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Eur Heart J. 2005 Mar;26(6):576-83. Epub 2005 Feb 21.
Clopidogrel administration prior to coronary artery bypass grafting surgery: the cardiologist's panacea or the surgeon's headache?
Kapetanakis EI, Medlam DA, Boyce SW, Haile E, Hill PC, Dullum MK, Bafi AS, Petro KR, Corso PJ.
Section of Cardiac Surgery, Department of Surgery, Washington Hospital Center, 106 Irving Street, NW, Suite 316, Washington, DC 20010-2975, USA.
AIMS: Thrombotic complications after percutaneous coronary intervention procedures have decreased in past years mainly due to the use of clopidogrel antiplatelet therapy. However, the risk of bleeding due to enhanced and irreversible platelet inhibition in patients who will require surgical coronary revascularization instead has not been adequately addressed in the literature. The purpose of this study was to evaluate the effect of pre-operative clopidrogel exposure in haemorrhage-related re-exploration rates, peri-operative transfusion requirements, morbidity, and mortality in patients undergoing coronary artery bypass grafting (CABG) surgery. METHODS AND RESULTS: A study population of 2359 patients undergoing isolated CABG between January 2000 and June 2002 was reviewed. Of these, 415 (17.6%) received clopidogrel prior to CABG surgery, and 1944 (82.4%) did not. A risk-adjusted logistic regression analysis was used to assess the association between clopidogrel pre-medication (vs. no) and haemostatic re-operation, intraoperative and post-operative blood transfusion rates, and multiple transfusions received. Haemorrhage-related pre-operative risk factors identified from the literature and those found significant in a univariate model were used. Furthermore, a sub-cohort, matched-pair by propensity scores analysis, was also conducted. The clopidogrel group had a higher likelihood of haemostatic re-operation [OR=4.9, (95% CI, 2.63-8.97), P<0.01], an increase in total packed red blood cell transfusions [OR=2.2, (95% CI, 1.70-2.84), P<0.01], multiple unit blood transfusions [OR=1.9, (95% CI, 1.33-2.75), P<0.01] and platelet transfusions [OR=2.6, (95% CI, 1.95-3.56), P<0.01]. Surgical outcomes and operative mortality [OR=1.5, (95% CI, 0.36-6.51), P=0.56] were not significantly different. CONCLUSION: Pre-operative clopidogrel exposure increases the risk of haemostatic re-operation and the requirements for blood and blood product transfusion during, and after, CABG surgery.

Catheter Cardiovasc Interv. 2005 Feb 25;64(3):369-372.
Closure devices and vascular complications among percutaneous coronary intervention patients receiving enoxaparin, glycoprotein IIb/IIIa inhibitors, and clopidogrel.
Exaire JE, Tcheng JE, Kereiakes DJ, Kleiman NS, Applegate RJ, Moliterno DJ.
Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio.
The objectives of this study were to explore the rate of vascular complications using closure devices (CDs) vs. manual compression (MC) among percutaneous coronary intervention (PCI) patients receiving enoxaparin, clopidogrel, aspirin, and GP IIb/IIIa inhibitors. The Evaluating Enoxaparin Clotting Times (ELECT) study enrolled patients receiving enoxaparin, clopidogrel, and GP IIb/IIIa inhibitors when necessary. Any approved CD or MC was allowed post-PCI, and clinical outcome data were prospectively collected. Four hundred forty-five patients had anti-Xa levels measured by a core laboratory and by a novel point-of-care device that reports ENOX(R) times. All received enoxaparin, aspirin, and clopidogrel, and 75% received a concomitant GP IIb/IIIa inhibitor. Major and minor bleeding were defined according to TIMI criteria. "Any bleeding" included the occurrence of access site complications including hematoma, significant rebleeding, or bleeding delaying hospital discharge. TIMI major plus minor bleeding occurred in 1.5% of the patients who received CD vs. 1.8% of patients with MC (P = 0.83). Any bleeding occurred in 12.2% of CD vs. 5.7% MC (P = 0.02), and in 9.5% of patients receiving GP IIb/IIIa inhibitor vs. 2.8% (P = 0.01) among those who did not. For patients receiving both a GP IIb/IIIa inhibitor and CD, any bleeding was observed in 13.7% vs. 3.4% (P = 0.006) among patients who received neither. While minor and major TIMI bleeding remained very low in both groups, CD was associated with a twofold increase in risk of any-bleeding event when compared to MC, especially when using GP IIb/IIIa inhibitors. Catheter Cardiovasc Interv 2005;64:369-372. (c) 2005 Wiley-Liss, Inc.

Thromb Haemost. 2005 Mar;93(3):535-43.
Nitroaspirin plus clopidogrel versus aspirin plus clopidogrel against platelet thromboembolism and intimal thickening in mice.
Momi S, Pitchford SC, Alberti PF, Minuz P, Soldato PD, Gresele P.
Department of Internal Medicine, Section of Internal and Cardiovascular Medicine, Via Enrico dal Pozzo, 06126 Perugia, Italy.
Clopidogrel plus aspirin is the treatment of choice for patients undergoing percutaneous, coronary interventions with stenting, but it does not prevent restenosis. NCX-4016, a nitric oxide-releasing aspirin (nitroaspirin), exerts a wider range of antiplatelet actions compared to aspirin, superior antithrombotic activity and reduces restenosis after arterial injury in animals. The aim of the present study was to compare the combination of nitroaspirin plus clopidogrel with aspirin plus clopidogrel in a model of platelet pulmonary thromboembolism, bleeding and intimal thickening in mice. Drugs were administered orally for 5 days; the antithrombotic effects were evaluated against collagen plus epinephrine-induced pulmonary thromboembolism, the haemorrhagic effects by tail transection bleeding time and the effects on neointima proliferation by histomorphology of photochemically injured femoral arteries. Lung platelet emboli were reduced significantly and more effectively by nitroaspirin plus clopidogrel (-56%, p<0.05 vs control) than by aspirin plus clopidogrel (-26%, p<0.05 vs control). Ex vivo platelet aggregation was inhibited maximally by nitroaspirin plus clopidogrel. Aspirin plus clopidogrel strikingly prolonged the bleeding time while nitroaspirin plus clopidogrel induced a lesser prolongation. Nitroaspirin plus clopidogrel significantly reduced intimal thickening of the femoral artery while aspirin plus clopidogrel was ineffective. Nitroaspirin plus clopidogrel is more effective and less prohaemorrhagic than aspirin plus clopidogrel in mice; provided these data are confirmed in other animal models, nitroaspirin plus clopidogrel may represent a new regimen to be tested in patients undergoing coronary revascularization procedures.

Circulation. 2005 Feb 28.
Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets. Results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) Study.
Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US.
Sinai Center for Thrombosis Research, Baltimore, Md.
BACKGROUND: Pretreatment is not the most common strategy practiced for clopidogrel administration in elective coronary stenting. Moreover, limited information is available on the antiplatelet pharmacodynamics of a 300-mg versus a 600-mg clopidogrel loading dose, and the comparative effect of eptifibatide with these regimens is unknown. METHODS AND RESULTS: Patients undergoing elective stenting (n=120) were enrolled in a 2x2 factorial study (300 mg clopidogrel with or without eptifibatide; 600 mg clopidogrel with or without eptifibatide) (Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets [CLEAR PLATELETS] Study). Clopidogrel was administered immediately after stenting. Aggregometry and flow cytometry were used to assess platelet reactivity. Eptifibatide added a >/=2-fold increase in platelet inhibition to 600 mg clopidogrel alone at 3, 8, and 18 to 24 hours after stenting as measured by 5 micromol/L ADP-induced aggregation (P<0.001). Without eptifibatide, 600 mg clopidogrel produced better inhibition than 300 mg clopidogrel at all time points (P<0.001). Glycoprotein IIb/IIIa (GPIIb/IIIa) blockade was associated with lower cardiac marker release. Active GPIIb/IIIa expression was inhibited most in the groups treated with eptifibatide (P<0.05). CONCLUSIONS: In elective stenting without clopidogrel pretreatment, use of a GPIIb/IIIa inhibitor produces superior platelet inhibition and lower myocardial necrosis compared with high-dose (600 mg) or standard-dose (300 mg) clopidogrel loading alone. In the absence of a GPIIb/IIIa inhibitor, 600 mg clopidogrel provides better platelet inhibition than the standard 300-mg dose. These results require confirmation in a large-scale clinical trial.

Thromb Haemost. 2005 Mar;93(3):527-34.
Effects of aspirin, clopidogrel and dipyridamole administered singly and in combination on platelet and leucocyte function in normal volunteers and patients with prior ischaemic stroke.
Zhao L, Fletcher S, Weaver C, Leonardi-Bee J, May J, Fox S, Willmot M, Heptinstal S, Bath P.
Division of Stroke Medicine, South Block, D Floor, Queen's Medical Centre, Nottingham NG7 2UH UK.
The aim of this study was to assess whether triple antiplatelet therapy is superior to dual and mono therapy in attenuating platelet and leucocyte function. Aspirin (A), clopidogrel (C), and dipyridamole (D) were administered singly and in various combinations (A, C, D,AC,AD, CD,ACD), each for two weeks (without washout) to 11 healthy subjects and to 11 patients with previous ischaemic stroke in two randomised multiway crossover trials. At the end of each two-week period platelet aggregation, platelet-leucocyte conjugate formation and leucocyte activation were measured ex vivo blinded to treatment. Platelets were stimulated with collagen; additional measurements were made with adenosine diphosphate (ADP), platelet activating factor (PAF), adrenaline and the combination of, ADP, PAF and adrenaline. Results show that in the presence of collagen, ACD was superior to all antagonists or combinations, except AC, in reducing aggregation, platelet-leucocyte conjugate formation, and monocyte activation (all p<0.05). ACD was also more potent than other treatments, except AC, in inhibiting the aggregation and platelet-monocyte conjugate formation induced by the combination of ADP, PAF and adrenaline. The effects were similar in both volunteers and stroke patients. No serious adverse events or major bleeding events occurred. Triple antiplatelet therapy did not appear to be more effective than combined aspirin and clopidogrel in moderating platelet and leucocyte function. Any additional clinical benefit provided by dipyridamole may be through other mechanisms of action.