The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting.

OBJECTIVES: We determined the effect of clopidogrel dosing on the incidence of nonresponsiveness (NR) and high post-treatment platelet aggregation (post-PA). BACKGROUND: We have reported NR after a 300-mg loading dose. Limited information is available on the comparative effect of a 600-mg loading dose on the incidence of NR and high post-PA. METHODS: Clopidogrel responsiveness and post-PA were measured in patients undergoing stenting (n = 190) randomly treated with either a 300-mg or a 600-mg clopidogrel load. Nonresponsiveness was defined as <10% absolute change in platelet aggregation, and high post-PA was defined as >75th percentile aggregation after 300 mg clopidogrel. RESULTS: Nonresponsiveness was lower after 600 mg compared to the 300-mg dose (8% vs. 28% and 8% vs. 32% with 5 and 20 microM ADP, respectively, p < 0.001). Among the patients with high post-PA after 300 mg clopidogrel, 62% to 65% had NR, whereas after the 600-mg dose, all of the patients with high post-PA had NR. CONCLUSIONS: A 600-mg clopidogrel loading dose reduces the incidence of NR and high post-PA as compared to a 300-mg dose. Higher dosing strategies and methods to confirm platelet inhibition should be further investigated in order to optimally use clopidogrel in patients undergoing stenting.

The Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study: Variation in Platelet Response to Clopidogrel and Aspirin.

Clopidogrel and aspirin are commonly prescribed anti-platelet medications indicated for patients who have experienced, or are at risk for, ischemic cardiovascular events. The Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study was designed to characterize determinants of clopidogrel and dual anti-platelet therapy (DAPT) response in a healthy cohort of Old Order Amish from Lancaster, PA. Following a loading dose, clopidogrel was taken once a day for 7 days. One hour after the last dose of clopidogrel, 325 mg of aspirin was given. Ex vivo platelet aggregometry was performed at baseline, post-clopidogrel, and post-DAPT. Platelet aggregation measurements were significantly lower after both interventions for all agonists tested (p <0.05), although there was large inter-individual variation in the magnitude of anti-platelet response. Female sex and older age were associated with higher platelet aggregation at all three time-points. Change in aggregation was correlated among the various agonists at each time point. Heritability (h2) of change in platelet aggregation was significant for most traits at all time-points (range h2=0.14-0.57). Utilization of a standardized, short-term intervention provided a powerful approach to investigate sources of variation in platelet aggregation response due to drug therapy. Further, this short-term intervention approach may provide a useful paradigm for pharmacogenomics studies.

Severe coronary artery disease: is there a place for percutaneous coronary intervention?

Management of severe coronary artery disease (CAD), defined as multivessel disease with or without significant left main artery disease remains a topic for considerable discussion. Although coronary artery bypass graft (CABG) surgery has been the mainstay of treatment, the steady pace of improvement in percutaneous coronary intervention (PCI) continues to beg the question as to whether PCI can perform as well as CABG for these patients. This short review is intended to place the recently published SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) trial in perspective, considering the previous major clinical trials in this field and to further consider whether PCI can be used appropriately in the management of patients with advanced CAD. The major clinical trials comparing PCI to CABG published prior to SYNTAX are briefly reviewed in chronologic order. The SYNTAX trial is reviewed in more depth and the implications of its results for contemporary clinical management are discussed. PCI has been applied to more advanced forms of CAD as percutaneous technology has evolved from balloon angioplasty to bare metal stents to drug eluting stents. Long-term survival has remained comparable between PCI and CABG patients despite the more advanced nature of disease treated in more recent trials, recognizing that a significant number of patients are excluded from randomization because equivalent revascularization is not achievable percutaneously. Repeat revascularization is more frequently required in PCI patients than in CABG patients. PCI has a role to play, although CABG remains the mainstay of therapy for patients with advanced CAD.

Bivalirudin and clopidogrel with and without eptifibatide for elective stenting: effects on platelet function, thrombelastographic indexes, and their relation to periprocedural infarction results of the CLEAR PLATELETS-2 (Clopidogrel with Eptifibatide to Arrest the Reactivity of Platelets) study.

OBJECTIVES: The primary objective of this study was to compare the effect of therapy with bivalirudin alone versus bivalirudin plus eptifibatide on platelet reactivity measured by turbidometric aggregometry and thrombin-induced platelet-fibrin clot strength (TIP-FCS) measured by thrombelastography in percutaneous coronary intervention (PCI) patients. The secondary aim was to study the relation of platelet aggregation and TIP-FCS to the occurrence of periprocedural infarction. BACKGROUND: Bivalirudin is commonly administered alone to clopidogrel naïve (CN) patients and to patients on maintenance clopidogrel therapy (MT) undergoing elective stenting. The effect of adding eptifibatide to bivalirudin on platelet reactivity (PR) and TIP-FCS, and their relation to periprocedural infarction in these patients are unknown. METHODS: Patients (n = 200) stratified to clopidogrel treatment status were randomly treated with bivalirudin (n = 102) or bivalirudin plus eptifibatide (n = 98). One hundred twenty-eight CN patients were loaded with 600 mg clopidogrel immediately after stenting, and 72 MT patients were not loaded. The PR, TIP-FCS, and myonecrosis markers were serially determined. RESULTS: In CN and MT patients, bivalirudin plus eptifibatide was associated with markedly lower PR at all times (5- and 20-microM adenosine diphosphate-induced, and 15- and 25-microM thrombin receptor activator peptide-induced aggregation; p < 0.001 for all) and reduced mean TIP-FCS (p < 0.05). Patients who had a periprocedural infarction had higher mean 18-h PR (p < 0.0001) and TIP-FCS (p = 0.002). CONCLUSIONS: For elective stenting, the addition of eptifibatide to bivalirudin lowered PR to multiple agonists and the tensile strength of the TIP-FCS, 2 measurements strongly associated with periprocedural myonecrosis. Future studies of PR and TIP-FCS for elective stenting may facilitate personalized antiplatelet therapy and enhance the selection of patients for glycoprotein IIb/IIIa blockade. (Peri-Procedural Myocardial Infarction, Platelet Reactivity, Thrombin Generation, and Clot Strength: Differential Effects of Eptifibatide + Bivalirudin Versus Bivalirudin [CLEAR PLATELETS-2]; NCT00370045.

Feasibility of off-pump ASD closure using real-time 3-D echocardiography.

BACKGROUND: If surgeons could "see " through blood and cardiac chamber walls, it would ultimately be unnecessary to open the heart or use cardiopulmonary bypass to perform procedures such as atrial septal defect (ASD) closure or mitral valve repair. Conventional echocardiography generates cross-sectional images that are not satisfactory as the only visualization for surgical procedures, and current 3-Dimensional (3-D) CT and echo systems take several minutes to compose and process a single still frame. Recently, however, the first system for real-time 3-D echocardiography has been developed. This study examines whether real-time 3-D echocardiography can provide images of sufficient anatomic definition, depth perception, and image resolution to substitute for optical visualization in performing ASD closures. METHODS: A prototype Volumetrics 3-D echocardiographic system was evaluated in a water bath on a complex-surfaced standard reference model to determine the image resolution and define the ideal imaging parameters. A static image and views of sutures being placed with an endoscopic needle driver and two commercial suture placement devices were evaluated at multiple angles and distances from the target. The resulting images were graded by a blinded reviewer. Once the best imaging parameters were determined, five porcine ASDs were closed with interrupted sutures, running sutures, or a pursestring suture using only echo visualization. RESULTS: The highest quality images were obtained with the probe at a distance of 4-6 cm and at angles perpendicular or 45 degrees forward to the target. Spatial and temporal resolutions were adequate to suture all ASDs closed under only echo guidance. CONCLUSIONS: The evaluated real-time 3-D echo system provided adequate spatial and temporal information to act as a guide for surgical procedures.