Clinical relevance of clopidogrel unresponsiveness during elective coronary stenting: experience with the point-of-care platelet function assay-100 C/ADP.

BACKGROUND: Early identification of nonresponders to clopidogrel may be important in identifying subgroups of patients that might be at risk for future thrombotic events. METHODS: We prospectively assessed postclopidogrel platelet reactivity in 250 consecutive patients scheduled for elective percutaneous coronary intervention (PCI). All patients received dual antiplatelet therapy with 160 mg aspirin and a 300 mg loading dose of clopidogrel >12 hours before PCI. A platelet aggregation test was performed at the time of the intervention using a point-of-care assay, the Platelet Function Assay (PFA-100C/ADP; Dade-Behring, Deerfield, IL). Nonresponders were defined as having a PFA closure time of <71 seconds under dual oral antiplatelet therapy, reflecting normal platelet reactivity. Myonecrosis post-PCI constituted the primary end point and was defined as the release of creatine kinase-MB >1x the upper limit of normal on a sample taken 12 to 24 hours after intervention. The secondary end point was a composite end point of major adverse cardiac events including death, myocardial infarction, and stent thrombosis after 6 months. RESULTS: The PFA closure time was available in 242 patients and ranged from 31 to 300 seconds with a mean value of 147 seconds. Nonresponders represented 7% (17/242) of the cases. Myonecrosis post-PCI occurred in 29 patients (12%) and was more common in nonresponders than in normal responders (29% vs 11%, respectively; P = .03 on multivariate analysis). Major adverse cardiac events at 6 months occurred in 13 patients (1 sudden death possibly related to stent thrombosis and 12 post-PCI myocardial infarctions) and were more common in the nonresponder group (12% vs 5%, respectively; P = .06 on multivariate analysis). CONCLUSIONS: Unresponsiveness to clopidogrel as assessed by the point-of-care test PFA-100C/ADP is an independent major risk factor for thrombotic complications after coronary intervention.

Haemostatic changes and acquired activated protein C resistance in normal pregnancy.

Influence of changes in levels of coagulation factors and anticoagulants on acquired activated protein C (APC) resistance were studied in 40 healthy women during normal pregnancy. Factor VIII (FVIII), von Willebrand factor antigen (VWF:Ag), free protein S (FPS) and protein C were determined at 5-13, 14-26 and 27-40 weeks gestation and more than 6 weeks postpartum. APC anticoagulant activity was determined by measuring the activated partial thromboplastin time before and after adding human APC, expressed as the APC-sensitivity ratio (APC-SR). During the second and third gestation trimesters a significant increase (P < 0.05) in FVIII and VWF:Ag levels and a decrease in FPS levels were seen compared with the first trimester. Postpartum FVIII and VWF:Ag levels significantly decreased and FPS levels increased compared with the third trimester. Protein C levels remained unchanged during pregnancy and postpartum. Between increased FVIII and lowered APC-SR a trend of inverse correlation (r = -0.329; P = 0.076) occurred in the second trimester. No correlation was found between APC-SR and FPS or VWF:Ag levels. A remarkable finding is the strong inverse relationship between APC-SR and protein C levels (r

Does pre-treatment with aspirin and loading dose clopidogrel obviate the need for glycoprotein IIb/IIIa antagonists during elective coronary stenting? A focus on peri-procedural myonecrosis.

AIMS: Although full platelet inhibition with aspirin and thienopyridines before coronary stenting has significantly reduced the risk of acute stent thrombosis, peri-procedural myonecrosis still occurs frequently and is associated with increased death rate. Whether further inhibition of platelet aggregation by a glycoprotein IIb/IIIa antagonist may provide an additional cardioprotection is unknown. METHODS AND RESULTS: A total of 200 patients pre-treated with aspirin and a loading dose of clopidogrel (450 mg) were randomized just before coronary intervention (percutaneous coronary intervention, PCI) to treatment with or without abciximab. Platelet aggregation was assessed in samples collected during the procedure and the degree of platelet aggregation inhibition was correlated with cardiac enzyme release post-PCI. Abciximab treatment achieved a more complete inhibition of aggregation than dual oral antiplatelet therapy alone (median value of 1 vs. 50%, normal 100%). Any pathological increase in creatinine kinase-MB (CK-MB) post-PCI was present in 21% of the abciximab group and in 22% of the no-abciximab group (P = 0.9). Also the occurrence of clinically relevant myonecrosis [myocardial infarction (MI) = CK-MB > 3x upper limit of normal] was not significantly influenced by treatment assignment: 9 vs. 10% (P = 0.9). In a multiple logistic regression model including clinical, angiographic, and procedural characteristics, post-PCI myonecrosis was not correlated with the degree of platelet aggregation inhibition but with procedural features (such as long inflation time) and with the presence of multi-vessel disease. There were no cases of acute or subacute stent thrombosis. At 6 months, major adverse cardiac events, including cardiac death, non-fatal MI, or target lesion revascularization occurred in 13% of abciximab patients and in 16% of the control patients (P = 0.6). CONCLUSIONS: In the studied patients scheduled for elective coronary stenting and pre-treated with aspirin and a loading dose of clopidogrel, further inhibition of platelet aggregation by abciximab does not afford additional cardioprotection. Our data suggest that distal athero-embolization rather than thrombo-embolization is involved in the phenomenon of myonecrosis post-elective stenting.

Comparison of turbidimetric aggregation and in vitro bleeding time (PFA-100) for monitoring the platelet inhibitory profile of antiplatelet agents in patients undergoing stent implantation.

The present study compared classical ADP-induced platelet aggregation vs. PFA-100 closure times using collagen/ADP membrane cartridges to monitor the degree of platelet-inhibiting effect of three drug regimens: ticlopidin, abciximab/ticlopidin and loading dose clopidogrel, each on top of aspirin (acetylsalicylic acid, ASA) during and after elective stent placement (intervention) in a total of 31 patients with acute coronary syndrome. Ticlopidin was started directly after stent implantation, abciximab was started before coronary intervention and given intravenously for 12 h, and a clopidogrel loading dose was given before intervention. The 10 patients treated with ticlopidin (500 mg daily) showed no significant prolongation of PFA closure times and a slight increase of ADP-induced platelet aggregation shortly after intervention. In 11 patients treated with abciximab/ticlopidin, the PFA closure times were significantly prolonged, and ADP-induced platelet aggregation was reduced by more than 80% during the 12-h abciximab infusion after intervention. The 10 patients pretreated with loading dose clopidogrel (450 mg followed by 75 mg daily) showed an intermediate but significant prolongation of PFA closure times and reduction of ADP-induced platelet aggregation at levels between the ticlopidin/aspirin- and the abciximab/ticlopidin/aspirin-treated groups. At 20 h after intervention, a similar degree of PFA closure time prolongation and inhibition of ADP-induced aggregation was observed in the abciximab/ticlopidin/aspirin- and the clopidogrel/aspirin-treated patient groups. Both measurement of PFA-100 closure times and inhibition of ADP-induced platelet aggregation showed a similar degree of platelet inhibition, but had rather broad SD ranges, which limit their precision for the follow-up of individual patients. In conclusion, abciximab on top of ticlopidin/aspirin showed a stronger antiplatelet effect for only less than 20 h, as compared to loading dose clopidogrel/aspirin in acute coronary syndrome patients undergoing stent implantation. Whether such a short-term superiority of abciximab, as compared to loading dose clopidogrel, translates into an overall clinical benefit of thombotic and bleeding complications remains to be established in a randomized clinical trial.