Clopidogrel Provides Significantly Greater Inhibition of Platelet Activity Than Aspirin When Combined With Atorvastatin After Coronary Artery Bypass Grafting: A Prospective Randomized Study

Abstract

Objective: We aimed to compare the effects of 2 different antiplatelet agents on platelet activity in patients receiv- ing atorvastatin after coronary artery bypass grafting (CABG). Methods: We prospectively randomized 50 patients undergoing CABG into 2 groups; group 1 started to receive atorvastatin (10 mg) plus clopidogrel (75 mg; C + A, n = 25) and group 2 atorvastatin (10 mg) and acetylsalicylic acid (ASA; 300 mg, ASA + A, n = 25) daily on postoperative day 1 and continued for 6 months after operation. Adenosine diphosphate (ADP)–induced pla- telet aggregation and the expressions of glycoprotein (Gp) IIb, GpIIIa, P-selectin, and fibrinogen (Fg) and low-density lipoprotein (LDL) binding to platelets were assessed preoperatively and at postoperative days 7, 90, and 180. Results: The mean age of the patients was 59.6 ± 7.6 years, and 82% of the patients were males. The combination of C + A markedly inhibited ADP-induced platelet aggregation compared with ASA + A at postoperative days 90 and 180 (52% ± 6.0% vs 56% ± 7.25% and 19.6% ± 3.2% vs 37% ± 4.1%, P = .039 and P = .0001, respectively). The therapy of C + A significantly suppressed the expressions of GpIIIa at postoperative days 7, 90, and 180 (P = .0001, P = .0001, and P = .0001, respectively) and P-selectin at postoperative days 90 and 180 (P = .035 and P = .002, respectively) when compared to ASA + A. The expression of GpIIb was also significantly depressed at postoperative day 180 in group 1 when compared to group 2 (P = .0001). Low-density lipoprotein binding was significantly increased at day 180 postoperatively in both the groups (basal: 42.9% ± 5.6% vs 45.3% ± 4.4% and day 180: 60.3% ± 4.6% vs 61.8% ± 5.7%, P = .0001). Conclusions: Our results demonstrate that the combination of C + A is more effective than that of ASA + A in inhibiting ADP-mediated platelet aggregation and expression of major platelet receptors after CABG.

Keywords

coronary artery bypass graft atorvastatin clopidogrel acetylsalicylic acid platelet aggregation flow cytometry

References

Goyal A. , Alexander JH , Hafley GE , et al, and the PREVENT IV Investigators. Outcomes associated with the use of secondary prevention medications after coronary artery bypass graft surgery. Ann Thorac Surg . 2007;83(3): 993-1001.

The 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(3):153-162.

Pan W. , Pintar T. , Anton J. , Lee V. , Vaughn WK , Collard CD Statins are associated with a reduced incidence of perioperative mortality after coronary artery bypass graft surgery. Circulation. 2004;110 (11 suppl 1): 1145-1149.

Dontani MI , Elnicki DM , Jain AC , Gibson CM Effect of preoperative statin therapy on cardiac outcomes after coronary artery bypass grafting. Am J Cardiol. 2000 ;86(10): 1128-1130, A6.

Chan AW , Bhatt DL , Chew DP , et al. Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention. Circulation. 2002;105(6):691-696.

Poldermans D. , Bax JJ , Kertai MD , et al. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation . 2003;107(14):1848-1851.

Rosenson RS , Tangney CC Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA. 1998;279(20):1643-1650.

Alexander JH , Harrington RA , Tuttle RH , et al. Prior aspirin use predicts worse outcomes in patients with non-ST elevation acute coronary syndromes. Am J Cardiol. 1999;83(8):1147-1151.

Pereillo JM , Maftouh M. , Andrieu A. Structure and stereochemistry of the active metabolite of clopidogrel . Drug Metab Dispos. 2002;30(11):1288-1295.

10.

Lau WC , Waskell LA , Watkins PB , et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation. Circulation. 2003;107(1):32-37.

11.

Brophy J. , Costa V. , Babapulle M. A pharmacoepidemiological study of the interaction between atorvastatin and clopidogrel following percutaneous coronary interventions. J Am Coll Cardiol. 2004; 43(suppl A):50A Abstract.

12.

Vinholt P. , Poulsen TS , Korsholm L. , et al. The antiplatelet effect of clopidogrel is not attenuated by statin treatment in stable patients with ischemic heart disease. Thromb Haemost. 2005;94(2):438-443.

13.

Smith SC Jr , Blair SN , Bonow RO , et al. AHA/ACC Guidelines for Preventing Heart Attack and Death in Patients With Atherosclerotic Cardiovascular Disease: 2001 Update: a statement for healthcare professionals from the American Heart Association and the atherosclerotic cardiovascular disease. Circulation. 2001;104(13):1577-1579.

14.

Ak K. , Atalan N. , Tekeli A. , et al. Thromboelastography and its use in cardiac surgery [in Turkish] . Anadolu Kardiyol Derg. 2008;8(2):154-162.

15.

Ak K. , Isbir CS , Tetik S. , et al. Thromboelastography-based transfusion algorithm reduces blood product use after elective CABG: a prospective randomized study. J Card Surg. 2009;24(4):404-410.

16.

Tetik S. , Uras F. , Ekşioğlu-Demiralp E. , Turay Yardimci K. Low-density lipoprotein specifically binds glycoprotein IIb/IIIa: a flow cytometric method for ligand-receptor interaction. Clin Appl Thrombos Hemostas. 2008;14(2): 210-219.

17.

Stein PD , Dalen JE , Goldman S. , Théroux P. Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts. Chest. 1998;114(5 suppl):658S-665S.

18.

Hirsh J. , Bhatt DL Comparative benefits of clopidogrel and aspirin in high-risk patient populations: lessons from the CAPRIE and CURE studies. Arch Intern Med . 2004;164(19):2106-2110.

19.

Sanguigni V. , Pignatelli P. , Lenti L. , et al. Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients. Circulation. 2005;111(4):412-419.

20.

Klinkhardt U. , Bauersachs R. , Adams J. , Graff J. , Lindhoff-Last E. , Harder S. Clopidogrel but not aspirin reduces P-selectin expression and formation of platelet-leukocyte aggregates in patients with atherosclerotic vascular disease. Clin Pharmacol Ther. 2003;73(3):232-241.

21.

Xiao Z. , Théroux P. Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome. J Am Coll Cardiol. 2004 ; 43(11):1982-1988.

22.

Yao SK , Ober JC , Fergusson JJ , et al. Clopidogrel is more effective than aspirin as adjuvant treatment to prevent reocclusion after thrombolysis. Am J Physiol. 1994; 267(2 pt 2):488-493.

23.

Moshfegh K. , Redondo M. , Julmy F. , et al. Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: enhanced inhibitory effects of combination therapy . J Am Coll Cardiol. 2000;36(3):699-705.

24.

Dietzen DJ , Page KL , Tetzloff TA , Bohrer A. , Turk J. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase blunts factor VIIa/tissue factor and prothrombinase activities via effects on membrane phosphatidylserine. Arterioscler Thromb Vasc Biol . 2007;27(3):690-696.

25.

Mitsios JV , Papathanasiou AI , Rodis FI , Elisaf M. , Goudevenos JA , Tselepis AD Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concominantly for 5 weeks in patients with acute coronary syndromes. Circulation. 2004;109(11): 1335-1338.

26.

Wierzbicki AS , Lumb PJ , Semra YK , Crook MA Effect of atorvastatin on plasma fibrinogen . Lancet. 1998; 351(9102):569-570.

27.

Tetik S. , Uras F. , Yardimci KT Purification and characterization of human platelet fibrinogen receptor the GpIIb/IIIa complex. J Pharm Sci. 2005;2(3): 155-162.

28.

Zimmermann N. , Kienzle P. , Weber AA , et al. Aspirin resistance after coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2001;121(5):982-984.