed that pretreatment with aspirin within the 5 days preceding CABG (n = 1316) had significantly lower postoperative in-hospital mortality compared with patients not receiving preoperative aspirin (1.7% vs 4.4%; OR 0.34, 95% CI 0.15–0.75; p = 0.007), without an increased risk of reoperation for bleeding (3.5% vs 3.4%; p = 0.96) or requirement for postoperative blood product transfusion (OR 1.17, 95% CI 0.88–1.54; p = 0.28). Similar results revealed a case–control study conducted by Dacey et al. [52] in 8641 patients undergoing CABG. Aspirin use in the week preceding surgery was associated with a significant decrease in the risk of in-hospital mortality (OR 0.73, 95% CI 0.54–0.97; p = 0.03), without any major change in the rate of re-exploration for haemorrhage, amount of chest tube drainage, or blood transfusion. But the results of both studies are limited since no information concerning the proximity of aspirin therapy to CABG (within the 5-day and 7-day period before surgery, respectively) and aspirin dosage is available. Moreover, the impact of aspirin application before CABG on potential aspirin resistance in the early period after surgery cannot be assessed, since platelet function was not investigated.

Taken together, the relation between preoperative aspirin treatment on clinical outcome and bleeding complications remains an issue open for discussion, the more so as the studies mentioned above were conducted prior to routine use of perioperative anti-fibrinolytic therapy (such as tranexamic acid or aprotinin).

3.2.3 Preoperative discontinuation of aspirin therapy
In this context, it has to be discussed whether aspirin should be discontinued before CABG in patients under continuous antiplatelet treatment. Current data focusing on aspirin discontinuation are still limited and of observational nature. Though prospective, randomised studies that investigate the relative risk of acute cardiovascular events after aspirin withdrawal compared with its continuation are not available, some reports have demonstrated benefits from the preoperative continuation of aspirin in patients undergoing CABG.

In the study performed by Mangano [48] about 50% of patients who had been receiving aspirin at the time of admission to the hospital discontinued antiplatelet therapy before surgery. Cessation of aspirin use before CABG was associated with an increased risk of death (OR 1.79, 95% CI 1.18–2.69; p = 0.01). This risk was substantially reduced, but still considerable, when aspirin was used within 48 h after surgery. Moreover, the use of aspirin was not associated with an increased frequency of adverse events.

Combining the studies of Mangano [48] and Dacey et al. [52] in a meta-analysis, Biondi-Zoccai et al. [53] endorsed the detrimental impact of aspirin discontinuation on the risk of adverse events (OR 2.20, 95% CI 1.58–3.08; p for effect = 0.002). Furthermore, these authors showed for patients with acute coronary syndrome or on secondary prevention for coronary artery disease a two-fold increased risk of adverse events for those discontinuing aspirin treatment (OR 1.82, 95% CI 1.52–2.18; p for effect <0.00001). In patients with intracoronary stents, a cessation of antiplatelet treatment was associated with an even higher risk of adverse events (OR 89.78, 95% CI 29.90–269.60; p for effect <0.00001).

But the increased risk for thromboembolic events after discontinuation of aspirin is a general problem that is not restricted to patients undergoing CABG, as shown by a meta-analysis of retrospective investigations in noncardiosurgical patients [54]. Aspirin withdrawal proceeded up to 10.2% of acute cardiovascular syndromes. The time interval between discontinuation and acute coronary syndromes was 8.5 ± 3.6 days, 14.3 ± 11.3 days for acute cerebral events, and 25.8 ± 18.1 days for acute peripheral arterial syndromes. But none of these retrospective studies reported the number of patients who did not suffer from a cardiovascular event despite periprocedural aspirin withdrawal. Thus, the exact incidence of cardiovascular events after aspirin cessation remains uncertain. In the setting of noncardiac operations, aspirin neither increased the level of the severity of bleeding complications nor the perioperative mortality because of bleeding complications.

Taken together, there is some evidence that withdrawal of aspirin treatment has ominous prognostic implication in patients with coronary heart disease, especially in those with intracoronary stents. In general, aspirin discontinuation should be advocated only when the bleeding risk clearly overwhelms that of atherothrombotic events. Biondi-Zoccai et al. [53] propose that aspirin should be continued before CABG, and only patients scheduled for major cardiac surgery should discontinue aspirin 3 days before the intervention, with reinstitution not later than 3 days afterwards, and using a parenteral anticoagulant drug, such as unfractioned or low-molecular-weight heparin, as bridging antithrombotic treatment.

3.2.4 Current guidelines
Nevertheless, there are different opinions concerning the perioperative administration of aspirin and the current guideline of the Society of Thoracic Surgeons and the Society of Cardiovascular Anethesiologists recommends [55]: ‘For the elective patient who requires CABG and does not have an acute coronary syndrome, it may be reasonable to discontinue aspirin for a few days (2 to 3 days) with the expectation that there will be less perioperative bleeding and blood transfusion.’ This is in line with the guideline of the American College of Chest Physicians [43] and the AHA/ACC guideline [56] that recommend the onset of aspirin treatment 6 h and within 48 h after CABG, respectively.

	4. Aspirin resistance

Top Abstract 1. Introduction 2. Aortocoronary vein graft... 3. Antiplatelet effect of... 4. Aspirin resistance 5. Therapeutic approaches of... 6. Future perspectives and... References

 
Besides the proven advantages when compared to placebo, clinical trials (mostly performed in the 80s and 90s of the last century) showed that aspirin does not eradicate completely the problem of early thrombosis following CABG, since a significant number of grafts still occlude within the first month after surgery despite ‘appropriate’ aspirin treatment [3–5,11]. New insight into the discussion concerning poor patency rates brought the recently recognised occurrence of ‘acquired’ aspirin nonresponsiveness in the most part of patients undergoing CABG [57,58].

4.1 Diagnosis of aspirin resistance
Since the critical platelet agonist in a particular patient is generally unknown, laboratory assays of aspirin resistance are surrogate measures, which are generally done under artificial conditions. No standardised definition or laboratory test is presently available to quantify aspirin resistance and the normal ranges of diagnostic methods are defined in different ways. Moreover, inhibition of platelet aggregation as measured in vitro does not necessarily translate into prevention of thrombosis in vivo and it is difficult to investigate in which amount the laboratory aspirin resistance corresponds to the clinical aspirin resistance, i.e. failure of aspirin to prevent thrombotic ischaemic events in patients prescribed aspirin.

There are several methods to measure platelet function; in the following, only the most common techniques are mentioned in brief (for review see [59]).

The assessment of the bleeding time is an in vivo method still used in clinical practice. After a standard incision in the skin of the forearm the time necessary for bleeding to stop is measured. But the diagnostic value of this test is very limited since it is nonspecific and poorly standardised.

One of the best-evaluated in vitro methods is the light transmission aggregometry that measures the increase in light transmission through a platelet suspension when platelets aggregate in vitro (turbidimetry according to Born). Because aspirin irreversibly blocks platelet TXA₂ synthesis, light aggregometry using arachidonic acid as agonist is an excellent qualitative assay to detect aspirin inhibition of platelets. Since analysis has to be done in platelet rich plasma, this time and laboratory consuming method is rarely used in clinical practice.

In platelets, COX-1 generates PGH₂ which is further transformed into TXA₂. This, in turn, is rapidly and nonenzymatically converted to inactive TXB₂ (TXB₂ is metabolised enzymatically to a range of products, the most abundant being 11-dehydro-TXB₂ and 2,3-dinor-TXB₂, both of which are excreted in urine). Thus, aspirin's inhibition of COX-1 is best assessed directly by measuring the capacity of platelets to generate TXB₂. Since this gold standard requires expensive laboratory methods, only few studies are based on serum TXB₂.

In contrast, the closure time of the platelet function analyser (PFA-100) is often used in clinical studies. This rapid method assesses platelet aggregation under high shear using whole blood that is aspirated though a small aperture coated with collagen and either epinephrine or ADP. Since platelet activation pathways are involved that are insensitive to aspirin, specificity and sensitivity of this bedside test are limited.

4.2 Prevalence of aspirin resistance after CABG
Each assay, however, measures a distinct aspect of platelet function and definitions of aspirin (non-) response are inconsistent, which may explain the variation in the reported prevalence of aspirin resistance. Hovens et al. [60] found a widely different prevalence of aspirin resistance in a meta-analysis of patients taking aspirin for secondary prevention and calculated a mean prevalence of 22.4%, 26.0%, and 27.3% in patients with coronary artery disease, stroke and miscellaneous diseases, respectively. Moreover, the analytical method itself was identified to provide an important impact and studies using arachidonic acid-induced light transmission aggregometry showed a significantly lower prevalence (15.4%, 95% CI 7.8–23.0) compared with the PFA-100 method (28.1%, 95% CI 22.2–33.9).

The prevalence of aspirin resistance after CABG depends, amongst others, on the time of measurement after surgery and varies from 10% up to >90% [61–64]; one study even found no evidence for aspirin resistance after CABG [65] (Table 2 ). Aspirin resistance acquired after CABG appears to be a transient phenomenon, especially within the first month after surgery.

4.3 Pathogenesis of aspirin resistance after CABG
These findings raise the question about the underlying mechanisms of the aspirin resistance. In this context, the (procedurally) ‘acquired’ aspirin resistance transiently seen after surgery has to be distinguished from (permanent) aspirin nonresponse due to genetic polymorphisms [67] or comorbidities, such as hypercholesterolaemia or diabetes [68].

Hitherto, the mechanisms of aspirin resistance are uncertain and concepts to explain aspirin resistance are largely hypothetical. Thus, only a brief overview is given discussing the impact of cardiopulmonary bypass, off-pump surgery, and concomitant medication on the antiplatelet effect of aspirin.

4.3.1 Impact of cardiopulmonary bypass on the antiplatelet effect of aspirin
About 80–90% of the coronary bypass procedures are performed with the help of extracorporeal circulation and it is well known that cardiopulmonary bypass (CPB) causes, amongst others, systemic inflammatory response [69,70] and platelet activation [71–73] with resultant structural and biochemical changes. Moreover, haemodilution due to the priming, mechanical disruption and adhesion to the CPB lead to platelet depletion during on-pump surgery and a postoperative recovery resulting in platelet counts that exceed the values before surgery. Thus, the increased platelet turn over with an elevated amount of platelets capable to form thromboxane despite aspirin treatment may contribute to aspirin resistance [58,74]. This hypothesis is endorsed by the finding that platelet aggregation and thromboxane formation are significantly increased after mechanical aortic valve replacement (without antiplatelet therapy), whereas platelet function remains nearly unchanged after CABG with persisting ability to aggregate in spite of oral aspirin treatment [75,76]. Thus, platelet hyper reactivity after CPB may blunt the antiplatelet effect of aspirin.

4.3.2 Impact of off-pump surgery on the antiplatelet effect of aspirin
In order to avoid systemic inflammatory reactions induced by CPB (and to decrease the incidence and/or severity of adverse outcomes), off-pump technologies have been developed and nowadays, the number of patients undergoing off-pump coronary artery bypass surgery (OPCAB) amounts up to 20%. Clinical trials that compare the platelet function of patients operated on using CPB with OPCAB patients allow investigating the impact of extracorporeal circulation on antiplatelet therapy, but prospective, randomised studies in this area are rare.

Ballotta et al. [73] compared 30 patients undergoing on-pump CABG with 30 OPCAB patients and found that platelet activation occurs to a much lesser extent early after OPCAB compared with on-pump CABG. Two hours after surgery, the decrease in ADP-induced platelet aggregation (0.8% vs 10.9%) and the increase in P-selectin-positive platelets indicating activated platelets (6.0% vs 9.1%) were significantly lower in the OPCAB group compared with patients operated on with CBP. But the postoperative course cannot be assessed because only one sample was collected at 2 h after surgery. Moreover, since cyclooxygenase dependent aggregation was not investigated, further conclusions regarding the antiplatelet effect of aspirin cannot be drawn.

A study performed by Møller and Steinbrüchel [77] that compared 15 OPCAB patients to 15 patients undergoing CABG with CPB has similar limitations. Platelet activating factor (PAF)-induced platelet aggregation was reduced to near half of preoperative values after on-pump CABG but significantly increased after off-pump surgery.

Similar results were found using a cyclooxygenase specific agonist (arachidonic acid) in a setting of 15 patients operated on with CPB compared to 14 OPCAB patients [78]. After a 5-day oral treatment with aspirin (100 mg per day, started at day 1 after surgery), platelet aggregation was inhibited significantly in OPCAB-patients to 55.7 ± 16.3% of control before surgery (p < 0.05), whereas aggregation remained unchanged after CPB (105.8 ± 26.9% of control before surgery; p > 0.05). In accordance, thromboxane formation was inhibited significantly after OPCAB (29.2 ± 13.0% of control before surgery, p < 0.05), but not after CPB (74.5 ± 21.4% of control before surgery, p > 0.05). Platelet counts of patients operated on without CPB showed no significant changes, whereas CPB caused the typical platelet depletion followed by a significant increase, indicating an enhanced platelet turn over.

Though the above-mentioned data may indicate that aspirin is more effective after OPCAB than after CABG with CPB, aspirin resistance has also been described after off-pump surgery [64]. The underlying reasons may in part be similar since an impact of OPCAB on systemic inflammation cannot totally be denied [79]. Moreover, a significantly diminished antiplatelet effect of aspirin has also been shown during carotid surgery [80], but seems to be rare on long-term aspirin therapy thereafter [81]. Thus, mechanisms of aspirin resistance independent of whether CPB is used or not have to be considered.

4.3.3 Impact of concomitant medication on the antiplatelet effect of aspirin
Some nonsteroidal analgesic anti-inflammatory drugs (NSAIDs), including indomethacin, ibuprofen and naproxen, as well as the pyrazole analgesic dipyrone (metamizol) may prevent the irreversible inhibition of platelet thromboxane formation by transiently binding to platelet COX-1 [82–84]. Since dipyrone is widely used for therapy of postoperative pain in many countries, the drug–drug interaction with aspirin might be of special importance for patients early after CABG.

Additionally, in the very early period after surgery, the impact of anaesthetics on platelet function has to be considered, but this issue is discussed controversially and results of many studies have been conflicting [85–87].

Finally, it is not surprising that also haemostatic drugs influence the antiplatelet effect of aspirin. In a setting of 60 OPCAB patients that were randomly assigned to full-dose aprotinin or placebo, patients treated with aprotinin had less postoperative aspirin resistance (20% vs 46%, p < 0.05), as investigated with the help of a modified thromboelastography, whole blood aggregometry, 11-dehydro-thromboxane B₂ levels, and flow cytometry [88].

4.4 Clinical impact of aspirin resistance
Since laboratory assays detecting platelet inhibition by aspirin are surrogate parameters, it has to be discussed whether laboratory nonresponse to aspirin is associated with an increased risk of clinical atherothrombotic events, such as graft thrombosis (clinical aspirin resistance).

Indeed, data from several studies in patients with atherosclerosis suggest that biochemical aspirin resistance increases the risk for thrombotic events [89,90]. In a meta-analysis of 20 clinical trials, 810 out of 2930 patients (28%) suffering from atherosclerotic diseases were classified as aspirin resistant [8]. Thirty-nine percent of aspirin resistant patients compared with 16% of aspirin sensitive patients had a cardiovascular event and showed a nearly four-fold increased risk of nonfatal and fatal cardiovascular, cerebrovascular, or vascular events while taking aspirin in comparison with aspirin sensitive counterparts (OR 3.85, 95% CI 3.08–4.80; p < 0.001), regardless of underlying clinical symptoms. The odds ratios for increased acute coronary syndrome, graft failure, or a new cerebrovascular event were 4.06, 4.35, and 3.78. Moreover, the odds ratio for increased mortality in aspirin resistant patients was 5.99 (95% CI 2.28–15.72; p < 0.003). Thus, the increased risk of these events in aspirin resistant patients occurred in those with stable cardiovascular disease or coronary artery disease, those who have had PCI or CABG, those undergoing other vascular procedures, and after stroke.

Nevertheless, concerning CABG, the number and size of trials investigating aspirin with clinical endpoints are very limited.

The Benefits and Risks of ASA on Thrombosis (BRAT) was the first prospective multicentre study with the objectives to determine the prevalence of aspirin responder or nonresponder status in patients undergoing CABG and to determine the clinical significance [63]. Using the bleeding time, aspirin response was assessed, when each of the 289 patients was off aspirin for at least 1 week (i.e. 4–24 h before CABG) and when each patient was on aspirin (325 mg per day), i.e. 10 days before surgery and/or more than 15 days after surgery. The mean bleeding times in aspirin responders were prolonged from 205 ± 80 s to 414 ± 227 s (p < 0.001) when on aspirin, without any effect in nonresponders (296 ± 116 s before and 306 ± 38 s on aspirin treatment). Surprisingly, platelet thromboxane synthesis was significantly inhibited in both groups to a similar extent (responders: from 14.3 ± 10.6 ng/ml to 2.1 ± 0.7 ng/ml; nonresponders: from 15.2 ± 9.4 ng/ml to 2.1 ± 0.6 ng/ml). The 2-year follow-up period failed to show significant differences in thrombotic event rates (myocardial infarction, unstable angina, cardiac death, or stroke) between aspirin responders and nonresponders (6.9% vs 9.5%; p = 0.526).

This data have two crucial limitations. Since response to aspirin was investigated 10 days before surgery and/or more than 15 days after surgery, an assessment of the antiplatelet effect of aspirin early after CABG is not possible. Moreover, it is unclear, whether the results before and after surgery were different, and if so, how those patients were classified. The discrepancy between the results of the bleeding time and the thromboxane levels make the classification of aspirin nonresponders used in this study questionable, the more so as bleeding time is an unspecific, operator dependent method.

In a setting of 225 patients undergoing elective off-pump CABG, aspirin resistance was defined by diagnostic findings on at least two of three separate assays (thromboelastography, whole blood aggregometry, and whole blood flow cytometry) [64]. Preoperative aspirin (325 mg per day) was continued and given within 6 h of surgery. Aspirin resistance occurred in 10 patients at baseline (4%), in 22 patients (10%) on day 1, in 67 patients (30%) on day 3 and it had resolved in all but seven patients (2%) by day 30. During a mean follow-up of 30 days the incidence of early thrombotic occlusions of vein grafts was highest in patients showing both aspirin resistance and endothelial cell lesions of the vein graft (aspirin resistance at any time point occurred in 45% of patients with early vein graft thrombosis vs 20% of patients with patent vein grafts; p < 0.05). After multivariate logistic regression analysis, aspirin resistance on day 1 was retained as independent predictor of vein graft thrombosis (OR 2.59, 95% CI 1.13–5.95; p < 0.025).

In a case–control study, 14 CABG patients who were shown to have at least one occluded saphenous vein graft on the late control coronary angiogram after CABG (mean 7.5 years) were compared for the presence of aspirin resistance (classified by PFA-100) with 14 age- and gender-matched patients, showing patent and well-functioning vein grafts (mean 6.5 years) [66]. The prevalence of aspirin resistance in patients with and without vein graft occlusion was 50% and 7.1%, respectively (p = 0.033). Being aspirin resistant increased the risk of late vein graft occlusion 13-fold and multivariate linear regression analysis identified the PFA-100 closure time to be an independent predictor. Nevertheless, this long-term follow-up provides no information about the critical period of aspirin resistance early after surgery.

Taken together, there is some evidence that platelets of patients with vein graft thrombosis after CABG are more likely to be resistant to aspirin therapy compared with patients without these complications.

	5. Therapeutic approaches of aspirin resistance after CABG

Top Abstract 1. Introduction 2. Aortocoronary vein graft... 3. Antiplatelet effect of... 4. Aspirin resistance 5. Therapeutic approaches of... 6. Future perspectives and... References

 
In spite of the increased risk for serious atherothrombotic events, up to now no guidelines have been established concerning either the diagnosis or the treatment of aspirin resistance [91]. In general, the antiplatelet therapy of an aspirin resistant patient may include a modified regimen or additional/alternative antiplatelet drugs.

Interestingly, a meta-analysis of 20 clinical trials including 2930 patients with cardiovascular diseases revealed that concomitant therapy with clopidogrel or tirofiban (an inhibitor of platelet glycoprotein IIb/IIIa), or both, provided no benefit to those patients identified as aspirin resistant (aspirin and clopidogrel: OR 3.06, 95% CI 1.99–4.70; aspirin alone: OR 2.52, 95% CI 1.79–3.56) [8]. Nevertheless, to what extent this finding applies to patients undergoing CABG remains to be shown and the available data are worth to be discussed in detail.

5.1.1 Modified aspirin regimen
The observation that extended incubation of platelets from aspirin resistant CABG patients in vitro achieved nearly complete inhibition of thromboxane formation [6] may suggest that aspirin resistance could be overcome by a prolonged administration, such as repeated doses per day. But clinical trials showed no advantage of aspirin administered two or three times per day compared to a single dosage regimen (see Section 1.2.2 and Table 1). Moreover, since intestinal absorption of aspirin can be delayed early after surgery, intravenous aspirin may be an alternative. Nevertheless, appropriate clinical trials in aspirin resistant patients are lacking, and both approaches can only be justified theoretically.

5.1.2 Other antiplatelet agents
Since the pathophysiological importance of thromboxane and other platelet activation agonists (e.g. ADP) may vary in different clinical settings, antiplatelet regimens beyond the cyclooxygenase pathway have to be considered in the context of ‘acquired’ aspirin resistance after CABG, such as thienopyridines, dipyridamole, and vitamin K-antagonists.

5.1.2.1 Thienopyridines
Thienopyridine derivatives, such as ticlopidine and clopidogrel, inhibit platelet aggregation by blocking the interaction between ADP and its platelet receptor.

Clinical trials angiographically showed an increased vein graft patency in CABG patients treated with ticlopidine (500 mg per day) compared to placebo. In a trial of 150 patients, vein graft patency at 3–8 months after surgery in the ticlopidine-treated group was 92.9% as compared with 78.2% in the placebo-treated group (p < 0.02) [92]. In another trial of 173 patients, 12-month vein graft patency was 84.1% in the ticlopidine-treated group and 73.9% in placebo-treated patients (p < 0.01) [93]. Despite impressive results, ticlopidine was not implemented clinically due to the high incidence (0.8%) of severe, but reversible neutropenia and agranulocytosis. Moreover, there are no published comparisons of vein graft patency rates with aspirin versus ticlopidine, or, more importantly, trials in CABG patients showing aspirin resistance.

Now, the ticlopidine analogue clopidogrel with a negligible incidence of neutropenia became the thienopyridine of choice. But in contrast to ticlopidine, clinical trials in CABG patients that investigated graft patency using postoperative angiograms are lacking. Nevertheless, five large multicentre trials give information about the clinical impact of clopidogrel (Table 3 ). The Clopidogerel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study [94,95] compared aspirin with clopidogrel, whereas the Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (CURE) trial [96,97], the Clopidogrel for the Reduction of Events During Observation (CREDO) trial [98], the Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management and Avoidance (CHARISMA) trial [99], and the Clopidogrel as Adjunctive Reperfusion Therapy-Thrombosis in Myocardial Infarction 28 (CLARITY-TIMI 28) trial [100] provide the opportunity to explore the combined use of aspirin plus clopidogrel compared to aspirin monotherapy for CABG patients. Moreover, a monocentre retrospective observational study investigated dual therapy (aspirin plus clopidogrel) in comparison with aspirin monotherapy after OPCAB [101].

Though the CAPRIE study provides some evidence that long-term therapy with clopidogrel is superior to aspirin in patients who have had previous cardiac surgery without an increase in bleeding risks, these results have important limitations: the subgroup analysis of CABG patients was not prespecified and data on revascularisation procedures during the study period are incomplete. Neither the proportion of patients receiving either vein or arterial grafts, nor the exact date of the previous surgery (and thus the mean age of the bypass grafts) can be determined. Finally, all patients enroled in CAPRIE had a qualifying ischaemic event, perhaps identifying a somewhat higher-risk group than the typical cardiac surgery patient.

5.1.2.3 Clopidogrel in addition to aspirin:
In the CURE trial, 12,562 patients with acute coronary syndrome (in the absence of ST-segment elevation) presenting within 24 h of symptom onset were randomised to receive a loading dose of clopidogrel (300 mg) or placebo and were maintained on clopidogrel (75 mg per day) or placebo in addition to aspirin (75–325 mg) for 3–12 months (median 9 months) [96]. The primary outcome was cardiovascular death, myocardial infarction, or stroke. The benefits were significant among those receiving medical therapy only (8.1% for clopidogrel, 10.0% for placebo; RR 0.80, 95% CI 0.69–0.92) and for those undergoing PCI (9.6% for clopidogrel, 13.2% for placebo; RR 0.72, 95% CI 0.57–0.90), but not for CABG patients (14.5% for clopidogrel, 16.2% for placebo; RR 0.89, 95% CI 0.71–1.11). A subgroup analysis for CABG patients was provided by Fox et al. [97]. Of the 2072 patients undergoing CABG, 1061 were randomly assigned to placebo and 1011 to clopidogrel. Before CABG, 1928 (93.1%) of the patients who proceeded to CABG stopped the study drug before CABG (median time before CABG 5 days), and 66 (3.2%) continued the drug (Data on timing was not available for 78 patients). Of the 1928 patients who stopped the study drug before CABG, 1451 (75.3%) restarted after CABG (median time after CABG 10 days). For those undergoing surgical revascularisation during the initial hospitalisation (530 placebo and 485 clopidogrel patients), 16.4% of the placebo-treated and 13.4% of the clopidogrel-treated patients experienced cardiovascular death, myocardial infarction, or stroke (RR 0.81, 95% CI 0.59–1.12). But benefits were observed mainly before CABG; 71 patients (6.7%) experienced a primary end point in the placebo group compared with 57 (5.6%) in the clopidogrel group (RR 0.82, 95% CI 0.58–1.16). After CABG, similar numbers of events occurred in both groups (112 placebo vs 103 clopidogrel; RR 0.97, 95% CI 0.74–1.26). There was no significant excess of major bleeding episodes after CABG (1.3% vs 1.1%; RR 1.26, 95% CI 0.93–1.71), but the risk of minor bleeding was significantly higher in the clopidogrel group than in the placebo group (5.1% vs 2.4%; p < 0.001).

In general, the following limitations have to be considered: the overall effect of aspirin cannot be clearly assessed because the timing of discontinuation of aspirin was not recorded, and it is possible that in some patients both drugs were used or discontinued simultaneously. Moreover, the trial was not specifically powered to demonstrate an independent treatment effect for patients undergoing CABG and beneficial effects did not reach the level of significance. Finally, it is questionable whether the results of CURE can be transferred to patients undergoing elective CABG without previous acute coronary syndrome.

The CREDO trial evaluated the short-term benefits of combined aspirin and clopidogrel pretreatment and the long-term benefits of sustained therapy in patients with symptomatic coronary artery disease and objective evidence for ischaemia who were referred for elective PCI [98]. Following randomisation and 3–24 h prior to PCI, patients received 325 mg of aspirin and clopidogrel (300 mg) or placebo. After PCI, both groups received 325 mg per day aspirin and 75 mg per day clopidogrel through day 28. After day 28, both groups received aspirin (81–325 mg), but only the pretreatment group continued to receive 75 mg per day clopidogrel, whereas the no-pretreatment group received placebo. Co-administration of a loading dose of clopidogrel (300 mg) with aspirin (325 mg) in the period 6–24 h before percutaneous coronary intervention resulted in a significant 38.6% risk reduction relative to aspirin in the composite endpoint of death, myocardial infarction or urgent target vessel revascularisation in the first month after intervention. During the 1-year follow-up 89 of 1053 patients (8.5%) taking clopidogrel and 122 of 1063 patients (11.5%) receiving placebo reached the composite endpoint (RR 0.73, 95% CI 0.56–0.96). Forty-one of 1053 (3.9%) patients randomised to clopidogrel and 42 of 1063 (4.0%) patients of the placebo group underwent CABG. In this group, approximately two thirds of all major bleeds appeared.

Nevertheless, there is no subgroup analysis of the small number of patients undergoing CABG so that no further conclusions can be drawn.

In the CHARISMA trial 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors received clopidogrel (75 mg per day) plus low-dose aspirin (75–162 mg per day) or placebo plus low-dose aspirin [99]. During a follow-up period of 28 months, the primary efficacy end point (composite of myocardial infarction, stroke, or death from cardiovascular causes) appeared in 6.8% with clopidogrel plus aspirin and 7.3% with placebo plus aspirin (RR 0.93, 95% CI 83–105; p = 0.22). 1525 (19.5%) of the patients receiving clopidogrel plus aspirin and 1554 (19.9%) of the patients taking placebo plus aspirin had a history of prior CABG. Analysis of this subgroup revealed no significant difference concerning the rate of myocardial infarction, stroke, or death from cardiovascular causes.

CLARITY-TIMI 28 enroled 3491 patients receiving fibrinolytic therapy for ST-segment elevation myocardial infarction [100]. Patients were randomised to clopidogrel (300 mg loading dose, then 75 mg daily) or placebo, begun at the time of fibrinolysis; 150–325 mg aspirin was administered on the first day and 75–162 mg afterward. Of the 3491 patients, 136 (3.9%) underwent CABG, of whom 66 (48.5%) had been randomised to clopidogrel and 70 (51.5%) to placebo (One patient was excluded from analysis due to the lack of data). Study medication was stopped a median of 5 days prior to CABG. After CABG, only 8 patients restarted clopidogrel. Among those undergoing CABG, the 30-day composite endpoint from randomisation of cardiovascular death, recurrent myocardial infarction, or ischaemia requiring urgent revascularisation occurred in 10 (15.2%) clopidogrel-treated patients and 15 (21.4%) placebo-treated patients (OR 0.66, 95% CI 0.27–1.63; p = 0.37). No statistically significant increase in major or minor perioperative bleeding was noted among patients receiving clopidogrel compared to placebo prior to CABG.

The results of this trial are limited, since the study was not powered to a statistically significant benefit in the subgroup of CABG patients. Moreover, the postoperative impact of clopidogrel therapy can hardly been assessed, because only eight patients (5.8%) restarted clopidogrel after CABG.

Taken together, the assessment of the antiplatelet effect of clopidogrel for CABG patients based on the above-mentioned multicentre trials is limited because the date of the surgical procedure is only known in CURE and CLARITY-TIMI 28, where patients with an acute coronary syndrome requiring urgent therapy were enroled. CREDO included patients with stable coronary heart disease undergoing elective PCI or at high likelihood of undergoing PCI. Only in these trials, the antiplatelet effect early after CABG can be estimated, with the limitation that the number of patients taking clopidogrel after surgery was very small in CLARITY-TIMI 28. Moreover, none of these studies had standardised drug therapy and monitoring after surgery. CAPRIE and CHARISMA investigated patients with cardiovascular disease, including those with a history of CABG and covered the late period after surgery, when aspirin resistance is unlikely to be found.

A monocentre observational study investigated a total of 591 patients undergoing elective OPCAB [101]. Three hundred and twenty-five mg of aspirin was administered in the first 6 h postoperatively; starting at day 1, 266 patients continued aspirin monotherapy (325 mg daily), whereas 325 patients received 81 mg aspirin and 75 mg clopidogrel per day. In this group, clopidogrel was administered for 30 days in 186 patients and 139 received long-term clopidogrel (mean 33.6 ± 12.0 months). Follow-up was 37.7 ± 13.4 months. In the multivariate analysis, postoperative clopidogrel independently decreased adverse cardiac events (myocardial infarction, coronary reintervention, and sudden cardiac death: OR 0.2, 95% CI 0.10–0.45; p < 0.0001) and symptom recurrence (angina and congestive heart failure: OR 0.3, 95% CI 0.15–0.99, p < 0.0001). There was no difference in the incidence of end points between short-term (30 days) and long-term receivers of the drug. A total of 15 patients showed bleeding complications without any difference in both groups; six were on clopidogrel in addition to aspirin (1.8%) while the remaining nine were on aspirin only (3.3%) at the time of bleeding (p = 0.8). Thus, clopidogrel therapy was associated with a significant decrease of adverse cardiac events and symptom recurrence, but extending clopidogrel use beyond 30 days did not gain further advantage.

Nevertheless, it is striking that the clopidogrel group had no case of myocardial infarction or sudden cardiac death after surgery. Moreover, the power of the trial is limited by the unblinded, observational design and the different doses of aspirin used in both study arms.

Though there seems to be some evidence for a favourable impact of clopidogrel, it remains unclear whether a potential benefit is related to the compensation for aspirin resistance with the addition of clopidogrel, and whether adding clopidogrel to a patient with aspirin resistance will help overcome clinical adverse outcomes. None of the above-mentioned studies identified aspirin nonresponders. Thus, randomised trials with clopidogrel plus aspirin versus aspirin (or clopidogrel) alone after CABG in aspirin nonresponders seem indispensable.

However, some studies also reported the presence of clopidogrel resistance [102,103] and a patient may even have aspirin and clopidogrel resistance at the same time. Lev et al. [104] assessed the relation between response to aspirin and to clopidogrel among patients scheduled to undergo cardiac and/or vascular surgery. Out of 100 patients (68 CABG, 10 CABG + valvular surgery, 22 vascular surgery) treated with aspirin (81–325 mg) for at least a week and with clopidogrel (75 mg) for at least 3 days, 13 were low responders to aspirin and 34 were low responders to clopidogrel; eight patients were low responders to both drugs. Similar to aspirin, clopidogrel resistance is found to be associated with increased risk of recurrent atherothrombotic events [105].

5.1.2.4 Dipyridamole
Dipyridamole was unnecessary for the reduction in vein graft occlusion noted for aspirin as determined in indirect or direct comparisons [21,106]. Aspirin plus dipyridamole versus aspirin alone showed no significant differences in vein graft patency and there appears to be no justification for routine postoperative administration of dipyridamole following coronary revascularisation. Moreover, there was no significant benefit of dipyridamole in other clinical settings as determined in the meta-analysis performed by the Antiplatelet Trialists’ Collaboration [1]. It is very probable, although untested, that dipyridamole by itself is ineffective in the antithrombotic therapy of CABG patients, with or without aspirin resistance.

5.1.2.5 Vitamin K-antagonists
Vitamin K-antagonists (VK-As) such as phenprocoumon and warfarin have also been investigated in patients after CABG. A meta-analysis performed by Fremes et al. [21] showed that VK-As reduced graft occlusion after CABG (VK-A vs placebo: OR 0.56, 95% CI 0.33–0.93; p = 0.025) and the results were similar to that achieved with aspirin (aspirin vs VK-A: OR 0.95, 95% CI 0.62–1.44; p = 0.871). All studies that allowed direct comparison of VK-As and aspirin suggested that both treatments were equivalent and provided similar protection for graft occlusion, but VK-A treatment protocols were associated with increased haemorrhagic complications. In accordance, the current guideline of the American College of Chest Physicians discourages the VK-A administration for patients undergoing CABG who have no other VK-A indication. For patients undergoing CABG in whom oral anticoagulants are indicated, such as those with heart valve replacement, VK-As are recommended in addition to aspirin [43].

	6. Future perspectives and clinical recommendation

Top Abstract 1. Introduction 2. Aortocoronary vein graft... 3. Antiplatelet effect of... 4. Aspirin resistance 5. Therapeutic approaches of... 6. Future perspectives and... References

 
Clinical studies investigating the critical period early after CABG are necessary to correlate the results of reproducible assays with clinical outcomes that can possibly be improved by alterations in antiplatelet strategy (e.g. increasing the dose of antiplatelet agent, adding or substituting a second antiplatelet agent). Prospective randomised trials that identify aspirin nonresponders are currently underway in patients suffering from stable coronary artery disease [107] or undergoing PCI [108], but not in CABG patients. According to the clinical experience of the authors the following criteria for the diagnosis of aspirin resistance can be recommended: (i) thromboxane in serum 10% of untreated controls [6,109], and/or (ii) arachidonic acid-induced platelet aggregation 20% of untreated controls [110]. Using these criteria, a prospective clinical trial in patients undergoing CABG should allow to identify whether laboratory findings (biochemical resistance) and their development over time are associated independently, significantly, and consistently with clinical outcome (clinical resistance), such as thrombotic vein graft occlusion or myocardial infarction. In addition, other diagnostic methods (including, for example point-of-care assays such as the platelet function analyser PFA-100, and the rapid platelet function assay RPFA) should be correlated with the occurrence of subsequent thromboembolic events after CABG in order to determine which method is most predictive in identifying patients at high risk of cardiovascular events despite aspirin therapy.

Taken together, the statement of the Working Group of Aspirin Resistance of the International Society of Thrombosis and Haemostasis [91] applies absolutely to the antiplatelet therapy after CABG: ‘A clinically meaningful definition of aspirin ‘resistance’ needs to be developed, based on data linking aspirin-dependent laboratory tests to clinical outcomes in patients.’

Nevertheless, a prospective randomised double-blinded study, Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE), is currently recruiting participants in order to address the efficacy of clopidogrel and aspirin therapy versus aspirin alone in the prevention of saphenous vein graft intimal hyperplasia following CABG [111]. Patients undergoing on-pump or off-pump CABG with at least two saphenous vein grafts are randomised to receive daily clopidogrel 75 mg or placebo, in addition to daily aspirin 162 mg, for a 1-year duration starting on the day of surgery. At the end of 1 year, all patients undergo coronary angiography and intravascular ultrasound assessment of one saphenous vein graft as selected by randomisation. The primary aim of this study is to evaluate the effect of combined antiplatelet therapy on the reduction of vein graft intimal hyperplasia 1 year after CABG by intravascular ultrasound. Secondary aims evaluate the safety of clopidogrel administration following CABG with regards to bleeding complications. Though platelet function is not investigated and nonresponders to antiplatelet therapy are not identified in this study, the results will probably help redefine modern antiplatelet management of coronary artery bypass patients.

A mnemonic for remembering issues to consider at the time of discharge after CABG (proposed by the American Heart Association – Committee on the management of patients with chromic stable angina) is ‘ABCDE’ (aspirin and antianginal therapy, beta-blockers and blood pressure, cigarette smoking and cholesterol, diet and diabetes, education and exercise) [112].

As far as antiplatelet therapy is concerned, the current recommendation is to prescribe aspirin alone, in a dose of 75–162 mg per day, to be commenced 6 h after surgery or, if initial bleeding prevents this, as soon as possible thereafter. Although aspirin has no discernible effect on vein graft patency beyond 1 year, it is indicated indefinitely because of its clear benefits in patients with native vessel coronary artery disease. Newer antiplatelet agents such as thienopyridines (clopidogrel) are recommended only for patients in whom aspirin is contraindicated, for example in salicylate allergy.

A combination of clopidogrel (75 mg per day) in addition to treatment with aspirin for 9–12 months following the procedure is recommended in patients who undergo CABG for non-ST-segment elevation acute coronary syndrome (ACS) [43].

Nevertheless, it remains to be determined whether clopidogrel should be used as an alternative to aspirin or in combination with aspirin in the early postoperative period since prospective clinical trials are lacking.

In conclusion, new aspects of and alternatives for the ‘old’ drug aspirin clear out same questions, but raise others – and hence, the aspirin story still goes on and might provide new exciting clinical and laboratory findings.

	References

Top Abstract 1. Introduction 2. Aortocoronary vein graft... 3. Antiplatelet effect of... 4. Aspirin resistance 5. Therapeutic approaches of... 6. Future perspectives and... References

 

1. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy-I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J 1994;308:81-106.[Abstract/Free Full Text]
2. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 1994;324:71-86.[CrossRef]
3. Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, Doherty J, Read R, Chesler E, Sako Y. Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a Veterans Administration Cooperative Study. Circulation 1988;77:1324-1332.[Abstract/Free Full Text]
4. Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, Doherty J, Read R, Chesler E, Sako Y. Saphenous vein graft patency 1 year after coronary artery bypass surgery and effects of antiplatelet therapy. Results of a Veterans Administration Cooperative Study. Circulation 1989;80:1190-1197.[Abstract/Free Full Text]
5. Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, Kern KB, Sethi G, Sharma GV, Khuri S. Long-term graft patency (3 years) after coronary artery surgery, effects of aspirin: results of a VA cooperative study. Circulation 1994;89:1138-1143.[Abstract/Free Full Text]
6. Zimmermann N, Wenk A, Kim U, Kienzle P, Weber AA, Gams E, Schrör K, Hohlfeld T. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 2003;108:542-547.[Abstract/Free Full Text]
7. Ferraris VA, Ferraris SP, Moliterno DJ, Camp P, Walenga JM, Messmore HL, Jeske WP, Edwards FH, Royston D, Shahian DM, Peterson E, Bridges CR, Despotis G, Society of Thoracic Surgeons The Society of Thoracic Surgeons practice guideline series: aspirin and other antiplatelet agents during operative coronary revascularization (executive summary). Ann Thorac Surg 2005;79:1454-1461.[Free Full Text]
8. Krasopoulos G, Brister SJ, Scott Beattie W, Buchanan MR. Aspirin resistance and risk of cardiovascular morbidity: systematic review and meta-analysis. Br Med J 2008;336:195-198.[Abstract/Free Full Text]
9. Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet 2006;367:606-617.[CrossRef][Medline]
10. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908-2913.[Abstract/Free Full Text]
11. Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease: pathogenesis, predisposition and prevention. Circulation 1998;97:916-931.[Abstract/Free Full Text]
12. Fuster V, Chesebro JH. Aorto-coronary artery vein graft disease: experimental and clinical approach for the understanding of the role of platelets and platelet inhibitors. Circulation 1985;72(Suppl. V):65-70.
13. Fuster V, Chesebro JH. Role of platelets and platelet inhibitors in aortocoronary artery vein-graft disease. Circulation 1986;73:227-232.[Abstract/Free Full Text]
14. Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton JR. Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol 1996;28:616-626.[Abstract]
15. Goldman S, Zadina K, Krasnicka B, Moritz T, Sethi G, Copeland J, Ovitt T, Henderson W. Predictors of graft patency 3 years after coronary artery bypass graft surgery. Department of Veterans Affairs Cooperative Study Group No. 297. J Am Coll Cardiol 1997;29:1563–68.
16. Lawrie GM, Weilbacher DE, Henry PD. Endothelium-dependent relaxation in human saphenous vein grafts. Effects of preparation and clinicopathologic correlations. J Thorac Cardiovasc Surg 1990;100:612-620.[Abstract]
17. Souza DS, Johansson B, Bojö L, Karlsson R, Geijer H, Filbey D, Bodin L, Arbeus M, Dashwood MR. Harvesting the saphenous vein with surrounding tissue for CABG provides long-term graft patency comparable to the left internal thoracic artery: results of a randomized longitudinal trial. J Thorac Cardiovasc Surg 2006;132:373-378.[Abstract/Free Full Text]
18. Kiaii B, Moon BC, Massel D, Langlois Y, Austin TW, Willoughby A, Guiraudon C, Howard CR, Guo LR. A prospective randomized trial of endoscopic versus conventional harvesting of the saphenous vein in coronary artery bypass surgery. J Thorac Cardiovasc Surg 2002;123:204-212.[Abstract/Free Full Text]
19. Perrault LP, Jeanmart H, Bilodeau L, Lespérance J, Tanguay JF, Bouchard D, Pagé P, Carrier M. Early quantitative coronary angiography of saphenous vein grafts for coronary artery bypass grafting harvested by means of open versus endoscopic saphenectomy: a prospective randomized trial. J Thorac Cardiovasc Surg 2004;127:1402-1407.[Abstract/Free Full Text]
20. Yun KL, Wu Y, Aharonian V, Mansukhani P, Pfeffer TA, Sintek CF, Kochamba GS, Grunkemeier G, Khonsari S. Randomized trial of endoscopic versus open vein harvest for coronary artery bypass grafting: six-month patency rates. J Thorac Cardiovasc Surg 2005;129:496-503.[Abstract/Free Full Text]
21. Fremes SE, Levinton C, Naylor CD, Chen E, Christakis GT, Goldman BS. Optimal antithrombotic therapy following aortocoronary bypass: a meta-analysis. Eur J Cardiothorac Surg 1993;7:169-180.[Abstract]
22. Jackson ZS, Ishibashi H, Gotlieb AI, Langille BL. Effects of anastomotic angle on vascular tissue responses at end-to-side arterial grafts. J Vasc Surg 2001;34:300-307.[CrossRef][Medline]
23. Collard CD, Body SC, Shernan SK, Wang S, Mangano DT, Multicenter Study of Perioperative Ischemia (MCSPI) Research Group Inc. Ischemia Research and Education Foundation (IREF) Investigators. Preoperative statin therapy is associated with reduced cardiac mortality after coronary artery bypass graft surgery. J Thorac Cardiovasc Surg 2006;132:392-400.[Abstract/Free Full Text]
24. Lazar HL. Role of statin therapy in the coronary bypass patient. Ann Thorac Surg 2004;78:730-740.[Abstract/Free Full Text]
25. Paraskevas KI. Applications of statins in cardiothoracic surgery: more than just lipid-lowering. Eur J Cardiothorac Surg 2008;33:377-390.[Abstract/Free Full Text]
26. Thielmann M, Neuhäuser M, Marr A, Jaeger BR, Wendt D, Schuetze B, Kamler M, Massoudy P, Erbel R, Jakob H. Lipid-lowering effect of preoperative statin therapy on postoperative major adverse cardiac events after coronary artery bypass surgery. J Thorac Cardiovasc Surg 2007;134:1143-1149.[Abstract/Free Full Text]
27. Jack DB. One hundred years of aspirin. Lancet 1997;350:437-439.[CrossRef][Medline]
28. Craven LL. Acetylsalicylic acid, possible preventive of coronary thrombosis. Ann West Med Surg 1950;4:95.[Medline]
29. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971;231:232-235.[Medline]
30. Simmons DL, Botting RM, Hla T. Cyclooxygenase isoenzymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 2004;56:387-437.[Abstract/Free Full Text]
31. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets – acetylation of a particulate fraction protein. J Clin Invest 1975;56:624-632.[Medline]
32. Maree AO, Curtin RJ, Dooley M, Conroy RM, Crean P, Cox D, Fitzgerald DJ. Platelet response to low-dose enteric coated aspirin in patients with stable cardiovascular disease. J Am Coll Cardiol 2005;46:1258-1263.[Abstract/Free Full Text]
33. Benedek IH, Joshi AS, Pieniaszek HJ, King SYP, Kornhauser DM. Variability in the pharmacokinetics and pharmacodynamics of low dose aspirin in healthy male volunteers. J Clin Pharmacol 1995;35:1181-1186.[Abstract]
34. Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982;69:1366-1372.[Medline]
35. Lorenz RL, Schacky CV, Weber M, Meister W, Kotzur J, Reichardt B, Theisen K, Weber PC. Improved aortocoronary bypass patency by low-dose aspirin (100 mg daily). Effects on platelet aggregation and thromboxane formation. Lancet 1984;1:1261-1264.[CrossRef][Medline]
36. Hockings BE, Ireland MA, Gotch-Martin KF, Taylor RR. Placebo-controlled trial of enteric coated aspirin in coronary bypass graft patients. Effect on graft patency. Med J Aust 1993;159:376-378.[Medline]
37. Sanz G, Pajaron A, Alegria E, Coello I, Cardona M, Fournier JA, Gomez-Recio M, Ruano J, Hidalgo R, Medina A. Prevention of early aortocoronary bypass occlusion by low-dose aspirin and dipyridamole. Grupo Espanol para el Seguimiento del Injerto Coronario (GESIC). Circulation 1990;82:765-773.[Abstract/Free Full Text]
38. Gavaghan TP, Gebski V, Baron DW. Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery. Circulation 1991;83:1526-1533.[Abstract/Free Full Text]
39. Sharma GV, Khuri SF, Josa M, Folland ED, Parisi AF. The effect of antiplatelet therapy on saphenous vein coronary artery bypass graft patency. Circulation 1983;68:II218-II221.[Medline]
40. Brown BG, Cukingnan RA, Derouen T, Goede LV, Wong M, Fee HJ, Roth JA, Carey JS. Improved graft patency in patients treated with platelet-inhibiting therapy after coronary bypass surgery. Circulation 1985;72:138-146.[Abstract/Free Full Text]
41. McEnany TM, Salzman EW, Mundth ED, DeSanctis RW, Harthorne JW, Weintraub RM, Gates S, Austen WG. The effect of antithrombotic therapy on patency rates of saphenous vein coronary artery bypass grafts. J Thorac Cardiovasc Surg 1982;83:81-89.[Abstract]
42. Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, Kern KB, Sethi G, Sharma GV, Khuri S, Richards K, Grover F, Morrison D, Johnston M, Chesler E, Sako Y, Pacold I, Montoya A, Demots H, Floten S, Doherty J, Read R, Scott S, Spooner T, Masud Z, Haakenson C, Harker L. Internal mammary artery and saphenous vein graft patency. Effects of aspirin. Circulation 1990;82(Suppl. 5):IV237-IV242.[Medline]
43. Stein PD, Schünemann HJ, Dalen JE, Guttermann D. Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts. Chest 2004;126:600S-608S.[CrossRef][Medline]
44. Patrono C, Ciabattoni G, Patrignani P, Pugliese F, Fillabozi P, Catella F, Davì G, Forni L. Clinical pharmacology of platelet cyclooxygenase inhibition. Circulation 1985;72:1177-1184.[Abstract/Free Full Text]
45. Lim E, Ali Z, Ali A, Routledge T, Edmonds L, Altman DG, Large S. Indirect comparison meta-analysis of aspirin therapy after coronary surgery. Br Med J 2003;327:1309-1313.[Abstract/Free Full Text]
46. Patrono C, Coller B, Dalen JE, FitzGerald GA, Fuster V, Gent M, Hirsh J, Roth G. Platelet active drugs; the relationships among dose, effectiveness, and side effects. Chest 2001;119:39S-63S.[CrossRef][Medline]
47. Ehsan A, Mann MJ, Dell’Acqua G, Tamura K, Braun-Dullaeus R, Dzau VJ. Endothelial healing in vein grafts: proliferative burst unimpaired by genetic therapy of neointimal disease. Circulation 2002;105:1686-1692.[Abstract/Free Full Text]
48. Mangano DT, Multicenter Study of Perioperative Ischemia Research Group Aspirin and mortality from coronary bypass surgery. N Engl J Med 2002;347:1309-1317.[Abstract/Free Full Text]
49. Alghamdi AA, Moussa F, Fremes SE. Does the use of preoperative aspirin increase the risk of bleeding in patients undergoing coronary artery bypass grafting surgery? Systematic review and meta-analysis. J Card Surg 2007;22:247-256.[CrossRef][Medline]
50. Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, Kern KB, Sethi G, Sharma GV, Khuri S. Starting aspirin therapy after operation. Effects on early graft patency. Department of Veterans Affairs Cooperative Study Group. Circulation 1991;84:520–26.
51. Bybee KA, Powell BD, Valeti U, Rosales AG, Kopecky SL, Mullany C, Wright RS. Preoperative aspirin therapy is associated with improved postoperative outcomes in patients undergoing coronary artery bypass grafting. Circulation 2005;112(Suppl. 9):I286-I292.[Medline]
52. Dacey LJ, Munoz JJ, Johnson ER, Leavitt BJ, Maloney CT, Morton JR, Olmstead EM, Birkmeyer JD, O’Connor GT. Northern New England Cardiovascular Disease Study Group. Effect of preoperative aspirin use on mortality in coronary artery bypass grafting patients. Ann Thorac Surg 2000;70:1986–90.
53. Biondi-Zoccai GG, Lotrionte M, Agostoni P, Abbate A, Fusaro M, Burzotta F, Testa L, Sheiban I, Sangiorgi G. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J 2006;27:2667-2674.[Abstract/Free Full Text]
54. Burger W, Chemnitius JM, Kneissl GD, Rücker G. Low-dose aspirin for secondary cardiovascular prevention – cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation – review and meta-analysis. J Intern Med 2005;257:399-414.[CrossRef][Medline]
55. Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris VA, Ferraris SP, Saha SP, Hessel EA 2nd, Haan CK, Royston BD, Bridges CR, Higgins RS, Despotis G, Brown JR; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion, Spiess BD, Shore-Lesserson L, Stafford-Smith M, Mazer CD, Bennett-Guerrero E, Hill SE, Body S. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg 2007;83(Suppl. 5):S27–S86.
56. Smith Jr. SC, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, Grundy SM, Hiratzka L, Jones D, Krumholz HM, Mosca L, Pasternak RC, Pearson T, Pfeffer MA, Taubert KA. AHA/ACC; National Heart, Lung, and Blood Institute. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006;113:2363-2372.[Free Full Text]
57. Buchanan MR, Brister SJ. Individual variation in the effects of ASA on platelet function: Implications for use of ASA clinically. Can J Cardiol 1995;11:221-227.[Medline]
58. Zimmermann N, Kienzle P, Weber A-A, Winter J, Gams E, Schrör K, Hohlfeld T. Aspirin resistance after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2001;121:982-984.[Free Full Text]
59. Schwartz KA. Aspirin resistance: a review of diagnostic methodology, mechanisms, and clinical utility. Advances Clin Chem 2006;42:81-110.[CrossRef][Medline]
60. Hovens MC, Snoep JD, Eikenboom JC, van der Bom JG, Mertens BJ, Huisman MV. Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review. Am Heart J 2007;153:175-181.[CrossRef][Medline]
61. Golaski J, Chopicki S, Golaski R, Gresner P, Iwaszkiewicz A, Watala C. Resistance to aspirin in patients after coronary artery bypass grafting is transient: impact on the monitoring of aspirin antiplatelet therapy. Ther Drug Monit 2005;27:484-490.[CrossRef][Medline]
62. Zimmermann N, Kurt M, Winter J, Gams E, Wenzel F, Hohlfeld T. Detection and duration of aspirin resistance after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2008;135:947-948.[Free Full Text]
63. Buchanan M, Schwartz L, Bourassa M, Brister S, Peniston C, BRAT investigators Results of the BRAT study: a pilot study investigating the possible significance of ASA non responsiveness on the benefits and risks of ASA on thrombosis in patients undergoing coronary artery bypass surgery. Can J Cardiol 2000;16:1385-1390.[Medline]
64. Poston RS, Gu J, Brown JM, Gammie JS, White C, Nie L, Pierson III RN, Griffith BP. Endothelial injury and acquired aspirin resistance as promoters of regional thrombin formation and early vein graft failure after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2006;131:122-130.[Abstract/Free Full Text]
65. Cornelissen J, Kirtland S, Lim E, Goddard M, Bellm S, Sheridan K, Large S, Vuylsteke A. Biological efficacy of low against medium dose aspirin regimen after coronary surgery: analysis of platelet function. Thromb Haemost 2006;95:476-482.[Medline]
66. Yilmaz MB, Balbay Y, Caldir V, Ayaz S, Guray Y, Guray U, Korkmaz S. Late saphenous vein graft occlusion is patients with coronary bypass: possible role of aspirin resistance. Thromb Res 2005;115:25-29.[CrossRef][Medline]
67. Marin F, Roldan V, Gonzalez-Conejero R, Corral J. The pharmacogenetics of antiplatelet drugs. Curr Opin Investig Drugs 2007;8:213-218.[Medline]
68. Davi G, Gresele P, Violi F, Basili S, Catalano M, Giammarresi C, Volpato R, Nenci GG, Ciabattoni G, Patrono C. Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease. Circulation 1997;96:69-75.[Abstract/Free Full Text]
69. Li S, Price R, Phiroz D, Swan K, Crane TA. Systemic inflammatory response during cardiopulmonary bypass and strategies. J Extra Corpor Technol 2005;37:180-188.[Medline]
70. Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 2003;75:S715-S720.[Abstract/Free Full Text]
71. Hyde JA, Chinn JA, Graham TR. Platelets and cardiopulmonary bypass. Perfusion 1998;13:389-407.[Free Full Text]
72. Weerasinghe A, Taylor KM. The platelet in cardiopulmonary bypass. Ann Thorac Surg 1998;66:2145-2152.[Abstract/Free Full Text]
73. Ballotta A, Saleh HZ, El Baghdady HW, Gomaa M, Belloli F, Kandil H, Balbaa Y, Bettini F, Bossone E, Menicanti L, Frigiola A, Bellucci C, Mehta RH. Comparison of early platelet activation in patients undergoing on-pump versus off-pump coronary artery bypass surgery. J Thorac Cardiovasc Surg 2007;134:132-138.[Abstract/Free Full Text]
74. Guthikonda S, Lev EI, Patel R, DeLao T, Bergeron AL, Dong JF, Kleiman NS. Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J Thromb Haemost. 2007;5:490-496.[CrossRef][Medline]
75. Zimmermann N, Roussiekan T, Winter J, Kurt M, Gams E, Wenzel F, Hohlfeld T. Platelet inhibition by aspirin after aortic valve replacement. J Thorac Cardiovasc Surg 2006;131:1392-1393.[Free Full Text]
76. Zimmermann N, Kurt M, Winter J, Gams E, Wenzel F, Weber AA, Hohlfeld T. Aspirin-induced platelet inhibition in patients undergoing cardiac surgery. Platelets 2007;18:528-534.[CrossRef][Medline]
77. Møller CH, Steinbrüchel DA. Platelet function after coronary artery bypass grafting: is there a procoagulant activity after off-pump compared with on-pump surgery?. Scand Cardiovasc J 2003;37:149-153.[CrossRef][Medline]
78. Zimmermann N, Kurt M, Wenk A, Winter J, Gams E, Hohlfeld T. Is cardiopulmonary bypass a reason for aspirin resistance after coronary artery bypass grafting?. Eur J Cardiothorac Surg 2005;27:606-610.[Abstract/Free Full Text]
79. Raja SG, Berg GA. Impact of off-pump coronary artery bypass surgery on systemic inflammation: current best available evidence. J Card Surg 2007;22:445-455.[CrossRef][Medline]
80. Payne DA, Jones CI, Hayes PD, Webster SE, Ross Naylor A, Goodall AH. Platelet inhibition by aspirin is diminished in patients during carotid surgery: a form of transient aspirin resistance?. Thromb Haemost 2004;92:89-96.[Medline]
81. Assadian A, Lax J, Meixner-Loicht U, Hagmüller GW, Bayer PM, Hübl W. Aspirin resistance among long-term aspirin users after carotid endarterectomy and controls: flow cytometric measurement of aspirin-induced platelet inhibition. J Vasc Surg 2007;45:1142-1147.[CrossRef][Medline]
82. Capone ML, Sciulli MG, Tacconelli S, Grana M, Ricciotti E, Renda G, Di Gregorio P, Merciaro G, Patrignani P. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J Am Coll Cardiol 2005;45:1295-1301.[Abstract/Free Full Text]
83. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345:1809-1817.[Abstract/Free Full Text]
84. Hohlfeld T, Zimmermann N, Weber AA, Jessen G, Weber H, Schrör K, Höltje HD, Ebel R. Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis. J Thromb Haemost 2008;6:166-173.[Medline]
85. Dordoni PL, Frassanito L, Bruno MF, Proietti R, de Cristofaro R, Ciabattoni G, Ardito G, Crocchiolo R, Landolfi R, Rocca B. In vivo and in vitro effects of different anaesthetics on platelet function. Br J Haematol 2004;125:79-82.[CrossRef][Medline]
86. Kozek-Langenecker SA. The effects of drugs used in anaesthesia on platelet membrane receptors and on platelet function. Curr Drug Targets 2002;3:247-258.[CrossRef][Medline]
87. Parolari A, Guarnieri D, Alamanni F, Toscano T, Tantalo V, Gherli T, Colli S, Foieni F, Franze V, Stanghellini M, Gianotti GA, Biglioli P, Tremoli E. Platelet function and anesthetics in cardiac surgery: an in vitro and ex vivo study. Anesth Analg 1999;89:26-31.[Abstract/Free Full Text]
88. Poston RS, White C, Gu J, Brown J, Gammie J, Pierson RN, Lee A, Connerney I, Avari T, Christenson R, Tandry U, Griffith BP. Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery bypass grafting. Ann Thorac Surg 2006;81:104-110.[Abstract/Free Full Text]
89. Sanderson S, Emery J, Baglin T, Kinmonth AL. Aspirin resistance and its clinical implications. Ann Intern Med 2005;142:370-380.[Abstract/Free Full Text]
90. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Jukema JW, Huisman MV. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 2007;154:221-231.[CrossRef][Medline]
91. Michelson AD, Cattaneo M, Eikelboom JW, Gurbel P, Kottke-Marchant K, Kunicki TJ, Pulcinelli FM, Cerletti C, Rao AK. Aspirin resistance: position paper of the Working Group on Aspirin Resistance. J Thromb Haemost 2005;3:1309-1311.[CrossRef][Medline]
92. Chevigne M, David JL, Rigo P. Effect of ticlopidine on saphenous vein bypass patency rates – a double blind study. Ann Thorac Surg 1984;37:371-378.[Abstract]
93. Limet R, David JL, Magotteaux P, Larock MP. Rigo P: Prevention of aorto-coronary bypass graft occlusion – beneficial effect of ticlopidine on early and late patency rates of venous coronary bypass grafts – a double-blind study. J Thorac Cardiovasc Surg 1987;94:773-783.[Abstract]
94. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996;348:1329-1339.[CrossRef][Medline]
95. Bhatt DL, Chew DP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 2001;103:363-368.[Abstract/Free Full Text]
96. The C.U.R.E. Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.[Abstract/Free Full Text]
97. Fox KA, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ, Yusuf S. Clopidogrel in unstable angina to prevent recurrent ischemic events trial. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome. The clopidogrel in unstable angina to prevent recurrent ischemic events (CURE) trial. Circulation 2004;110:1202-1208.[Abstract/Free Full Text]
98. Steinhubl SR, Berger PB, Mann 3rd JT, Fry ET, DeLago A, Wilmer C, Topol EJ. CREDO Investigators. Clopidogrel for the reduction of events during observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomised controlled trial. JAMA 2002;288:2411-2420.[Abstract/Free Full Text]
99. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather, MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ, for the CHARISMA Investigators Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-1717.[Abstract/Free Full Text]
100. McLean DS, Sabatine MS, Guo W, McCabe CH, Cannon CP. Benefits and risks of clopidogrel pretreatment before coronary artery bypass grafting in patients with ST-elevation myocardial infarction treated with fibrinolytics in CLARITY-TIMI 28. J Thromb Thrombolysis 2007;24:85-91.[CrossRef][Medline]
101. Gurbuz AT, Zia AA, Vuran AC, Cui H, Aytac A. Postoperative clopidogrel improves mid-term outcome after off-pump coronary artery bypass graft surgery: a prospective study. Eur J Cardiothorac Surg 2006;29:190-195.[Abstract/Free Full Text]
102. Gurbel PA, Tantry US. Aspirin and clopidogrel resistance: consideration and management. J Interven Cardiol 2006;19:439-448.[CrossRef][Medline]
103. Fitzgerald DJ, Maree A. Aspirin and clopidogrel resistance. Hematology 2007;2007:114-120.[CrossRef][Medline]
104. Lev EI, Ramchandani M, Garg R, Wojciechowski Z, Builes A, Vaduganathan M, Tripathy U, Kleiman NS. Response to aspirin and clopidogrel in patients scheduled to undergo cardiovascular surgery. J Thromb Thrombolysis 2007;24:15-21.[CrossRef][Medline]
105. Maree AO, Fitzgerald DJ. Variable platelet response to aspirin and clopidogrel in atherothrombotic disease. Circulation 2007;115:2196-2207.[Free Full Text]
106. Stein PD, Dalen JE, Goldman S, Schwartz L, Theroux P, Turpie AG. Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts. Chest 1995;108:424S-430S.[CrossRef][Medline]
107. Pettersen AA, Seljeflot I, Abdelnoor M, Arnesen H. Unstable angina, stroke, myocardial infarction and death in aspirin non-responders. A prospective, randomized trial. The ASCET (ASpirin non-responsiveness and Clopidogrel Endpoint Trial) design. Scand Cardiovasc J 2004;38:353-356.[CrossRef][Medline]
108. Cheng X, Chen WH, Simon DI. Aspirin resistance or variable response or both?. Am J Cardiol 2006;98:S11-S17.[CrossRef]
109. Reilly IA, Fitzgerald GA. Inhibition of thromboxane formation in vivo and ex vivo – implications for therapy with platelet inhibitory drugs. Blood 1987;69:180-186.[Abstract/Free Full Text]
110. Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003;41:961-965.[Abstract/Free Full Text]
111. Kulik A, LeMay M, Wells GA, Mesana TG, Ruel M. The clopidogrel after surgery for coronary artery disease (CASCADE) randomized controlled trial: clopidogrel and aspirin versus aspirin alone after coronary bypass surgery (NCT00228423). Curr Control Trials Cardiovasc Med 2005;6:15.[CrossRef][Medline]
112. Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, Ferguson TB, Fihn SD, Fraker Jr TD, Gardin JM, O’Rourke RA, Pasternak RC, Williams SV. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee to update the 1999 guidelines on the management of patients with chronic stable angina). J Am Coll Cardiol 2003;41:159–68.

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