HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Guest Access | Sign In via User Name/Password

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stein, P. D. Articles by Gutterman, D. Search for Related Content PubMed PubMed Citation Articles by Stein, P. D. Articles by Gutterman, D.

Antithrombotic Therapy in Patients With Saphenous Vein and Internal Mammary Artery Bypass Grafts

The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy

Correspondence to: Paul D. Stein, MD, FCCP, St. Joseph Mercy-Oakland, 44555 Woodward Ave, Suite 107, Pontiac, MI 48341; e-mail steinp{at}trinity-health.org

	Abstract

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

 
This chapter about prevention of coronary artery bypass occlusion is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients’ values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S–187S). Among the key recommendations in this chapter are the following: For patients undergoing coronary artery bypass grafting (CABG), we recommend aspirin, 75 to 162 mg/d, starting 6 h after operation over preoperative aspirin (Grade 1A). In patients in whom postoperative bleeding prevents the administration of aspirin at 6 h after CABG, we recommend starting aspirin as soon as possible thereafter (Grade 1C). For patients undergoing CABG, we recommend against addition of dipyridamole to aspirin therapy (Grade 1A). For patients with coronary artery disease undergoing CABG who are allergic to aspirin, we recommend clopidogrel, 300 mg, as a loading dose 6 h after operation followed by 75 mg/d po (Grade 1C+). In patients who undergo CABG for non–ST-segment elevation acute coronary syndrome (ACS), we recommend clopidogrel, 75 mg/d for 9 to 12 months following the procedure in addition to treatment with aspirin (Grade 1A). For patients who have received clopidogrel for ACS and are scheduled for CABG, we recommend discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A). For patients undergoing CABG who have no other indication for vitamin K antagonists (VKAs), we suggest clinicians to not administer VKAs (Grade 2B). For patients undergoing CABG in whom oral anticoagulants are indicated, such as those with heart valve replacement, we suggest clinicians administer VKA in addition to aspirin (Grade 2C). For all patients with coronary artery disease who undergo internal mammary artery (IMA) bypass grafting, we recommend aspirin, 75 to 162 mg/d, indefinitely (Grade 1A). For all patients undergoing IMA bypass grafting without other indication for VKA, we suggest clinicians not use VKA (Grade 2C).

Key Words: antithrombotic • arterial bypass • graft • postoperative therapy

	Introduction

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

 
One of the major complications of coronary artery bypass grafting (CABG) is graft closure, and this is largely related to platelet aggregation. Almost immediately after harvesting the saphenous vein, the endothelium is lost and the raw surface is vulnerable to platelet aggregation.¹ This may explain the need for early antithrombotic treatment. Several factors may affect graft patency: (1) Intraoperative factors may partially relate to endothelial damage.² For example, graft patency was reduced if operation time exceeded 5 h, bypass time exceeded 2 h, cross-clamp time exceeded 80 min, the temperature of the vein preservation solution exceeded 5°C, intermittent cross-clamping rather than continuous cross-clamping was used, or if there were two or more proximal anastomoses²; (2) The medium used for storage and rinsing of the vein grafts affects endothelial function and affects graft patency³; (3) Graft size: grafts 1.5 mm in diameter had a higher patency rate after 1 year than smaller grafts⁴; (4) Graft location: grafts inserted in regions of normal wall motion had higher patency rates than grafts with abnormal wall motion in the region of insertion; (5) Lipid levels: aggressive lowering of low-density lipoprotein cholesterol results in a reduced number of occluded grafts.⁵

Table 1 lists the question definition and eligibility criteria for the studies considered in this review. The first section describes the prevention of saphenous vein graft occlusion following CABG. Table 2 lists details of studies comparing the effects of antithrombotic therapy with placebo on graft patency in randomized controlled trials (RCTs) in CABG with vein grafts. The second section describes the prevention of internal mammary artery (IMA) bypass graft occlusion following CABG.

	1.0 Prevention of Saphenous Vein Graft Occlusion following CABG

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

Individual trials:
Table 2 shows results of trials comparing aspirin with placebo. A 3-year follow-up study of 455 patients the study by Goldman et al⁷ published in 1994 showed that continued use of aspirin, 325 mg/d, for 2 additional years after an initial year of therapy for the prevention of saphenous vein bypass graft occlusion showed no long-term benefit on graft patency compared to placebo at the end of the third year (62/365 = 17% vs 74/ 376 = 19.7%; p = 0.404). Among patients with patent saphenous vein bypass grafts 7 to 10 days after operation, the 3-year patency was more related to operative technique and underlying disease than to therapy with aspirin after the first year.² However, aspirin is indicated indefinitely in all patients with coronary heart disease (see chapter by Harrington et al in this Supplement).

Aspirin dosing:
There were no significant differences in graft patency between high- and low-dose aspirin regimens.⁶ In clinical practice, there is enthusiasm to use the lowest possible dose of aspirin. Unfortunately, when examining graft patency, there are no studies that directly compare low doses of aspirin, such as 50 to 100 mg/d, to the regimens of 325 mg/d.

Timing of aspirin administration:
Indirect comparison of studies that started aspirin before vs after surgery administration of aspirin did not reveal differences in patency rates. One RCT published in 1991 compared the effects of preoperative aspirin, 325 mg/d (started the day before surgery), with aspirin begun 6 h after surgery.⁸ Early aspirin was not more effective than aspirin after operation (started on the day of surgery) at improving early (7- to 10-day) graft patency, but it was associated with increased bleeding complications.

	Recommendations

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

 
1.1.1.1. For all patients with coronary artery disease, we recommend aspirin, 75 to 162 mg/d, indefinitely (Grade 1A).

1.1.1.2. For patients undergoing CABG, we recommend aspirin, 75 to 325 mg/d, starting 6 h after operation over preoperative aspirin (Grade 1A).

1.1.1.3. In patients in whom bleeding prevents the administration of aspirin at 6 h after CABG, we recommend starting aspirin as soon as possible thereafter (Grade 1C).

Underlying values and preferences: This recommendation places a relatively high value on avoiding cardiovascular complications and a relatively low value on avoiding bleeding complications.

1.1.2 Aspirin in combination with dipyridamole
Metaanalysis:
The Antiplatelet Trialists’ Collaboration overview⁶ found no benefit of the combination of aspirin and dipyridamole over aspirin alone on graft patency. This section of the overview pooled data from nine RCTs conducted until 1990.

Individual trials:
A later study by van der Meer et al⁹ assessed 1-year angiographic vein-graft patency after CABG surgery in 948 patients assigned to aspirin, aspirin plus dipyridamole, or oral anticoagulants in a blinded RCT. Dipyridamole, 5 mg/kg per 24 h IV for 28 h, followed by 200 mg bid, and oral anticoagulants (desired prothrombin time range 2.8 to 4.8 international normalized ratio) were started before surgery, and aspirin, 50 mg/d, was started after surgery. The authors assessed clinical outcome as incidence of myocardial infarction, thrombosis, major bleeding, or death. Occlusion rate of distal anastomoses was 11% in the aspirin-plus-dipyridamole group vs 15% in the aspirin group (relative risk, 0.76; 95% confidence interval [CI], 0.54 to 1.05) and 13% in the oral anticoagulants group. Clinical events occurred in 20.3% of patients receiving aspirin plus dipyridamole compared with 13.9% of the aspirin group (relative risk, 1.46; 95% CI, 1.02 to 2.08) and 16.9% of the oral anticoagulants group. The data provided no convincing evidence that addition of dipyridamole to 50 mg/d of aspirin improves aortocoronary vein graft patency, and there was evidence for increased overall clinical event rate.

Agnew et al¹⁰ randomized 100 patients to aspirin, 100 mg/d, or aspirin, 100 mg/d, and dipyridamole, 300 mg/d, before undergoing CABG. Patients received treatment at least 36 h before operation and were followed up for 1 year. Angiography at 9 weeks and 1 year showed vein graft patency rates of 93% and 87% for subjects treated with aspirin alone; and 90% and 89% in those who received aspirin plus dipyridamole, respectively. There was similar progression of coronary lesions in both groups. The study did not establish superiority of one regimen over another in terms of graft patency or progress of lesions in native vessels. Patients reportedly tolerated low-dose aspirin better than combination therapy.

One trial¹¹ compared placebo, aspirin at 150 mg/d alone, and aspirin at 150 mg/d plus dipyridamole at 225 mg/d, all begun the day after surgery in patients who received dipyridamole, 400 mg/d, until the day of surgery. Aspirin plus dipyridamole showed improved graft patency vs placebo, whereas aspirin alone showed only a trend toward a benefit.¹¹ However, there was no significant difference comparing aspirin alone with aspirin plus dipyridamole.¹¹

Indirect comparisons of the effects of aspirin plus dipyridamole with aspirin alone, begun no later than 1 day following surgery, showed no benefit with the addition of dipyridamole.^{111213141516171819} Dipyridamole in combination with high doses of aspirin, 975 to 1,300 mg/d, started 2 days before operation to 1 day after operation was not consistently more beneficial than aspirin alone.^131417181920 Dipyridamole in combination with high doses of aspirin, 975 to 990 mg/d, started 2 to 5 days after operation was no more effective than aspirin alone and often no different from placebo.^21222324

	Recommendation

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

 
1.1.2. For patients undergoing CABG, we recommend against addition of dipyridamole to aspirin therapy (Grade 1A).

1.1.3 Dipyridamole as single agent
Only one trial²⁵ compared dipyridamole alone (100 mg/d po for 2 days preoperatively, 5 mg/kg body weight/24 h IV preoperatively, and 100 mg/d po for 1 year postoperatively) to placebo in 360 patients undergoing CABG. A total of 48 patients receiving dipyridamole and 57 patients receiving placebo were withdrawn from the study, and in the remaining patients there was no greater graft patency in the dipyridamole group compared with placebo when all grafts were evaluated. The Étude de la Perméabilité des Pontages Aorto-coronaires was a randomized, blinded RCT²⁶ that compared the patency of coronary bypass grafts in two groups of coronary patients after surgery: one group treated with an oral vitamin K antagonists (VKAs) and placebo (n = 196), and one group treated with VKAs and dipyridamole (n = 182). Two independent observers evaluated graft patency at coronary angiography performed 6 months after surgery. There was no benefit of dipyridamole over placebo in patients receiving oral VKAs. Because of the sparse evidence, we are not making a recommendation regarding use of dipyridamole, as a single agent, in patients with CABG.

1.1.4 Indobufen
Indobufen is a reversible platelet cyclooxygenase inhibitor that allows platelet function to recover promptly after discontinuation. In three randomized trials,²⁷²⁸²⁹ graft patency after indobufen was compared to aspirin combined with dipyridamole. Efficacy was comparable,²⁷²⁸²⁹ although indobufen was associated with fewer adverse events or better tolerance.²⁸²⁹ In one of the investigations,²⁹ both the indobufen arm of the study and the aspirin-plus-dipyridamole arm showed low patency rates. Indirect comparison to aspirin alone suggests similar patency rates for indobufen. Since there is a lack of direct comparison with aspirin and because indobufen has no proven effects on long-term patency, we do not make a recommendation for the use of indobufen.

1.1.5 Ticlopidine
Ticlopidine, 500 mg/d, starting 2 days after operation was effective in maintaining graft patency in two RCTs.³⁰³¹ However, ticlopidine is associated with serious adverse effects including fatal thrombocytopenic purpura or neutropenia.³²³³ Because of the uncertain balance of benefits and risks and because other antiplatelet agents are available, we do not make a recommendation regarding ticlopidine.

1.1.6 Clopidogrel
Clopidogrel is a newer antiplatelet agent (see chapter by Patrono et al in this Supplement).³⁴ It has been compared to aspirin in subgroup analyses of large RCTs (see chapters by Harrington et al in this Supplement).³⁵

Individual trials:
Investigators compared clopidogrel to aspirin in a subgroup analysis of the Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events trial.³⁶ In subgroup analyses, these investigators³⁷ sought to determine whether antiplatelet therapy with clopidogrel would be more effective than aspirin in patients who underwent coronary artery bypass surgery. They determined the event rates for all-cause mortality, vascular death, myocardial infarction, stroke, and rehospitalization for the 1,480 patients with a history of cardiac surgery randomized to either clopidogrel or aspirin. The annual event rates were 22.3% in the 705 patients randomized to aspirin and 15.9% in the 775 patients randomized to clopidogrel (p = 0.001). They observed a relative risk reduction in each of the individual end points examined, including a 42.8% relative risk reduction in vascular death in patients receiving clopidogrel vs aspirin (p = 0.030).

The Clopidogrel in Unstable Angina To Prevent Recurrent Events trial³⁸ randomized 12,562 patients with non–ST-segment elevation acute coronary syndrome (ACS) to receive clopidogrel (300 mg immediately followed by 75 mg qd) or placebo in addition to aspirin, 75 to 325 mg/d, for 3 to 12 months. The first primary outcome was a composite of death from cardiovascular causes, nonfatal MI, or stroke, and the second primary outcome was death from cardiovascular causes, nonfatal MI, stroke, or refractory ischemia. The benefits of clopidogrel were consistent across a broad range of patient subsets including those with revascularization procedures following randomization (n = 4,577). Moreover, the benefit of clopidogrel tended to be higher in patients who had undergone a revascularization procedure prior to enrollment in the study (relative risk of the first primary outcome, 0.56; 95% CI, 0.43 to 0.72). The study did not report results of the primary end point separately for the 2,072 patients (16.5%) who underwent CABG after randomization or the 2,568 patients (21.2%) who underwent percutaneous transluminal coronary angioplasty. There was no difference in overall bleeding risk between patients with CABG receiving clopidogrel or placebo (1.3% vs 1.1%; relative risk, 1.26; 95% CI, 0.93 to 1.71). However, in most patients scheduled for CABG surgery, investigators discontinued the study medication before the procedure (median time before the procedure, 5 days). In the 910 patients in whom the study medication was discontinued > 5 days before the procedure (5 days being the duration of the effect of clopidogrel), there was no apparent excess of major bleeding within 7 days after surgery (4.4% of the patients in the clopidogrel group vs 5.3% of those in the placebo group). In the 912 patients who stopped taking the medications within 5 days before CABG surgery, the rate of major bleeding was 9.6% in the clopidogrel group and 6.3% in the placebo group (relative risk, 1.53; p = 0.06). Overall, the risk of minor bleeding was significantly higher in clopidogrel-treated patients (5.1% vs 2.4%; p = 0.001).

	Recommendations

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

 
1.1.6.1. For patients with coronary artery disease undergoing CABG who are allergic to aspirin, we recommend clopidogrel, 300 mg, as a loading dose 6 h after operation followed by 75 mg/d po (Grade 1C+).

1.1.6.2. In patients who undergo CABG for non–ST-segment elevation ACS, we recommend clopidogrel, 75 mg/d, for 9 to 12 months following the procedure in addition to treatment with aspirin (Grade 1A).

Underlying values and preferences: This recommendation places a relatively high value on avoiding myocardial infarction and a relatively low value on avoiding bleeding complications.

1.1.6.3. For patients who have received clopidogrel for ACS and are scheduled for coronary bypass surgery, we recommend discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A).

1.1.7 Other antiplatelet agents
Sulfinpyrazone, 800 mg/d, compared to aspirin or placebo, starting from 2 days before operation to 1 day after, was not consistently effective in maintaining graft patency at 2 weeks up to 1 year after CABG.¹³¹⁴³⁹ Triflusal is a platelet inhibitor structurally related to aspirin. It is a weaker inhibitor of cyclooxygenase than aspirin, but a stronger inhibitor of cyclic adenosine monophosphate phosphodiesterase.⁴⁰ When started 1 day preoperatively, therapy with triflusal, 900 mg/d, plus dipyridamole, 225 mg/d, resulted in fewer distal anastomotic occlusions compared to aspirin, 150 mg/d, plus dipyridamole, 225 mg/d.⁴⁰ Because of the limited evidence about efficacy of sulfinpyrazone and triflusal, we do not make a recommendation regarding these antiplatelet agents.

	1.2 Treatment with oral anticoagulants

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

 
1.2.1 VKAs
Individual trials:
Three randomized trials²¹⁴¹⁴² compared oral anticoagulants with placebo for long-term graft patency; in each case, anticoagulants were started 3 to 7 days after operation. One study⁴² investigated long-term patency of vein grafts after follow-up of up to 24 to 48 months. From an initial group of 216 patients, vein graft patency was determined in only 111 patients (220 grafts) during the follow-up period, and discontinuation of therapy was high (55 patients were not reevaluated). There was a trend toward better cumulative graft patency in patients receiving warfarin, but the results did not achieve statistical significance. Improved results with warfarin were most marked among patients who were restudied within 24 months of CABG operation, in most instances because of the development of recurrent angina pectoris.

One study⁴¹ showed increased graft patency with VKAs. This study enrolled 89 patients with 251 saphenous vein grafts who were treated with phenoprocoumon (prothrombin time 1.5 to 2.0 times the control) beginning on the seventh postoperative day. The control group was similar in terms of clinical characteristics with 84 patients receiving 238 grafts. Eight weeks following surgery, graft patency (90.4% vs 84.6%) and numbers of patients with all grafts patent (81% vs 67%) were significantly greater in the anticoagulation group. Patients with a graft flow of < 90 mL/min at the time of surgery benefited from anticoagulation. No graft with a flow > 90 mL/min was occluded.

Pantely et al²¹ randomly assigned 50 patients to one of four groups to determine the effects of antiplatelet or anticoagulant therapy on graft patency: 24 patients served as controls; 13 patients received aspirin, 325 mg tid, and dipyridamole, 75 mg tid; and 13 patients received closely regulated warfarin therapy begun on the third postoperative day. Six months after surgery, all patients underwent coronary angiography to assess graft patency. There were no statistically significant differences between groups in various clinical, hemodynamic, and angiographic findings. Vein graft patency was 50 of 61 grafts (82%) in control patients and 29 of 37 grafts (78%) with warfarin (p < 0.5). All patients had at least one patent graft. There was no benefit from treatment with either aspirin plus dipyridamole or VKAs.

In other studies, VKAs begun from 14 days prior to operation to 2 days after operation (sometimes with heparin) yielded a graft patency comparable to low-dose aspirin (50 mg or 100 mg) or low-dose aspirin in combination with dipyridamole.^9434445 Fewer bleeding complications occurred with aspirin plus dipyridamole than with oral anticoagulants.⁴³ Warfarin has also been compared to dipyridamole alone (both started 2 or 3 days after surgery).⁴⁶ Graft patency after 1 year or 2 years was comparable for the two regimens (96% for dipyridamole and 89% for warfarin).⁴⁶

	Recommendations

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

 
1.2.1. For patients undergoing CABG who have no other indication for VKA, we suggest clinicians not administer VKAs (Grade 2B).

1.2.2. For patients undergoing CABG in whom oral anticoagulants are indicated, such as those with heart valve replacement, we suggest clinicians administer VKA in addition to aspirin (Grade 2C).

Bleeding complications of antithrombotic therapy in CABG:
Evidence on bleeding complications during CABG with vein grafts is limited because only few selected trials^1213151642 report this data. Therefore, there is a high risk of reporting bias for blood loss associated with antithrombotic therapy. For example, Lorenz et al¹⁵ reported that there was no blood loss in aspirin-treated (100 mg started one day postoperatively, n = 29) and placebo-treated (n = 32) patients. Hockings and colleagues¹⁶ described blood loss of 1,193 mL in aspirin-treated patients (100 mg started 7days preoperatively), compared to 989 mL in the placebo group (n = 52, p > 0.05). In the RCT by Gavaghan and coworkers¹² blood loss in the aspirin group (325 mg started on the day of CABG, n = 127) was similar compared to the placebo group (n = 708; 732 mL vs 708 mL, p > 0.05). Goldman et al¹³ reported higher blood loss in the aspirin-treated group (started one day preoperatively) compared to the placebo group. In that RCT, 154 patients receiving 325 mg of aspirin had 965 mL of blood loss, and 155 patients receiving 975 mg had 1,175 mL of blood loss, compared to 805 mL in the 153 patients randomized to placebo (p < 0.02 for both comparisons). VKA-treated patients were more likely to cause major and minor bleeding in 68 patients receiving a VKA started on days 3 or 4 postoperatively (4.4% major bleeding and 10.3% minor bleeding), compared to no reported bleeding in the placebo group (p < 0.01).⁴²

	2.0 Prevention of Internal Mammary Bypass Graft Occlusion Following CABG

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

 
No study included only patients with IMA bypass grafts, and the data for prevention of IMA bypass graft occlusion following CABG is restricted to subgroup analysis of studies investigating bypass grafting with both venous and arterial grafts.

2.1 Aspirin With and Without Dipyridamole
Individual trials:
The VA Cooperative study⁷ evaluated the efficacy of aspirin in long-term patency of internal mammary grafts. After receiving 325 mg/d of aspirin for 3 years, IMA graft occlusion rate was 10.3% (8 of 78 patients) vs 7.9% for those treated with placebo (7 of 89 patients, p = 0.60). There was also no effect on IMA graft patency when investigators compared aspirin initiated 12 h before with aspirin administered 6 h after surgery.⁴⁷

An RCT¹⁹ evaluated the effect of high-dose aspirin, 1,300 mg/d, plus dipyridamole, 100 mg/d, starting on the first postoperative day, on IMA patency rates at 3 to 6 months in 18 patients with IMA grafts to the left anterior descending artery. At follow-up, overall patency was 98% (44 of 45 IMA grafts remained patent) with no differences between placebo and treatment groups.

Van der Meer and colleagues⁴⁸ compared the efficacy and safety of aspirin, aspirin plus dipyridamole, and oral anticoagulant agents on IMA graft occlusion. The investigators assessed graft patency at 1 year in 494 patients who received both IMA and vein grafts. These patients were a subgroup of a prospective, randomized vein graft patency study⁴⁸ in 948 patients assigned to treatment with aspirin, aspirin plus dipyridamole, or VKAs. The design was blinded for both aspirin groups, but open-label for VKA treatment. Patients received dipyridamole (5 mg/kg body weight per 24 h IV, followed by 200 mg bid) or VKA (target international normalized ratio, 2.8 to 4.8) before operation, or low-dose aspirin (50 mg/d) after operation. The combined clinical outcomes were myocardial infarction, thrombosis, major bleeding, or death. Occlusion rates of distal anastomoses were 4.6% in the aspirin-plus-dipyridamole group and 6.8% in the oral anticoagulant group, vs 5.3% in the aspirin group (p > 0.05). Rates of the combined outcomes were 23.3% and 13.3% in the aspirin-plus-dipyridamole group and the aspirin group, respectively, and 17.1% in the VKA group. Thus, IMA graft patency at 1 year was not improved with oral anticoagulant agents over aspirin plus dipyridamole or low-dose aspirin alone.

Mayer et al¹⁹ performed an RCT in patients with left IMA to the left anterior descending coronary artery. Saphenous vein grafts were used for the left anterior descending coronary artery if the IMA was inadequate and for all other vessels. Patients (n = 174) received either 1,300 mg of aspirin and 100 mg of dipyridamole (po each day) or no drug. Patients returned 3 to 6 months after operation for repeat angiography. Of the 45 IMA grafts in both groups, only 1 IMA graft was occluded and there was no significant difference between the two groups.

	Recommendation

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

 
2.1.1. For all patients with coronary artery disease who undergo IMA bypass grafting, we recommend aspirin, 75 to 162 mg/d, indefinitely (Grade 1A).

Remarks: This recommendation reflects that aspirin is indicated in all patients with coronary artery disease, irrespective of its effects on graft patency (see chapter by Harrington et al in this Supplement).³⁵

2.2 VKAs
Individual trials:
In the study by van der Meer and colleagues,⁴⁸ graft patency at 1 year was not different between patients assigned to aspirin plus dipyridamole, low-dose aspirin alone, or oral anticoagulant agents.

	Recommendation

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

 
2.2. For all patients undergoing IMA bypass grafting who have no other indication for VKAs, we suggest physicians not use VKAs (Grade 2C).

	3.0 Methodologic Considerations for Studies in Patients Undergoing CABG

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

 
Data from trials of antithrombotic therapy in CABG are confounded by methodologic limitations. For example, most trials report data on graft patency rather than on important clinical outcomes, such as hospitalizations, recurrent angina, requirements for repeat interventions, myocardial infarction, and death.^{141516171920212225313941} In addition, in most studies^{711121314151617192122243031394142} investigators treated the number of patent vessels as independent within patients; for example, a patient with four patent vessels contributed four events to the analysis. Such analysis may violate statistical assumptions of independence and bears the risk of important bias. Future studies should include patient important outcomes and adjust in their analysis for multiple outcomes within patients when appropriate.

	SUMMARY OF RECOMMENDATIONS

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

 
1.0 Prevention of Saphenous Vein Graft Occlusion Following CABG
1.1 Treatment with antiplatelet agents
1.1.1.1. For all patients with coronary artery disease, we recommend aspirin, 75 to 162 mg/d, indefinitely (Grade 1A).

1.1.1.2. For patients undergoing CABG, we recommend aspirin, 75 to 162 mg/d, starting 6 h after operation over preoperative aspirin (Grade 1A).

1.1.1.3. In patients in whom bleeding prevents the administration of aspirin at 6 h after CABG, we recommend starting aspirin as soon as possible thereafter (Grade 1C).

Underlying values and preferences: This recommendation places a relatively high value on avoiding cardiovascular complications and a relatively low value on avoiding bleeding complications.

1.1.2. For patients undergoing CABG, we recommend against the addition of dipyridamole to aspirin therapy (Grade 1A).

1.1.6.1. For patients with coronary artery disease undergoing CABG who are allergic to aspirin, we recommend clopidogrel, 300 mg, as a loading dose 6 h after operation followed by 75 mg/d po (Grade 1C+).

1.1.6.2. In patients who undergo CABG for non–ST-segment elevation ACS, we recommend clopidogrel, 75 mg/d, for 9 to 12 months following the procedure in addition to treatment with aspirin (Grade 1A).

Underlying values and preferences: This recommendation places a relatively high value on avoiding myocardial infarction and a relatively low value on avoiding bleeding complications.

1.1.6.3. For patients who have received clopidogrel for ACS and are scheduled for coronary bypass surgery, we recommend discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A).

1.2 Treatment with oral anticoagulants
1.2.1. For patients undergoing CABG who have no other indication for VKAs, we suggest clinicians not administer VKAs (Grade 2B).

1.2.2. For patients undergoing CABG in whom oral anticoagulants are indicated, such as those with heart valve replacement, we suggest clinicians administer VKAs in addition to aspirin (Grade 2C).

2.0 Prevention of Internal Mammary Bypass Graft Occlusion Following CABG
2.1 Aspirin with and without dipyridamole
2.1.1. For all patients with coronary artery disease who undergo IMA bypass grafting, we recommend aspirin, 75 to 162 mg/d, indefinitely (Grade 1A).

Remarks: This recommendation reflects that aspirin is indicated in all patients with coronary artery disease, irrespective of its effects on graft patency (see chapter by Harrington et al in this Supplement).

2.2 Vitamin K antagonists
2.2. For all patients undergoing IMA bypass grafting who have no other indication for VKAs, we suggest clinicians not use VKAs (Grade 2C).

	Acknowledgements

 
We are grateful to Gabriela Neagoe, MD, and Ranjan Chanda, MD, for help with reviewing the literature.

	Footnotes

 
Abbreviations: ACS = acute coronary syndrome; CABG = coronary artery bypass grafting; CI = confidence interval; IMA = internal mammary artery; RCT = randomized controlled trial; VKA = vitamin K antagonist

	References

TOP Abstract Introduction 1.0 Prevention of Saphenous... Recommendations Recommendation Recommendations 1.2 Treatment with oral... Recommendations 2.0 Prevention of Internal... Recommendation Recommendation 3.0 Methodologic Considerations... Summary of Recommendations References

 

1. Unni, KK, Kottke, BA, Titus, JL, et al (1974) Pathologic changes in aortocoronary saphenous vein grafts. Am J Cardiol 34,526-532[CrossRef][ISI][Medline]
2. Goldman, S, Zadina, K, Krasnicka, B, et al for the Department of Veterans Affairs Cooperative Study Group No. 297. Predictors of graft patency 3 years after coronary artery bypass graft surgery. J Am Coll Cardiol 1997;29,1563-1568[Abstract]
3. Zerkowski, HR, Knocks, M, Konerding, MA, et al Endothelial damage of the venous graft in CABG: influence of solutions used for storage and rinsing on endothelial function. Eur J Cardiothorac Surg 1993;7,376-382[Abstract]
4. Cataldo, G, Braga, M, Pirotta, N, et al on behalf of Studio Indobufene nel Bypass Aortocoronarico (SINBA). Factors influencing 1-year patency of coronary artery saphenous vein grafts. Circulation 1993;88,II93-II98
5. Post-Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;336,153-162[Abstract/Free Full Text]
6. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy-II: Maintenance of vascular graft or arterial patency by antiplatelet therapy. BMJ 1994;308,159-168[Abstract/Free Full Text]
7. Goldman, S, Copeland, J, Moritz, T, et al Long-term graft patency (3 years) after coronary artery surgery: effects of aspirin; results of a VA cooperative study. Circulation 1994;89,1138-1143[ISI][Medline]
8. Goldman, S, Copeland, J, Moritz, T, et al Starting aspirin therapy after operation: effects on early graft patency. Circulation 1991;84,520-526[ISI][Medline]
9. Van der Meer, J, Hillege, HL, Kootstra, GJ, et al Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: a comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. Lancet 1993;342,257-264[CrossRef][ISI][Medline]
10. Agnew, TM, French, JK, Neutze, JM, et al The role of dipyridamole in addition to low dose aspirin in the prevention of occlusion of coronary artery bypass grafts. Aust N Z J Med 1992;22,665-670[ISI][Medline]
11. Sanz, G, Pajarón, A, Alegria, E, et al Prevention of early aortocoronary bypass occlusion by low-dose aspirin and dipyridamole. Circulation 1990;82,765-773[ISI][Medline]
12. Gavaghan, TP, Gebski, V, Baron, DW Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery: a placebo-controlled, randomized study. Circulation 1991;83,1526-1533[ISI][Medline]
13. Goldman, S, Copeland, J, Moritz, T, et al 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[ISI][Medline]
14. Goldman, S, Copeland, J, Moritz, T, et al 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[ISI][Medline]
15. Lorenz, RL, Schacky, CV, Weber, M, et al Improved aortocoronary bypass patency by low-dose aspirin (100 mg daily): effects on platelet aggregation and thromboxane formation. Lancet 1984;1,1261-1264[CrossRef][ISI][Medline]
16. Hockings, BE, Ireland, MA, Gotch-Martin, KF, et al Placebo-controlled trial of enteric coated aspirin in coronary bypass graft patients: effect on graft patency. Med J Aust 1993;159,376-378[ISI][Medline]
17. Rajah, SM, Salter, MC, Donaldson, DR, et al Acetylsalicylic acid and dipyridamole improve the early patency of aorta-coronary bypass grafts: a double-blind, placebo-controlled, randomized trial. J Thorac Cardiovasc Surg 1985;90,373-377[Abstract]
18. Stein, PD, Dalen, JE, Goldman, S, et al Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts. Chest 1998;114,658S-665S[Abstract/Free Full Text]
19. Mayer, JE, Jr, Lindsay, WG, Castaneda, W, et al Influence of aspirin and dipyridamole on patency of coronary artery bypass grafts. Ann Thorac Surg 1981;31,204-210[Abstract]
20. Chesebro, JH, Fuster, V, Elveback, LR, et al Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations. N Engl J Med 1984;310,209-214[Abstract]
21. Pantely, GA, Goodnight, SH, Jr, Rahimtoola, SH, et al Failure of antiplatelet and anticoagulant therapy to improve patency of grafts after coronary-artery bypass: a controlled, randomized study. N Engl J Med 1979;301,962-966[Abstract]
22. Sharma, GV, Khuri, SF, Josa, M, et al The effect of antiplatelet therapy on saphenous vein coronary artery bypass graft patency. Circulation 1983;68,II218-II221
23. Brooks, N, Wright, J, Sturridge, M, et al Randomised placebo controlled trial of aspirin and dipyridamole in the prevention of coronary vein graft occlusion. Br Heart J 1985;53,201-207[Abstract/Free Full Text]
24. Brown, BG, Cukingnan, RA, DeRouen, T, et al Improved graft patency in patients treated with platelet-inhibiting therapy after coronary bypass surgery. Circulation 1985;72,138-146[Medline]
25. Ekeström, E, Gunnes, S, Brodin, U Effect of dipyridamole (Persantin) on blood flow and patency of aortocoronary vein bypass grafts. Scand J Thorac Cardiovasc Surg 1990;24,191-196[ISI][Medline]
26. Ollivier, J Patency of aorto-coronary bypass grafts at 6 months: a French multicenter study. Arch Mal Coeur 1991;84,537-542
27. The SINBA Group.. Indobufen versus aspirin plus dipyridamole after coronary artery bypass surgery. Coron Artery Dis 1991;2,897-905
28. Rajah, SM, Nair, U, Rees, M, et al Effects of antiplatelet therapy with indobufen or aspirin-dipyridamole on graft patency one year after coronary artery bypass grafting. J Thorac Cardiovasc Surg 1994;107,1146-1153[Abstract/Free Full Text]
29. Rohn, V, Pirk, J, Mach, T The effect of indobufen on aortocoronary bypass patency after 1 week and after 1 year [Czechoslovakian]. Cor Vasa 1993;35,162-164[Medline]
30. Limet, R, David, JL, Magotteaux, P, et al Prevention of aorta-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]
31. Chevigné, M, David, JL, Rigo, P, et al Effect of ticlopidine on saphenous vein bypass patency rates: a double-blind study. Ann Thorac Surg 1984;37,371-378[Abstract]
32. Bennett, CL, Davidson, CJ, Raisch, DW, et al Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention. Arch Intern Med 1999;159,2524-2528[Abstract/Free Full Text]
33. Moussa, I, Oetgen, M, Roubin, G, et al Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation. Circulation 1999;99,2364-2366[ISI][Medline]
34. Patrono, C, Coller, B, Fitzgerald, G, et al Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest 2004;126(suppl),2345-2645
35. Harrington, R, Becker, R, Ezekowitz, M, et al Antithrombotic therapy for coronary artery disease. Chest 2004;126(suppl),5135-5485
36. CAPRIE Steering Committee.. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events. Lancet 1996;348,1329-1339[CrossRef][ISI][Medline]
37. Bhatt, DL, Chew, DP, Hirsch, AT, et al Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 2001;103,363-368[ISI][Medline]
38. CURE 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]
39. Baur, HR, VanTassel, RA, Pierach, CA, et al Effects of sulfinpyrazone on early graft closure after myocardial revascularization. Am J Cardiol 1982;49,420-424[CrossRef][ISI][Medline]
40. Guiteras, P, Altimiras, J, Aris, A, et al Prevention of aortocoronary vein-graft attrition with low-dose aspirin and triflusal, both associated with dipyridamole: a randomized, double-blind, placebo-controlled trial. Eur Heart J 1989;10,159-167[Abstract/Free Full Text]
41. Gohlke, H, Gohlke-Bärwolf, C, Stürzenhofecker, P, et al Improved graft patency with anticoagulant therapy after aortocoronary bypass surgery: a prospective, randomized study. Circulation 1981;64,II22-II27
42. McEnany, MT, Salzman, EW, Mundth, ED, et al The effect of antithrombotic therapy on patency rates of saphenous vein coronary artery bypass grafts. J Thorac Cardiovasc Surg 1982;83,81-89[Abstract]
43. Pfisterer, M, Burkart, F, Jockers, G, et al Trial of low-dose aspirin plus dipyridamole versus anticoagulants for prevention of aortocoronary vein graft occlusion. Lancet 1989;2,1-7[CrossRef][ISI][Medline]
44. Yli-Mäyry, S, Huikuri, HV, Korhonen, UR, et al Efficacy and safety of anticoagulant therapy started pre-operatively in preventing coronary vein graft occlusion. Eur Heart J 1992;13,1259-1264[Abstract/Free Full Text]
45. Weber, MA, Hasford, J, Taillens, C, et al Low-dose aspirin versus anticoagulants for prevention of coronary graft occlusion. Am J Cardiol 1990;66,1464-1468[CrossRef][ISI][Medline]
46. Harjola, PT, Frick, MH, Meurala, H, et al The effect of dipyridamole and warfarin on the patency rate of coronary artery bypass grafts. Thorac Cardiovasc Surgeon 1983;31,374-376[ISI][Medline]
47. Goldman, S, Copeland, J, Moritz, T, et al Internal mammary artery and saphenous vein graft patency: effects of aspirin. Circulation 1990;82,IV237-II242
48. van der Meer, J, Hillege, HL, van Gilst, WH, et al CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands. A comparison of internal mammary artery and saphenous vein grafts after coronary artery bypass surgery: no difference in 1-year occlusion rates and clinical outcome. Circulation 1994;90,2367-2374[ISI][Medline]
49. Pirk, J, Vojáek, J, Ková, J, et al Improved patency of the aortocoronary bypass by antithrombotic drugs. Ann Thorac Surg 1986;42,312-314[Abstract]

This article has been cited by other articles:

				A. Parolari, F. Alamanni, E. Tremoli, and P. Biglioli Efficacy and Safety of Edifoligide JAMA, April 5, 2006; 295(13): 1513 - 1513. [Full Text] [PDF]

				J. C.J. Sun, M. A. Crowther, T. E. Warkentin, A. Lamy, and K. H.T. Teoh Should Aspirin Be Discontinued Before Coronary Artery Bypass Surgery? Circulation, August 16, 2005; 112(7): e85 - e90. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal