**10. Discussions**

Multiple clinical trials showed the favorable effects of Clopidogrel alone or combined with Aspirin extending the indication for using Clopidogrel in a wide range of at risk patients and in long-term prevention in various manifestations of atherosclerosis.

and antithrombotic therapy have been demonstrated to favorably modify clinical outcome, and recent trials of revascularization in ACSs have demonstrated a reduction in the frequency

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The benefits versus risks of early and long-term clopidogrel therapy (freedom from CV death, MI, stroke, or life-threatening bleeding) are similar in those undergoing revascularization (CABG or PCI) and in the study population as a whole. Overall, the benefits of starting clopidogrel on admission appear to outweigh the risks, even among those who proceed to

Actually the field of the indications of use of the antiagregant therapy is being continuously updated.The role of the aspirin in the primary prevention has extended its prescription based on related factors of cardiovascular and/or neurological risk. Moreover the combination of two antiagregant drugs (mainly Aspirin and clopidogrel) in high risk patients is a practice more and more extended [18]. Dual antiplatelet therapy has to be maintained at least 12 months after drug eluting stent placement and, in this patient a specific protocol of antiaggregation in type,

For patients undergoing coronary artery bypass graft surgery, controversy remains regarding the safety of preoperative antiplatelet therapy and the optimal postoperative antiplatelet regimen to maintain graft patency and reduce ischemic complications. There are also of this systematic reviews trying to evaluate the risks and benefits of preoperative aspirin and clopidogrel therapy, to identify the optimal timing and dose of aspirin following CABG, and to assess the role of postoperative clopidogrel therapy.[20]Following surgery, extensive evidence supports the use of aspirin, in doses of 100 - 325 mg daily, to be administered in 48 h postoperatively and continued indefinitely. Less is known regarding the use of clopidogrel following CABG, although it is now recommended as postoperative antiplatelet therapy in patients with recent acute coronary syndromes.Despite > 30 years of experience with antipla‐ telet agents during CABG, questions remain regarding their perioperative safety and efficacy. The results of continuing randomized controlled trials should further clarify the role of perioperative aspirin and clopidogrel therapy and help redefine the modern antiplatelet

Also, the optimal aspirin dose for the prevention of cardiovascular events remains controver‐ sial.[32]: Daily aspirin doses of 100 mg or greater were associated with no clear benefit in patients taking aspirin only and possibly with harm in patients taking clopidogrel. Daily doses of 75 to 81 mg may optimize efficacy and safety for patients requiring aspirin for long-term

The response to aspirin and/or clopidogrel and its impact on graft patency after off-pump coronary artery bypass grafting is characterised by individual variability, but, overall com‐ bined clopidogrel and aspirin overcome single drug resistances, were are safe for bleeding and

At first sight, clopidogrel appears to be undesirable for cardiac surgeons: antiplatelet therapy can increase the risk of bleeding during coronary artery bypass graft surgery (CABG).1 Traditionally, many surgeons have felt that, with impeccable technique, their personally

of major cardiac events[2-14].

CABG during the initial hospitalization.

combination and duration need to be applied [30, 31].

management of coronary artery bypass patients.

improve venous graft patency. [33]

prevention, especially for those receiving dual antiplatelet therapy.

In recent years, enormous growth in the use of coronary stenting procedures has resulted in a significant decrease in restenosis rates, while acute and sub-acute stent thrombosis remain a significant potential complication. It has been shown, however, that the risk of acute and subacute stent thrombosis is greatly reduced by the administration of antiplatelet therapies following stenting. Much clinical experience with combination of aspirin and ticlopidine has been gained, however ticlopidine has been shown to be associated with rare risk of haemato‐ logical adverse events.

The CLASSICS study demonstrated the safety and efficacy of clopidogrel (with or without loading dose) in combination with aspirin for use following coronary stenting.

A large randomized trial has demonstrated that the acute administration of clopidogrel—a long-acting antiplatelet therapy—to patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS) can reduce subsequent risk for death, myocardial infarction, or stroke by 20% when continued for a mean duration of nine months [21]. However, single-center case series have demonstrated that, in patients requiring coronary artery bypass graft surgery, the use of Clopidogrel is associated with increased risk of perioperative bleeding and a need for transfusion [22- 26].

This risk appears to be time dependent. For example, post-hoc data analysis from the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial revealed that bleeding risks were increased when patients had CABG surgery within 5 days of clopidogrel treatment but not when surgery was delayed for >5 days after treatment with clopidogrel [21]

These findings are reflected in the American College of Cardiology/American Heart Associa‐ tion (ACC/AHA) guidelines for the acute management of patients with NSTE ACS, which endorse the acute use of clopidogrel but also recommend withholding clopidogrel for at least 5 days before CABG surgery (27).

Adherence in community practice to this guidelines recommendation is very unclear. has not been characterized previously. There are studies trying to characterize patterns of Clopidogrel use before CABG and to examine the time-dependent risks for postop‐ erative transfusion among NSTE ACS patients treated at 264 hospitals participating in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) National Quality Improvement Initiative [15, 28- 29].

Combined antiplatelet therapy was also studied in a lot of trials and most of them showed good safety and efficacy profiles. Antiplatelet therapy and antithrombin therapy have been demonstrated to reduce the risk of cardiac events in patients presenting with acute coronary syndrome, yet all effective therapies also increase the risk of bleeding. Antiplatelet therapy and antithrombotic therapy have been demonstrated to favorably modify clinical outcome, and recent trials of revascularization in ACSs have demonstrated a reduction in the frequency of major cardiac events[2-14].

**10. Discussions**

306 Artery Bypass

logical adverse events.

transfusion [22- 26].

5 days before CABG surgery (27).

Quality Improvement Initiative [15, 28- 29].

Multiple clinical trials showed the favorable effects of Clopidogrel alone or combined with Aspirin extending the indication for using Clopidogrel in a wide range of at risk patients and

In recent years, enormous growth in the use of coronary stenting procedures has resulted in a significant decrease in restenosis rates, while acute and sub-acute stent thrombosis remain a significant potential complication. It has been shown, however, that the risk of acute and subacute stent thrombosis is greatly reduced by the administration of antiplatelet therapies following stenting. Much clinical experience with combination of aspirin and ticlopidine has been gained, however ticlopidine has been shown to be associated with rare risk of haemato‐

The CLASSICS study demonstrated the safety and efficacy of clopidogrel (with or without

A large randomized trial has demonstrated that the acute administration of clopidogrel—a long-acting antiplatelet therapy—to patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS) can reduce subsequent risk for death, myocardial infarction, or stroke by 20% when continued for a mean duration of nine months [21]. However, single-center case series have demonstrated that, in patients requiring coronary artery bypass graft surgery, the use of Clopidogrel is associated with increased risk of perioperative bleeding and a need for

This risk appears to be time dependent. For example, post-hoc data analysis from the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial revealed that bleeding risks were increased when patients had CABG surgery within 5 days of clopidogrel treatment but

These findings are reflected in the American College of Cardiology/American Heart Associa‐ tion (ACC/AHA) guidelines for the acute management of patients with NSTE ACS, which endorse the acute use of clopidogrel but also recommend withholding clopidogrel for at least

Adherence in community practice to this guidelines recommendation is very unclear. has not been characterized previously. There are studies trying to characterize patterns of Clopidogrel use before CABG and to examine the time-dependent risks for postop‐ erative transfusion among NSTE ACS patients treated at 264 hospitals participating in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) National

Combined antiplatelet therapy was also studied in a lot of trials and most of them showed good safety and efficacy profiles. Antiplatelet therapy and antithrombin therapy have been demonstrated to reduce the risk of cardiac events in patients presenting with acute coronary syndrome, yet all effective therapies also increase the risk of bleeding. Antiplatelet therapy

loading dose) in combination with aspirin for use following coronary stenting.

not when surgery was delayed for >5 days after treatment with clopidogrel [21]

in long-term prevention in various manifestations of atherosclerosis.

The benefits versus risks of early and long-term clopidogrel therapy (freedom from CV death, MI, stroke, or life-threatening bleeding) are similar in those undergoing revascularization (CABG or PCI) and in the study population as a whole. Overall, the benefits of starting clopidogrel on admission appear to outweigh the risks, even among those who proceed to CABG during the initial hospitalization.

Actually the field of the indications of use of the antiagregant therapy is being continuously updated.The role of the aspirin in the primary prevention has extended its prescription based on related factors of cardiovascular and/or neurological risk. Moreover the combination of two antiagregant drugs (mainly Aspirin and clopidogrel) in high risk patients is a practice more and more extended [18]. Dual antiplatelet therapy has to be maintained at least 12 months after drug eluting stent placement and, in this patient a specific protocol of antiaggregation in type, combination and duration need to be applied [30, 31].

For patients undergoing coronary artery bypass graft surgery, controversy remains regarding the safety of preoperative antiplatelet therapy and the optimal postoperative antiplatelet regimen to maintain graft patency and reduce ischemic complications. There are also of this systematic reviews trying to evaluate the risks and benefits of preoperative aspirin and clopidogrel therapy, to identify the optimal timing and dose of aspirin following CABG, and to assess the role of postoperative clopidogrel therapy.[20]Following surgery, extensive evidence supports the use of aspirin, in doses of 100 - 325 mg daily, to be administered in 48 h postoperatively and continued indefinitely. Less is known regarding the use of clopidogrel following CABG, although it is now recommended as postoperative antiplatelet therapy in patients with recent acute coronary syndromes.Despite > 30 years of experience with antipla‐ telet agents during CABG, questions remain regarding their perioperative safety and efficacy. The results of continuing randomized controlled trials should further clarify the role of perioperative aspirin and clopidogrel therapy and help redefine the modern antiplatelet management of coronary artery bypass patients.

Also, the optimal aspirin dose for the prevention of cardiovascular events remains controver‐ sial.[32]: Daily aspirin doses of 100 mg or greater were associated with no clear benefit in patients taking aspirin only and possibly with harm in patients taking clopidogrel. Daily doses of 75 to 81 mg may optimize efficacy and safety for patients requiring aspirin for long-term prevention, especially for those receiving dual antiplatelet therapy.

The response to aspirin and/or clopidogrel and its impact on graft patency after off-pump coronary artery bypass grafting is characterised by individual variability, but, overall com‐ bined clopidogrel and aspirin overcome single drug resistances, were are safe for bleeding and improve venous graft patency. [33]

At first sight, clopidogrel appears to be undesirable for cardiac surgeons: antiplatelet therapy can increase the risk of bleeding during coronary artery bypass graft surgery (CABG).1 Traditionally, many surgeons have felt that, with impeccable technique, their personally constructed grafts would be nearly 'immune' to thrombosis, even without antiplatelet therapy. However, it could theoretically reduce the risk for early vein graft failure, which is predomi‐ nantly thrombosis related.

bed (cerebrovascular, cardiovascular, peripheral). The incidence of death, MI, and re‐ vascularization occurring at one and three-year following a CABG is greater than 15%. 3. Therefore, patients who undergo CABG could benefit from long-term therapy that provides improved protection against all types of atherothrombotic events such as my‐

The Antiagregant Treatment After Coronary Artery Surgery Depending on Cost – Benefit Report

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309

First, our comparisons of clinical outcomes by treatment strategy were observational. Al‐ though we adjusted all comparisons for baseline clinical factors, we cannot exclude any persistent unmeasured confounding. Nonetheless, because a randomized clinical trial evaluating the benefits and risks of different antiagregant regimen of patients undergoing CABG is unlikely to be undertaken, this study is the first to provide insight into the scope of this issue at a national level.we considered the diagnostic of ischemia using stress test, Holter monitoring and, in case of a positive result, invasive coronarography as sufficient. Second, we did not collect data on the incidence of re-exploration at 2 or three years after CABG, although we had some information about that and we did nor perform routinely coronarography at 1

**1.** Antiplatelet therapy with Clopidogrel plus Aspirin in the immediate postoperative period in patients with CABG was associated with an better cost-benefit report, proving to be

Taking into account both efficacy and safety, the combined antiplatelet therapy with

**2.** The favourable cost/benefit ratio of Clopidogrel over Aspirin established by this study, combined with its characteristics related to rapid onset of action, loading dose, pretreatment efficacy and ease of use, justify the consideration of routinely using Clopidogrel in CABg patients and in long-term prevention in various manifestations of atherosclerosis

**3.** Taking into account cost-benefit report when comparing antiplatelet strategies after CABG,treatment with Aspirin alone was associated with an cost benefit report almost 1 in terms of reducing mortality and graft oclusion, Clopidogrel alone with a little bit more than one and the asociated therapy had an cost benefit ratio about 3, emerged as the best treatment inthis trial. It should be regarded as an attractive alternative pharmacological antiplatelet strategy in the immediate postoperative period in CABG patients,deserving

Clopidogrel and Aspirin emerged as the best treatment in this trial.

ocardial infarction, ischemic strokes, and vascular death.

**11. Study limitations**

year postoperatively to all patients.

more effective than Aspirin alone.

**12. Conclusions**

further studies

There are three different principal mechanisms that play a role in vein graft failure during postoperative periods: early (<1 month): thrombosis; related to technical factors, Intermediate (1 to 12 months): intimal hyperplasia and Later postoperative (>12 months): accelerated atherosclerosis [34]

Concern about possible hemorrhagic complications arising from use of oral antiplatelet agents in immediate proximity to coronary artery bypass graft (CABG) surgery leads many clinicians to avoid or discontinue these agents preoperatively. Recent evidence suggests that.the modest hemorrhagic risk may be acceptable, given the clinical benefits of sustained antiplatelet therapy in preventing graft occlusion and ischemic complications pre- and post-CABG. [35]

Also, other analysis provide insight into patterns of clopidogrel use and outcomes in the setting of CABG performed on patients with NSTE ACS [36] and found that as many as 30% of patients currently receive clopidogrel before CABG surgery, and, of these, nearly 90% have surgery within 5 days of treatment, contrary to the ACC/AHA guidelines recommendations. These data demonstrating a modest increase in transfusion risk in part reflect a more stable estimate of risks based on a much larger case sample in the CRUSADE Initiative.

The benefits versus risks of early and long-term clopidogrel therapy (freedom from CV death, MI, stroke, or life-threatening bleeding) were similar in those undergoing revascularization (CABG or PCI) and in the study population as a whole. Overall, the benefits of starting clopidogrel on admission appear to outweigh the risks, even among those who proceed to CABG during the initial hospitalization.[26]

Data from the Antiplatelet Trialists' Collaboration support the use of antiplatelet therapy (mostly data for aspirin) after CABG and further data support the initiation of aspirin within 48 hours of CABG. The CURE trial provides the opportunity to explore the combined use of aspirin and clopidogrel for those undergoing CABG.[26]

Clopidogrel offers multiple advantages in acute and chronic use in coronary intervention. The favorable benefit/risk ratio of clopidogrel over aspirin established by CAPRIE, combined with its characteristics related to rapid onset of action, loading dose, pre-treatment efficacy and ease of use, justify the consideration of using clopidogrel in a wide range of at risk patients and in long-term prevention in various manifestations of atherosclerosis / atherothrombosis.

Combined antiplatelet therapy employing agents from different pharmacological classes after CABG was characterised by good safety and efficacy profiles. The absence of interaction, and the potential synergistic effect when used with other antithrombotic agents, will allow clinicians to optimise treatment in acute situations. Combination therapy, using clopidogrel and other drugs commonly administered for a range of cardiovascular and other disorders, appears safe after CABG.

Despite routine use of ASA before CABG, and lifelong following the revascularization, patients who undergo CABG remain at high risk of long-term events in any vascular bed (cerebrovascular, cardiovascular, peripheral). The incidence of death, MI, and re‐ vascularization occurring at one and three-year following a CABG is greater than 15%. 3. Therefore, patients who undergo CABG could benefit from long-term therapy that provides improved protection against all types of atherothrombotic events such as my‐ ocardial infarction, ischemic strokes, and vascular death.
