Coronary artery bypass surgery aspirin and clopidogrel

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Mohammed A. Sbeih, M.D.[3], Varun Kumar, M.B.B.S. [4]

Aspirin and Clopidogrel

Aspirin is a simple cost effective therapy that has been associated with improved clinical outcomes among patients undergoing CABG. The optimal timing of aspirin administration appears to be in the 48 hours immediately after CABG.[1][2][3][4][5][6][7][8] [9][10][11][12][13][14]

Rigorous randomized trials have been required to document the benefits of aspirin, to determine the optimal timing of aspirin, and to overcome fears surrounding the risk of bleeding associated with administration of aspirin in the setting of CABG. There has been a hesitancy to recommend the administration of antiplatelet agents in the setting of CABG for several reasons:

  • Platelet counts and platelet concentration are reduced during the peri-operative period as a result of sequestration and hemodilution[15]
  • Platelet function is impaired following CABG due to both hypothermia [16] and/or mechanical filtering.[17][18][19]

In so far as the focus of clinical care has at times been on reducing the risk of bleeding rather than on reducing the risk of thrombosis, there has likewise been a tendency to discontinue aspirin and reverse anticoagulant therapy before surgery, to administer platelet transfusions during surgery,[20][21][22] There is little randomized controlled data to support these practices adn non-randomized data suggest that these practices are associated with a significant increase in death and ischemic events.[6]

Benefit of early post-operative aspirin administration

In one of the first studies in this field, Goldman et al compared the rate of SVG patency among CABG patients treated with a variety of antiplatelet regimens.[1] All therapies except aspirin were started 48 hours before CABG. When aspirin was part of the regime, one 325 mg dose was given 12 hours pre-operatively, and the assigned therapy was maintained thereafter. The 60 day rates of angiographic patency (555 patients with 1,781 grafts) were:

  • Aspirin, 325 mg daily: 93.5%
  • Aspirin, 325 mg three times daily: 92.3%
  • Aspirin plus dipyridamole (325 mg and 75 mg, respectively, three times daily): 91.9%
  • Sulfinpyrazone (267 mg three times daily): 90.2%
  • Placebo (three times daily): 85.2%

(P<0.05 for all aspirin regimens vs placebo)

Aspirin was associated with a greater median chest tube drainage within the first 35 hours post-operatively compared with placebo (p<0.02):

  • Aspirin daily (965 ml)
  • Aspirin three times daily (1175 ml)
  • Aspirin plus dipyridamole (1000 ml)
  • Sulfinpyrazone (775 ml)
  • Placebo (805 ml)

The rate of reoperation was higher (p<0.01) among patients treated with aspirin (6.5%) than among those patients not treated with aspirin (1.7%).

At one year of follow-up in the same cohort of patients (n=406 patients with 1,315 SVGs), the rate of SVG occlusion was 15.8% in all the aspirin groups combined vs 22.6% among those treated with placebo (p = 0.029).[2] This benefit was signficant among those SVGs in which the target vessel was less than or equal to 2.0 mm in diameter (20.1% vs 32.3% for the placebo group (p = 0.008), while in those SVGs anastomosed to target vessels > 2.0 mm in diameter there was no difference in the rate of SVG occlusion (8.7% vs. 9.0%, p = 0.918).

While there were benefits in early patency and patency at one year in this cohort of patients, between years one and three, there was no benefit in the rate of occlusion. Among those SVGs that were patent at 1 year, the occlusion rate at 3 years was 4.8% for aspirin treated patients vs 4.2% for placebo treated patients (p=NS).[3]

The benefits of early antiplatelet therapy were also documented by Chesebro et al who performed a double blind randomized trial evaluating the benefit of dipyridamole (administered two days before operation) plus aspirin (added seven hours after operation) in 407 patients.[4] At one month, the angiographic rate of SVG occlusion on a per lesion basis was 3% vs 10% of grafts, and on a per patient basis the rate of having at least one SVG occluded was 8% vs 21% for treated vs untreated patients respectively. Likewise, at one year, the angiographic rate of SVG occlusion on a per lesion basis was 11% vs 25% of grafts, and on a per patient basis the rate of having at least one SVG occluded was 22% vs 47% for treated vs untreated patients respectively.[5]

In a non-randomized retrospective analysis of 7,500 variables, Mangano et al evaluated the relationship between early aspirin use and clinical outcomes in 5,065 patients at 70 centers in 17 countries.[6] Mortality was 1.3% among those patients treated with aspirin in the first 48 hours after CABG vs 4.0% among those who were not treated with aspirin (p<0.001). Likewise, aspirin therapy reduced the risk of MI from 5.4% to 2.8% (p<0.001), the risk of stroke from 2.6% to 1.3% (p=0.01), the risk of bowel infarction from 0.8% to 0.3% (p=0.01) and the risk of renal failure from 3.4% to 0.9%, p<0.001). Aspirin treatment was not associated with an increased risk of hemorrhage or impaired wound healing.

Pre-Operative vs Post-Operative Administration of Aspirin

Although the aforementioned studies demonstrated improved early and late patency with the pre-operative administration of aspirin, there was a higher rate of bleeding. Goldman et al conducted a prospective, randomized, double-blind, placebo-controlled trial to compare the safety and effectiveness of 325 mg of aspirin therapy initiated either the night before before CABG vs aspirin initiated via nasogastric tube 6 hours post-operatively.[23] The rate of saphenous vein graft occlusion rate was 7.4% vs 7.8% for pre vs post-operative aspirin administration. Pre-operative aspirin was associated with a greater amount of blood volume transfused (900 versus 725 cc, p = 0.006), greater chest tube drainage at 6 hours (500 vs 448 cc, p=0.011) and a higher rate of re-operation for bleeding (6.3% vs 2.4%, p = 0.036).

Post-operative clopidogrel

There are no randomized controlled trials that demonstrate the benefit of clopidogrel in the post-operative management of CABG patients.[24] Furthermore, retrospective subgroup analyses from large trials of acute coronary syndrome patients (1 trial) and stable coronary artery disease patients (3 trials) have not demonstrated a benefit of post-operative clopidogrel. They did, however, demonstrate a trend toward an increased risk of major and minor bleeding with the combined use of clopidogrel plus aspirin.

2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery (DO NOT EDIT)[25]

Preoperative Antiplatelet Therapy (DO NOT EDIT)[25]

Class I
"1. Aspirin (100 mg to 325 mg daily) should be administered to CABG patients preoperatively.[26][27][6] (Level of Evidence: B)"
"2. In patients referred for elective CABG, clopidogrel and ticagrelor should be discontinued for at least 5 days before surgery[28][29][30] (Level of Evidence: B) and prasugrel for at least 7 days (Level of Evidence: C) to limit blood transfusions."
"3. In patients referred for urgent CABG, clopidogrel and ticagrelor should be discontinued for at least 24 hours to reduce major bleeding complications.[29][31][32][33] (Level of Evidence: B)"
"4. In patients referred for CABG, short-acting intravenous glycoprotein IIb/IIIa inhibitors (eptifibatide or tirofiban) should be discontinued for at least 2 to 4 hours before surgery[34][35] and abciximab for at least 12 hours beforehand[36] to limit blood loss and transfusions. (Level of Evidence: B)"
Class IIb
"1. In patients referred for urgent CABG, it may be reasonable to perform surgery less than 5 days after clopidogrel or ticagrelor has been discontinued and less than 7 days after prasugrel has been discontinued. (Level of Evidence: C)"

References

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  2. 2.0 2.1 Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, Doherty J, Read R, Chesler E, Sako Y (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 (5): 1190–7. PMID 2680158. Retrieved 2010-07-22. Unknown parameter |month= ignored (help)
  3. 3.0 3.1 Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, Kern KB, Sethi G, Sharma GV, Khuri S (1994). "Long-term graft patency (3 years) after coronary artery surgery. Effects of aspirin: results of a VA Cooperative study". Circulation. 89 (3): 1138–43. PMID 8124800. Retrieved 2010-07-22. Unknown parameter |month= ignored (help)
  4. 4.0 4.1 Chesebro JH, Clements IP, Fuster V, Elveback LR, Smith HC, Bardsley WT, Frye RL, Holmes DR, Vlietstra RE, Pluth JR, Wallace RB, Puga FJ, Orszulak TA, Piehler JM, Schaff HV, Danielson GK (1982). "A platelet-inhibitor-drug trial in coronary-artery bypass operations: benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency". N. Engl. J. Med. 307 (2): 73–8. PMID 7045659. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  5. 5.0 5.1 Chesebro JH, Fuster V, Elveback LR, Clements IP, Smith HC, Holmes DR, Bardsley WT, Pluth JR, Wallace RB, Puga FJ (1984). "Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations". N. Engl. J. Med. 310 (4): 209–14. PMID 6361561. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  6. 6.0 6.1 6.2 6.3 Mangano DT (2002). "Aspirin and mortality from coronary bypass surgery". N. Engl. J. Med. 347 (17): 1309–17. doi:10.1056/NEJMoa020798. PMID 12397188. Retrieved 2010-07-22. Unknown parameter |month= ignored (help)
  7. Lorenz RL, Schacky CV, Weber M; et al. (1984). "Improved aortocoronary bypass patency by low-dose aspirin (100 mg daily). Effects on platelet aggregation and thromboxane formation". Lancet. 1 (8389): 1261–4. PMID 6144975. Unknown parameter |month= ignored (help)
  8. Hockings BE, Ireland MA, Gotch-Martin KF, Taylor RR (1993). "Placebo-controlled trial of enteric coated aspirin in coronary bypass graft patients. Effect on graft patency". Med. J. Aust. 159 (6): 376–8. PMID 8377686. Unknown parameter |month= ignored (help)
  9. Sanz G, Pajarón A, Alegría E; et al. (1990). "Prevention of early aortocoronary bypass occlusion by low-dose aspirin and dipyridamole. Grupo Español para el Seguimiento del Injerto Coronario (GESIC)". Circulation. 82 (3): 765–73. PMID 2203555. Unknown parameter |month= ignored (help)
  10. 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 (5): 1526–33. PMID 2022014. Unknown parameter |month= ignored (help)
  11. Sharma GV, Khuri SF, Josa M, Folland ED, Parisi AF (1983). "The effect of antiplatelet therapy on saphenous vein coronary artery bypass graft patency". Circulation. 68 (3 Pt 2): II218–21. PMID 6347428. Unknown parameter |month= ignored (help)
  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 (1): 138–46. PMID 3874009. Unknown parameter |month= ignored (help)
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  15. Khuri SF, Wolfe JA, Josa M, Axford TC, Szymanski I, Assousa S, Ragno G, Patel M, Silverman A, Park M (1992). "Hematologic changes during and after cardiopulmonary bypass and their relationship to the bleeding time and nonsurgical blood loss". J. Thorac. Cardiovasc. Surg. 104 (1): 94–107. PMID 1614220. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
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  23. Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, Kern KB, Sethi G, Sharma GV, Khuri S (1991). "Starting aspirin therapy after operation. Effects on early graft patency. Department of Veterans Affairs Cooperative Study Group". Circulation. 84 (2): 520–6. PMID 1860197. Retrieved 2010-07-22. Unknown parameter |month= ignored (help)
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