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(Chest. 2001;119:278S-282S.)
© 2001 American College of Chest Physicians

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

Paul D. Stein, MD, FCCP, Chairman; James E. Dalen, MD, FCCP; Steven Goldman, MD and Pierre Theroux, MD

Correspondence to: Paul D. Stein, MD, FCCP, St. Joseph Mercy-Oakland Hospital, 44555 Woodward Ave, Suite 107, Pontiac, MI 48341-2964.


   Introduction
TOP
 Introduction
Saphenous Vein Bypass Grafting
 Internal Mammary Artery Bypass...
 Recommendations
 References
 
One of the major complications of coronary artery bypass grafts 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. Intraoperative factors affect graft patency,2 and these may partially relate to endothelial damage. Graft patency was reduced if operation time was > 5 h, bypass time was > 2 h,cross-clamp time was > 80 min, the temperature of the vein preservation solution was > 5°C, intermittent cross-clamping rather than continuous cross-clamping was used, or if there were more than two proximal anastomoses.2 Some types of fluid used for storage and rinsing of the vein grafts preserved endothelial function better than others and contributed to graft patency.3 Grafts >= 1.5 mm in diameter had a higher patency rate after 1 year than smaller grafts.3 4 Grafts inserted in regions of normal wall motion had higher patency rates than grafts with abnormal wall motion in the region of insertion.4 Aggressive lowering of low-density lipoprotein cholesterol levels resulted in a reduced number of occluded grafts.5


   Saphenous Vein Bypass Grafting
TOP
 Introduction
 Saphenous Vein Bypass Grafting
Internal Mammary Artery Bypass...
 Recommendations
 References
 
Results of randomized trials in which the effects of treatment with antithrombotic agents on saphenous vein bypass graft patency were compared with placebo are shown in Table 1 . Randomized trials showing the effects on chest tube drainage of antithrombotic agents in comparison with placebo are shown in Table 2 . Randomized trials in which the effects on saphenous vein bypass patency of various antithrombotic agents were compared with other antithrombotic agents or combinations of agents were shown in tables in our previous review.6 These tables are not repeated. A table showing the effects on chest tube drainage of various agents or combinations of agents also was shown previously and is not repeated.6


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  		Table 1. Saphenous Vein Graft Patency**

 

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  		Table 2. Bleeding Complications With Antithrombotic Therapy in Patients With Saphenous Vein Bypass Grafts

 
Aspirin
Aspirin, 325 mg/d, usually increased saphenous vein graft patency provided therapy was begun before operation or within 1 day after operation.7 8 9
  1. Aspirin therapy, 325 mg/d, started the day of operation showed a patency rate of 94%, which was higher than controls (patency 88%).7
  2. Aspirin therapy, 325 mg/d, started the day before operation was effective, but did not increase the graft patency rate in comparison with aspirin therapy, 325 mg/d, started on the day of operation.8 9
  3. Aspirin therapy, 975 mg/d, started preoperatively was effective in one trial,8 but not in another,9 and it was not more effective than aspirin therapy, 325 mg/d, started the day of operation.7
  4. Aspirin therapy, 600 to 975 mg/d, started 3 to 5 days after operation was not effective.10 11 12
  5. Aspirin therapy in doses of 100 mg/d, started 7 days before operation or 1 day after operation, was not consistently effective.13 14

The 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 additional long-term benefit on graft patency at the end of the third year.15 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 and not to therapy with aspirin after the first year.2 However, aspirin therapy is indicated indefinitely in all patients with coronary heart disease. In clinical practice, there is enthusiasm to use lower and lower doses of aspirin. Unfortunately, when examining graft patency, there are no studies (to our knowledge) that compare low doses of aspirin, such as 50 to 100 mg/d, to the regimen we recommend, 325 mg/d. The major support for lower doses of aspirin appears to be the concept that less GI bleeding would result. Although this is not an easy question to address, large clinical trials that used different doses of aspirin to treat cardiovascular disease indicate that doses of aspirin < 325 mg/d did not result in less bleeding. Therefore, we do not recommend low doses of aspirin.

Aspirin in Combination With Dipyridamole
The effects of aspirin were not enhanced by dipyridamole, irrespective of the dose of aspirin or the time of commencement of aspirin therapy (Table 1) .8 11 12 16 17 18 19 20 21

  1. Aspirin therapy, 325 to 975 mg/d, in some patients in combination with dipyridamole therapy, started 1 to 2 days before operation, was not more effective than placebo in a subgroup analysis of saphenous vein grafts to the left anterior descending coronary artery.16
  2. Dipyridamole therapy in combination with high doses of aspirin (975 to 1,300 mg/d) started 2 days before operation to 1 day after operation was usually,8 17 18 19 but not always,4 effective. This combination was not more effective than aspirin, 325 mg/d, started the day of operation.7
  3. Dipyridamole therapy in combination with high doses of aspirin (975 to 990 mg/d) started 2 to 5 days after operation was not effective.11 12 20 21
  4. Aspirin therapy, 150 mg/d, starting the day of operation, and preceded by dipyridamole therapy 225 mg/d, started 2 days before operation, but discontinued after 100 mg given 1 h after operation, showed a tendency toward being more effective than this regimen of dipyridamole alone.22 Graft patency at 1 month was 86% vs 82% (p = 0.058).

Indobufen
In three randomized trials, graft patency with indobufen, a reversible platelet cyclooxygenase inhibitor that allows platelet function to recover in 24 h after discontinuation of treatment, was compared with aspirin in combination with dipyridamole.23 24 25 Results were comparable. However, in one of the investigations, both the indobufen arm of the study and the aspirin plus dipyridamole arm showed low patency rates.

Ticlopidine and Clopidogrel
Ticlopidine therapy, 500 mg/d, starting 2 days after operation, was effective in maintaining graft patency (Table 1) .26 27 However, ticlopidine may cause fatal thrombocytopenic purpura28 or neutropenia.29 Clopidogrel is an analog of ticlopidine that is safer. Clopidogrel is effective in reducing ischemic events,30 but to our knowledge, it has not been tested for coronary artery bypass graft patency.

Sulfinpyrazone
Sulfinpyrazone therapy, 800 mg/d, starting from 2 days before operation to 1 day after, was not consistently effective in maintaining graft patency (Table 1) .8 9 31

Oral Anticoagulants
Data on the use of oral anticoagulants in the prevention of saphenous vein graft occlusion are less clear than the data regarding aspirin. In three randomized trials that compared oral anticoagulants with controls, anticoagulant therapy was started 3 to 7 days after operation (Table 1) .10 21 32 Only one study showed increased graft patency in comparison with placebo.32 Oral anticoagulant therapy, with starting times ranging from 14 days preoperatively to the day of operation (sometimes with heparin) gave a graft patency comparable to low-dose aspirin or low-dose aspirin in combination with dipyridamole therapy.33 34 35 36 No comparisons were made with placebo.33 34 35 36 Among patients who received only oral anticoagulant therapy starting the day before operation, international normalized ratios of 1.8 to 3.8 and 2.8 to 4.8 gave patency rates of 89% and 87%, respectively.37 Although there was no control group, the high patency rates suggest that oral anticoagulants were effective.

Bleeding
Aspirin therapy, 325 mg/d or 975 mg/d, if started before operation, was associated with more bleeding than placebo (Table 2) .8 Bleeding was more severe among patients who received aspirin therapy, 325 mg/d, starting 12 h before operation than among those receiving it 6 h after operation.38 In a retrospective study, the estimated odds ratio for reoperation for bleeding after coronary artery bypass grafting was 1.82 among patients who received aspirin (dose not stated) within 7 days before operation.39 Regarding starting aspirin therapy, 325 mg/d, on the day of operation, some investigators showed no increased bleeding in comparison with controls,7 but others found increased bleeding with aspirin 300 mg/d (Table 2) .40 Treatment with aspirin in low doses (100 mg/d), when started before operation, was not associated with more bleeding than placebo.14 However, when low-dose aspirin was given on the day of operation and dipyridamole was given before operation, more bleeding occurred.22

Increased bleeding in comparison with controls occurred with oral anticoagulants even when treatment was started 3 to 4 days after surgery (Table 2) .16 Blood loss was less23 or the same24 among patients treated with indobufen, 400 mg/d, compared with aspirin, 900 to 975 mg/d, in combination with dipyridamole, 225 mg/d.


   Internal Mammary Artery Bypass Grafts
TOP
 Introduction
 Saphenous Vein Bypass Grafting
 Internal Mammary Artery Bypass...
Recommendations
 References
 
Antithrombotic agents among patients with internal mammary artery bypass grafts showed no benefit in comparison with placebo.15 16 19 Patency with placebo was 96 to 100% at 3 months to 1 year after operation16 19 and patency with placebo was 92% at 3 years after operation.15 Among patients with internal mammary artery bypass grafts, comparisons were made with aspirin, aspirin plus dipyridamole, and coumarin derivatives.35 41 No statistically significant difference of patency was observed with any of these prophylactic regimens. Some have argued that these results reflect the selection of advantageous vessels for internal mammary bypass grafts.42 Distal anastomoses and internal diameter of the coronary artery were identified as independent predictors of graft occlusion rather than whether the graft was artery or vein.42


   Recommendations
TOP
 Introduction
 Saphenous Vein Bypass Grafting
 Internal Mammary Artery Bypass...
 Recommendations
References
 
Remark: These recommendations are based on available evidence. As new information is obtained, the recommendations may change. Treatment should be based on appraisal of the individual patient, and may properly differ from these consensus recommendations.

Saphenous Vein Bypass Grafting

  1. For patients who undergo saphenous vein bypass grafting for coronary artery disease, we recommend life-long aspirin therapy (grade 1A). We recommend aspirin therapy, 325 mg/d, starting 6 h after operation for 1 year to reduce the frequency of saphenous vein bypass graft closure (grade 1A).
  2. If bleeding prevents the administration of aspirin at 6 h after surgery, we recommend starting aspirin therapy as soon as possible thereafter (grade 1C+).
  3. For patients allergic to aspirin, we recommend clopidogrel, 300 mg, as a loading dose 6 h after operation followed by 50 to 100 mg daily po (grade 2C).
  4. We recommend that oral anticoagulants alone or in combination with aspirin should be considered after coronary artery bypass surgery in patients in whom oral anticoagulants are simultaneously indicated, for example, because of heart valve replacement (grade 2C).

Internal Mammary Artery Bypass Grafting

  1. For patients who undergo internal mammary artery bypass grafting for coronary artery disease, we recommend life-long aspirin therapy (grade 1A). Aspirin has not been shown to be beneficial in maintaining internal mammary artery bypass graft patency, and we do not recommend aspirin if other diagnoses prompted internal mammary artery bypass grafting (grade 2C).


   References
TOP
 Introduction
 Saphenous Vein Bypass Grafting
 Internal Mammary Artery Bypass...
 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 (1997) Predictors of graft patency 3 years after coronary artery bypass graft surgery. J Am Coll Cardiol 29,1563-1568[Abstract]
  3. Zerkowski, H-R, Knocks, M, Konerding, MA, et al (1993) Endothelial damage of the venous graft in CABG: influence of solutions used for storage and rinsing on endothelial function. Eur J Cardiothorac Surg 7,376-382[Abstract]
  4. Cataldo, G, Braga, M, Pirotta, N, et al (1993) Factors influencing 1-year patency of coronary artery saphenous vein grafts. Circulation 88,93-98
  5. . Post Coronary Artery Bypass Graft Trial Investigators. (1997) 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 336,153-162[Abstract/Free Full Text]
  6. Stein, PD, Dalen, JE, Goldman, S, et al (1998) Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts. Chest 114(suppl),658S-665S[Abstract/Free Full Text]
  7. Gavaghan, TP, Gebski, V, Baron, DW (1991) Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery: a placebo-controlled, randomized study. Circulation 83,1526-1533[ISI][Medline]
  8. Goldman, S, Copeland, J, Moritz, T, et al (1988) Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a Veterans Administration cooperative study. Circulation 77,1324-1332[ISI][Medline]
  9. Goldman, S, Copeland, J, Moritz, T, et al (1989) Saphenous vein graft patency 1 year after coronary artery bypass surgery and effects of antiplatelet therapy: results of a Veterans Administration cooperative study. Circulation 80,1190-1197[ISI][Medline]
  10. McEnany, MT, Salzman, EW, Mundth, ED, et al (1982) The effect of antithrombotic therapy on patency rates of saphenous vein coronary artery bypass grafts. J Thorac Cardiovasc Surg 83,81-89[Abstract]
  11. Sharma, GVRK, Khuri, SF, Josa, M, et al (1983) The effect of antiplatelet therapy on saphenous vein coronary artery bypass graft patency. Circulation 68(suppl 2),218-221
  12. Brown, BG, Cukingnan, RA, DeRouen, T, et al (1985) Improved graft patency in patients treated with platelet-inhibiting therapy after coronary bypass surgery. Circulation 72,138-146[Medline]
  13. Lorenz, RL, Weber, M, Kotzur, J, et al (1984) Improved aortocoronary bypass patency by low-dose aspirin (100 mg daily): effects of platelet aggregation and thromboxane formation. Lancet 1,1261-1264[CrossRef][ISI][Medline]
  14. Hockings, BEF, Ireland, MA, Gotch-Martin, KF, et al (1993) Placebo-controlled trial of enteric coated aspirin in coronary bypass graft patients. Med J Aust 159,376-378[ISI][Medline]
  15. Goldman, S, Copeland, J, Moritz, T, et al (1994) Long-term graft patency (3 years) after coronary artery surgery: effects of aspirin: results of a VA cooperative study. Circulation 89,1138-1143[ISI][Medline]
  16. Goldman, S, Copeland, J, Moritz, T, et al (1990) Internal mammary artery and saphenous vein graft patency: effects of aspirin. Circulation 82(suppl 4),237-242
  17. Chesebro, JH, Fuster, V, Elveback, LR, et al (1984) Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations. N Engl J Med 310,209-214[Abstract]
  18. Rajah, SM, Salter, MCP, Donaldson, DR, et al (1985) Acetylsalicylic acid and dipyridamole improve the early patency of aortocoronary bypass grafts. J Thorac Cardiovasc Surg 90,373-377[Abstract]
  19. Mayer, JE, Jr, Lindsay, WG, Castaneda, W, et al (1981) Influence of aspirin and dipyridamole on patency of coronary artery bypass grafts. Ann Thorac Surg 31,204-210[Abstract]
  20. Brooks, N, Wright, J, Sturridge, M, et al (1985) Randomized placebo controlled trial of aspirin and dipyridamole in the prevention of coronary vein graft occlusion. Br Heart J 53,201-207[Abstract/Free Full Text]
  21. Pantely, GA, Goodnight, SH, Jr, Rahimtoola, SH, et al (1979) Failure of antiplatelet and anticoagulant therapy to improve patency of grafts after coronary artery bypass: a controlled, randomized study. N Engl J Med 301,962-966[Abstract]
  22. Sanz, G, Pajaron, A, Alegria, E, et al (1990) Prevention of early aortocoronary bypass occlusion by low-dose aspirin and dipyridamole. Circulation 82,765-773[ISI][Medline]
  23. Rajah, SM, Nair, U, Rees, M, et al (1994) Effects of antiplatelet therapy with indobufen or aspirin-dipyridamole on graft patency one year after coronary artery bypass grafting. J Thorac Cardiovasc Surg 107,1146-1153[Abstract/Free Full Text]
  24. . The SINBA Group (Studio Indobufene nel Bypass Aortocoronarico) (1991) Indobufen versus aspirin plus dipyridamole after coronary artery bypass surgery. Coron Artery Dis 2,897-905
  25. Rohn, V, Pirk, J, Mach, T (1993) Effect of indobufen on aortocoronary bypass patency one week and one year postoperatively. Cor Vasa 35,162-164[Medline]
  26. Limet, R, David, JL, Magotteaux, P, et al (1987) Prevention of aortocoronary bypass graft occlusion. J Thorac Cardiovasc Surg 94,773-783[Abstract]
  27. Chevigne, M, David, J-L, Rigo, P, et al (1984) Effect of ticlopidine on saphenous vein bypass patency rates: a double-blind study. Ann Thorac Surg 37,371-378[Abstract]
  28. 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 199; 159:2524–2528
  29. Moussa, I, Oetgen, M, Roubin, G, et al (1999) Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation. Circulation 99,2364-2366[ISI][Medline]
  30. . CAPRIE Steering Committee. (1996) A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 348,1329-1339[CrossRef][ISI][Medline]
  31. Baur, HR, Van Tassel, RA, Pierach, CA, et al (1982) Effects of sulfinpyrazone on early graft closure after myocardial revascularization. Am J Cardiol 49,420-424[CrossRef][ISI][Medline]
  32. Gohlke, H, Gohlke-Barwolf, C, Sturzenhofecker, P, et al (1981) Improved graft patency with anticoagulant therapy after aortocoronary bypass surgery: a prospective, randomized study. Circulation 64(suppl 2),22-27
  33. Weber, MAJ, Hasford, J, Taillens, C, et al (1990) Low-dose aspirin versus anticoagulants for prevention of coronary graft occlusion. Am J Cardiol 66,1464-1468[CrossRef][ISI][Medline]
  34. van der Meer, J, Hillege, HL, Kootstra, GJ, et al (1993) 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 342,257-264[CrossRef][ISI][Medline]
  35. Yli-Mayry, S, Huikuri, HV, Korhonen, UR, et al (1992) Efficacy and safety of anticoagulant therapy started pre-operatively in preventing coronary vein graft occlusion. Eur Heart J 13,1259-1264[Abstract/Free Full Text]
  36. Pfisterer, M, Jockers, G, Regenass, S, et al (1989) Trial of low-dose aspirin plus dipyridamole versus anticoagulants for prevention of aortocoronary vein graft occlusion. Lancet 2,1-7[CrossRef][ISI][Medline]
  37. van der Meer, J, Hillege, HL, Dunselman, PHJM, et al (1994) Oral anticoagulation in the prevention of one-year graft occlusion after aortocoronary bypass surgery: optimal therapeutic range and practical limitations. Thromb Haemost 72,676-681[ISI][Medline]
  38. Goldman, S, Copeland, J, Moritz, T, et al (1991) Starting aspirin therapy after operation: effects on early graft patency. Circulation 84,520-526[ISI][Medline]
  39. Bashein, G, Nessly, ML, Rice, AL, et al (1991) Preoperative aspirin therapy and reoperation for bleeding after coronary artery bypass surgery. Arch Intern Med 151,89-93[Abstract]
  40. Kallis, P, Tooze, JA, Talbot, S, et al (1994) Pre-operative aspirin decreases platelet aggregation and increases post-operative blood loss: a prospective, randomized, placebo controlled, double-blind clinical trial in 100 patients with chronic stable angina. Eur J Cardiothorac Surg 8,404-409[Abstract]
  41. van der Meer, J, De La Riviere, AB, Van Gilst, WH, et al (1994) Effects of low dose aspirin (50 mg/day), low dose aspirin plus dipyridamole, and oral anticoagulant agents after internal mammary artery bypass grafting: patency and clinical outcome at 1 year. J Am Coll Cardiol 24,1181-1188[Abstract]
  42. van der Meer, J, Hillege, HL, Van Gilst, WH, et al (1994) A comparison of internal mammary artery and saphenous vein grafts after coronary artery bypass surgery: no difference in one-year occlusion rates and clinical outcome. Circulation 90,2367-2374[ISI][Medline]



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