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Wei C Lau

Publications and source records attributed to Wei C Lau.

10 recordsLinked to original sources
PubMed2006

Antiplatelet drug resistance and drug-drug interactions: Role of cytochrome P450 3A4.

Antiplatelet therapy provided pivotal advances in the treatment of cardiovascular disease. Aspirin and thienopyridine, clopidogrel, is currently the treatment of choice in acute coronary syndromes and the prevention of thrombosis after coronary stent implantation. Despite the efficacy of this dual antiplatelet therapy in reduction of adverse coronary events in patients with acute coronary syndromes, complications persist in a subgroup of these patients. Emerging causes of aspirin and clopidogrel resistance may translate to increase risk for recurrent myocardial infarction, stroke, or cardiac related mortality. However, the mechanism of antiplatelet drug resistance remains incompletely characterized, and a sensitive and specific assay of aspirin and clopidogrel effect that reliably predicts treatment failure has not emerged. To date, evidence supporting antiplatelet drug resistance are pharmacokinetic response variability, drug-drug interaction through competitive inhibition a specific enzymatic pathway, genetic variability, and variability in the induction of enzymatic pathway in metabolic activation of prodrugs, like clopidogrel. Further investigation or guidelines are needed to optimize antiplatelet treatment strategies to identify and treat patients resistant to aspirin and/or clopidogrel.

Animals↗
PubMed2006

Clopidogrel resistance: implications for coronary stenting.

Clopidogrel, in combination wih aspirin, is currently the drug of choice to prevent thrombosis after coronary stent implantation. Currently, clopidogrel is administered to the vast majority of patients without any assessment of platelet inhibition. Response variability and resistance, however, definitely occur to clopidogrel treatment. Preliminary data support the hypothesis that patients with reactive or clopidogrel nonresponsive platelets are at risk for thrombotic events. However, the magnitude of the clinical effect remains unknown and relationship between nonresponsiveness and risk of clinical events is under-investigated. Several important questions that must be answered are: A) What is the relation of clopidogrel resistance and high platelet reactivity to the occurrence of stent thrombosis, recurrent myocardial infarction, stroke and death?; B) Is there a threshold of platelet reactivity that correlates with the onset of thrombotic risk?; and C) What is the cost of administering clopidogrel to non-responsive patients? Finally, our understanding of the clinical relevance of drug resistance and high platelet reactivity should be facilitated by the use of validated point-of-service devices. The mechanisms of the response variability to clopidogrel remain incompletely defined. The contribution of intra- and extracellular pathways are under investigation.

Animals↗
PubMed2004

Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance.

BACKGROUND: Interindividual variability of platelet inhibition after aspirin or clopidogrel administration has been described. Additionally, aspirin resistance and clopidogrel resistance occur in some individuals. Because the prodrug clopidogrel is activated by hepatic cytochrome P450 (CYP) 3A4, we hypothesized that interindividual variability in clopidogrel efficacy might be related to interindividual differences in CYP3A4 metabolic activity. METHODS AND RESULTS: Platelet aggregation was measured before and after clopidogrel treatment in 32 patients undergoing coronary artery stent implantation and in 35 healthy volunteers. The erythromycin breath test was used to measure CYP3A4 activity in vivo in 25 of the healthy volunteers. Individual platelet aggregation was studied in 10 healthy volunteers after the coadministration of clopidogrel and rifampin (a CYP3A4 inducer). Clopidogrel nonresponders, low responders, and responders were defined by a relative inhibition of adenosine diphosphate (20 micromol/L)-induced platelet aggregation of <10%, 10% to 29%, and > or =30%, respectively. Among patients, 22% were clopidogrel nonresponders, 32% were low responders, and 47% were responders. Among volunteers, 16% were nonresponders, 12% were low responders, and 72% were responders. Percent platelet aggregation after clopidogrel inversely correlated with CYP3A4 activity (r=-0.6, P=0.003). Improved platelet inhibition in volunteers resistant to clopidogrel was observed with the coadministration of clopidogrel and rifampin. CONCLUSIONS: Clopidogrel administration results in interindividual variability in platelet inhibition, which correlates with CYP3A4 metabolic activity. Measurement of antiplatelet drug efficacy with a point-of-care device and alternative antithrombotic strategies for aspirin or clopidogrel nonresponders and low responders could reduce the incidence of thrombotic events that continue to occur despite oral antiplatelet therapy.

Clopidogrel↗
PubMed2003

Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction.

BACKGROUND: We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing. Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4. METHODS AND RESULTS: Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated with clopidogrel and either erythromycin or troleandomycin, CYP3A4 inhibitors, or rifampin, a CYP3A4 inducer. Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner. Percent platelet aggregation was 34+/-23, 58+/-15 (P=0.027), 74+/-10 (P=0.002), and 89+/-7 (P=0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively. Erythromycin attenuated platelet aggregation inhibition (55+/-12 versus 42+/-12% platelet aggregation; P=0.002), as did troleandomycin (78+/-18 versus 45+/-18% platelet aggregation; P<0.0003), whereas rifampin enhanced platelet aggregation inhibition (33+/-18 versus 56+/-20% platelet aggregation, P=0.001). CONCLUSIONS: CYP3A4 activates clopidogrel. Atorvastatin, another CYP3A4 substrate, competitively inhibits this activation. Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel.

Adolescent↗
PubMed2002

Intraoperative transesophageal echocardiographic assessment of the effect of protamine on paraprosthetic aortic insufficiency immediately after stentless tissue aortic valve replacement.

Mild paravalvular aortic insufficiency (AI) is common immediately after stentless bioprosthetic aortic valve replacement. Although resolution of paraprosthetic jets with protamine has been described, the predictability of resolution has not been addressed. Intraoperative transesophageal echocardiography was performed before and after protamine administration among 2 groups. The first group (n = 20) was used to define the prevalence and severity of paravalvular AI after stentless tissue AVR, and define a threshold value for jet size associated with resolution with protamine. A second group (n = 18) was used to prospectively test the determined threshold. Paravalvular AI occurred in 13 of 20 (65%) patients. Using a threshold value of 0.3 cm or less jet width, prospective testing revealed positive and negative predictive values for AI resolution with protamine of 93% (14 of 15) and 100% (3 of 3), respectively. Protamine administration is associated with resolution of small AI jets immediately after implantation of a stentless aortic bioprosthesis, with a jet width 0.3 cm or less strongly predictive of resolution.

Adult↗