The Experts below are selected from a list of 22065 Experts worldwide ranked by ideXlab platform

Christian Gachet - One of the best experts on this subject based on the ideXlab platform.

  • Clopidogrel 150 mg day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention results from the vasp 02 vasodilator stimulated phosphoprotein 02 randomized study
    Jacc-cardiovascular Interventions, 2008
    Co-Authors: Boris Aleil, Gilles Montalescot, Jeanphilippe Collet, L Jacquemin, Fabien De Poli, Michel Zaehringer, Jeanpierre Cazenave, Marieclaude Dickele, J P Monassier, Christian Gachet
    Abstract:

    Objectives We investigated whether maintenance therapy with Clopidogrel 150 mg/day produces greater platelet inhibition than the standard 75-mg/day dose and whether the higher maintenance dose increases platelet inhibition in low responders to Clopidogrel 75 mg/day. Background Patients show interindividual variability in their platelet response to Clopidogrel. Low responders could potentially obtain greater clinical benefit from greater doses of Clopidogrel. Methods One hundred fifty-three elective percutaneous coronary intervention patients were randomized to Clopidogrel 150 mg/day (n = 58) or 75 mg/day (n = 95) for 4 weeks, with vasodilator-stimulated phosphoprotein assay-guided switching to Clopidogrel 150 mg/day after 2 weeks in low responders (platelet reactivity index ≥69%). All patients received aspirin 75 mg/day. Results After 2 weeks, Clopidogrel 150 mg/day produced a significantly lower platelet reactivity index than Clopidogrel 75 mg/day (43.9 ± 17.3% vs. 58.6 ± 17.7%; p l 0.0001). The proportion of low responders was significantly lower in patients randomized to Clopidogrel 150 mg/day than in those randomized to Clopidogrel 75 mg/day (8.6% vs. 33.7%; p = 0.0004). In the Clopidogrel 75 mg/day group, 64.5% (20 of 31) of low responders became responders after switching to Clopidogrel 150 mg/day for 2 weeks. No major bleeds occurred during the study; the incidence of minor bleeds was similar in each treatment group. Conclusions In elective percutaneous coronary intervention patients, a 150-mg/day Clopidogrel maintenance dose produces greater inhibition of platelet function than Clopidogrel 75 mg/day. In low responders to Clopidogrel 75 mg/day, switching to Clopidogrel 150 mg/day overcomes low responsiveness in a majority of patients. These findings warrant further clinical evaluation. (VASP-02; EudraCT number: 2004-005230-40).

  • flow cytometric analysis of intraplatelet vasp phosphorylation for the detection of Clopidogrel resistance in patients with ischemic cardiovascular diseases
    Journal of Thrombosis and Haemostasis, 2005
    Co-Authors: Boris Aleil, Catherine Ravanat, J P Cazenave, G Rochoux, A Heitz, Christian Gachet
    Abstract:

    Summary.  Interindividual variability of the inhibitory effect of Clopidogrel on platelet functions leading to Clopidogrel resistance has been described in some patients with ischemic cardiovascular disease. A reliable laboratory test is therefore needed to identify patients insufficiently protected by this antiplatelet treatment. The phosphorylation of vasodilator-stimulated phosphoprotein (VASP), an intraplatelet actin regulatory protein, is dependent on the level of activation of the platelet P2Y12 receptor, which is targeted by Clopidogrel. The aim of this study was to use a flow cytometric VASP phosphorylation assay to evaluate the efficacy of Clopidogrel therapy. The platelet reactivity index (PRI), expressed as a percentage, is the difference in VASP fluorescence intensity between resting (+PGE1) and activated (+ADP) platelets. In vitro, the PRI was strongly correlated with the inhibition of platelet aggregation induced by specific blockade of the P2Y12 receptor by the competitive antagonist AR-C69931MX (R = 0.72, P < 0.0001). Ex vivo, the PRI was 78.3 ± 4.6% in 47 healthy donors, 79.0 ± 4.1% in 34 patients not receiving Clopidogrel and 61.1 ± 17.0% in 33 patients treated with Clopidogrel (P < 0.0001). In the Clopidogrel group, the PRI values were widely dispersed (from 6.6 to 85.8%) and more than 30% of these patients had a PRI equivalent of values in patients not receiving Clopidogrel. The flow cytometric analysis of VASP phosphorylation seems to be a suitable test to evaluate the efficacy of Clopidogrel treatment. This assay demonstrated a wide interindividual variability of the inhibitory response of platelets to Clopidogrel and showed that one-third of the patients treated appeared to be ‘unprotected’ by this therapy.

  • flow cytometric analysis of intraplatelet vasp phosphorylation for the detection of Clopidogrel resistance in patients with ischemic cardiovascular diseases
    Journal of Thrombosis and Haemostasis, 2005
    Co-Authors: Boris Aleil, Catherine Ravanat, J P Cazenave, G Rochoux, A Heitz, Christian Gachet
    Abstract:

    Summary.  Interindividual variability of the inhibitory effect of Clopidogrel on platelet functions leading to Clopidogrel resistance has been described in some patients with ischemic cardiovascular disease. A reliable laboratory test is therefore needed to identify patients insufficiently protected by this antiplatelet treatment. The phosphorylation of vasodilator-stimulated phosphoprotein (VASP), an intraplatelet actin regulatory protein, is dependent on the level of activation of the platelet P2Y12 receptor, which is targeted by Clopidogrel. The aim of this study was to use a flow cytometric VASP phosphorylation assay to evaluate the efficacy of Clopidogrel therapy. The platelet reactivity index (PRI), expressed as a percentage, is the difference in VASP fluorescence intensity between resting (+PGE1) and activated (+ADP) platelets. In vitro, the PRI was strongly correlated with the inhibition of platelet aggregation induced by specific blockade of the P2Y12 receptor by the competitive antagonist AR-C69931MX (R = 0.72, P < 0.0001). Ex vivo, the PRI was 78.3 ± 4.6% in 47 healthy donors, 79.0 ± 4.1% in 34 patients not receiving Clopidogrel and 61.1 ± 17.0% in 33 patients treated with Clopidogrel (P < 0.0001). In the Clopidogrel group, the PRI values were widely dispersed (from 6.6 to 85.8%) and more than 30% of these patients had a PRI equivalent of values in patients not receiving Clopidogrel. The flow cytometric analysis of VASP phosphorylation seems to be a suitable test to evaluate the efficacy of Clopidogrel treatment. This assay demonstrated a wide interindividual variability of the inhibitory response of platelets to Clopidogrel and showed that one-third of the patients treated appeared to be ‘unprotected’ by this therapy.

Paul A Gurbel - One of the best experts on this subject based on the ideXlab platform.

  • the influence of smoking status on the pharmacokinetics and pharmacodynamics of Clopidogrel and prasugrel the paradox study
    Journal of the American College of Cardiology, 2013
    Co-Authors: Paul A Gurbel, Kevin P Bliden, Dominick J Angiolillo, Douglas Logan, Dean J Kereiakes, Kenneth C Lasseter, Alex White, Thomas D Nolin, William L Bailey
    Abstract:

    Objectives The goal of this study was to evaluate the effect of smoking on the pharmacokinetics and pharmacodynamics (PD) of Clopidogrel and prasugrel therapy. Background Major randomized trial data demonstrated that nonsmokers experience less or no benefit from Clopidogrel treatment compared with smokers (i.e., the “smokers9 paradox”). Methods PARADOX was a prospective, randomized, double-blind, double-dummy, placebo-controlled, crossover study of objectively assessed nonsmokers (n = 56) and smokers (n = 54) with stable coronary artery disease receiving aspirin therapy. Patients were randomized to receive Clopidogrel (75 mg daily) or prasugrel (10 mg daily) for 10 days and crossed over after a 14-day washout. PD was assessed by using VerifyNow P2Y12 and vasodilator-stimulated phosphoprotein phosphorylation assays. Clopidogrel and prasugrel metabolite levels, cytochrome P450 1A2 activity, CYP2C19 genotype, and safety parameters were determined. Results During Clopidogrel therapy, device-reported inhibition of platelet aggregation (IPA) trended lower in nonsmokers than smokers (least squares mean treatment difference ± SE: 7.7 ± 4.1%; p = 0.062). Device-reported IPA was significantly lower in Clopidogrel-treated smokers than prasugrel-treated smokers (least squares mean treatment difference: 31.8 ± 3.4%; p  Conclusions PARADOX demonstrated lower Clopidogrel active metabolite exposure and PD effects of Clopidogrel in nonsmokers relative to smokers. Prasugrel was associated with greater active metabolite exposure and PD effects than Clopidogrel regardless of smoking status. The poorer antiplatelet response in Clopidogrel-treated nonsmokers may provide an explanation for the smokers9 paradox. (The Influence of Smoking Status on Prasugrel and Clopidogrel Treated Subjects Taking Aspirin and Having Stable Coronary Artery Disease; NCT01260584)

  • the association of cigarette smoking with enhanced platelet inhibition by Clopidogrel
    Journal of the American College of Cardiology, 2008
    Co-Authors: Kevin P Bliden, Udaya S Tantry, William L Bailey, Joseph Dichiara, Lookman Lawal, Anand Singla, Mark J Antonino, Brian A Baker, Paul A Gurbel
    Abstract:

    The Association of Cigarette Smoking With Enhanced Platelet Inhibition by Clopidogrel Kevin P. Bliden, Joseph DiChiara, Lookman Lawal, Anand Singla, Mark J. Antonino, Brian A. Baker, William L. Bailey, Udaya S. Tantry, Paul A. Gurbel Cigarette smoking induces CYP1A2 and may enhance the metabolism of Clopidogrel. We examined the effect of smoking on platelet function in 104 current smokers (CS) and 155 nonsmokers (NS) undergoing stenting. Current smokers on chronic Clopidogrel displayed lower platelet aggregation (PA) and active glycoprotein (GP) IIb/IIIa expression compared with NS (p ≤ 0.0008 for both). Similarly, CS treated with 600 mg of Clopidogrel displayed greater inhibition and lower active GP IIb/IIIa expression compared with NS. In a multivariate Cox regression analysis, current smoking was an independent predictor of low platelet aggregation. Clopidogrel therapy in CS is associated with increased platelet inhibition and lower aggregation compared with NS. Objectives The purpose of this study was to examine the effect of cigarette smoking on the platelet response to Clopidogrel. Background Response variability to Clopidogrel therapy has been demonstrated. Clopidogrel is metabolically activated by several hepatic cytochrome P450 (CYP) isoenzymes, including CYP1A2. Cigarette smoking induces CYP1A2 and may, therefore, enhance the conversion of Clopidogrel to its active metabolite. Methods Among 259 consecutive patients undergoing elective coronary stenting; 120 were on chronic Clopidogrel therapy and were not loaded; and 139 were Clopidogrel naive and were loaded with 600 mg. There were 104 current smokers (CS) and 155 nonsmokers (NS). The adenosine diphosphate (ADP)-stimulated platelet aggregation (PA) was assessed by conventional aggregometry. The ADP-stimulated total and active glycoprotein (GP) IIb/IIIa expression were assessed with flow cytometry. Low PA was defined as the lowest quartile of 5 μmol/l ADP-induced post-treatment PA. Results Current smokers on chronic Clopidogrel therapy displayed significantly lower PA and ADP-stimulated active GP IIb/IIIa expression compared with NS (p ≤ 0.0008 for both). Similarly, CS treated with 600 mg of Clopidogrel displayed greater platelet inhibition and lower active GP IIb/IIIa expression compared with NS (p ≤ 0.05). In a multivariate Cox regression analysis, current smoking was an independent predictor of low PA (p = 0.0001). Conclusion Clopidogrel therapy in CS is associated with increased platelet inhibition and lower aggregation as compared with NS. The mechanism of the smoking effect deserves further study and may be an important cause of response variability to Clopidogrel therapy.

  • inhibition of platelet aggregation by azd6140 a reversible oral p2y12 receptor antagonist compared with Clopidogrel in patients with acute coronary syndromes
    Journal of the American College of Cardiology, 2007
    Co-Authors: Robert F Storey, Robert A. Harrington, Paul A Gurbel, Steen Husted, Stanley Heptinstall, Robert G Wilcox, Gary Peters, Mark Wickens, Hakan Emanuelsson, Peer Grande
    Abstract:

    Objectives In a substudy of DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. Clopidogrel in non–ST-segment Elevation myocardial infarction)-2, we compared the antiplatelet effects of AZD6140 and Clopidogrel and assessed the effects of AZD6140 in Clopidogrel-pretreated patients. Background Clopidogrel, in combination with aspirin, reduces cardiovascular events in patients with acute coronary syndromes (ACS). However, patients with poor inhibition of platelet aggregation with Clopidogrel may be less well protected. AZD6140 is a reversible oral P2Y 12 receptor antagonist that has been studied in ACS patients in comparison with Clopidogrel (DISPERSE-2 study). Methods Patients were randomized to receive either AZD6140 90 mg twice a day, AZD6140 180 mg twice a day, or Clopidogrel 75 mg once a day for up to 12 weeks in a double-blind, double-dummy design. One-half the patients allocated AZD6140 received a 270-mg loading dose. Patients randomized to receive Clopidogrel were given a 300-mg loading dose unless they had already been treated with Clopidogrel. Adenosine diphosphate-induced platelet aggregation was assessed by optical aggregometry on day 1 and at 4-week intervals. Results AZD6140 inhibited platelet aggregation in a dose-dependent fashion and both doses achieved greater levels of inhibition than Clopidogrel (e.g., 4 weeks, 4-h postdose [mean (±SD)]: Clopidogrel 64% [±22%], AZD6140 90 mg 79% [±22%], AZD6140 180 mg 95% [±8%]. AZD6140 also produced further suppression of platelet aggregation in patients previously treated with Clopidogrel. Conclusions AZD6140 exhibited greater mean inhibition of platelet aggregation than a standard regimen of Clopidogrel in ACS patients. In addition, AZD6140 further suppressed platelet aggregation in Clopidogrel pretreated patients.

  • 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
    Circulation, 2005
    Co-Authors: Paul A Gurbel, Kevin P Bliden, Kazi A Zaman, Jason A Yoho, Kevin Hayes, Udaya S Tantry
    Abstract:

    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 2×2 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 μmol/L ADP–induced aggregation (P<0.001). Without eptifibatide, 600 mg Clopidogrel produced bet...

  • 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
    Circulation, 2005
    Co-Authors: Paul A Gurbel, Kevin P Bliden, Kazi A Zaman, Jason A Yoho, Kevin Hayes, Udaya S Tantry
    Abstract:

    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 2×2 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 μmol/L ADP–induced aggregation (P<0.001). Without eptifibatide, 600 mg Clopidogrel produced bet...

Boris Aleil - One of the best experts on this subject based on the ideXlab platform.

  • Clopidogrel 150 mg day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention results from the vasp 02 vasodilator stimulated phosphoprotein 02 randomized study
    Jacc-cardiovascular Interventions, 2008
    Co-Authors: Boris Aleil, Gilles Montalescot, Jeanphilippe Collet, L Jacquemin, Fabien De Poli, Michel Zaehringer, Jeanpierre Cazenave, Marieclaude Dickele, J P Monassier, Christian Gachet
    Abstract:

    Objectives We investigated whether maintenance therapy with Clopidogrel 150 mg/day produces greater platelet inhibition than the standard 75-mg/day dose and whether the higher maintenance dose increases platelet inhibition in low responders to Clopidogrel 75 mg/day. Background Patients show interindividual variability in their platelet response to Clopidogrel. Low responders could potentially obtain greater clinical benefit from greater doses of Clopidogrel. Methods One hundred fifty-three elective percutaneous coronary intervention patients were randomized to Clopidogrel 150 mg/day (n = 58) or 75 mg/day (n = 95) for 4 weeks, with vasodilator-stimulated phosphoprotein assay-guided switching to Clopidogrel 150 mg/day after 2 weeks in low responders (platelet reactivity index ≥69%). All patients received aspirin 75 mg/day. Results After 2 weeks, Clopidogrel 150 mg/day produced a significantly lower platelet reactivity index than Clopidogrel 75 mg/day (43.9 ± 17.3% vs. 58.6 ± 17.7%; p l 0.0001). The proportion of low responders was significantly lower in patients randomized to Clopidogrel 150 mg/day than in those randomized to Clopidogrel 75 mg/day (8.6% vs. 33.7%; p = 0.0004). In the Clopidogrel 75 mg/day group, 64.5% (20 of 31) of low responders became responders after switching to Clopidogrel 150 mg/day for 2 weeks. No major bleeds occurred during the study; the incidence of minor bleeds was similar in each treatment group. Conclusions In elective percutaneous coronary intervention patients, a 150-mg/day Clopidogrel maintenance dose produces greater inhibition of platelet function than Clopidogrel 75 mg/day. In low responders to Clopidogrel 75 mg/day, switching to Clopidogrel 150 mg/day overcomes low responsiveness in a majority of patients. These findings warrant further clinical evaluation. (VASP-02; EudraCT number: 2004-005230-40).

  • flow cytometric analysis of intraplatelet vasp phosphorylation for the detection of Clopidogrel resistance in patients with ischemic cardiovascular diseases
    Journal of Thrombosis and Haemostasis, 2005
    Co-Authors: Boris Aleil, Catherine Ravanat, J P Cazenave, G Rochoux, A Heitz, Christian Gachet
    Abstract:

    Summary.  Interindividual variability of the inhibitory effect of Clopidogrel on platelet functions leading to Clopidogrel resistance has been described in some patients with ischemic cardiovascular disease. A reliable laboratory test is therefore needed to identify patients insufficiently protected by this antiplatelet treatment. The phosphorylation of vasodilator-stimulated phosphoprotein (VASP), an intraplatelet actin regulatory protein, is dependent on the level of activation of the platelet P2Y12 receptor, which is targeted by Clopidogrel. The aim of this study was to use a flow cytometric VASP phosphorylation assay to evaluate the efficacy of Clopidogrel therapy. The platelet reactivity index (PRI), expressed as a percentage, is the difference in VASP fluorescence intensity between resting (+PGE1) and activated (+ADP) platelets. In vitro, the PRI was strongly correlated with the inhibition of platelet aggregation induced by specific blockade of the P2Y12 receptor by the competitive antagonist AR-C69931MX (R = 0.72, P < 0.0001). Ex vivo, the PRI was 78.3 ± 4.6% in 47 healthy donors, 79.0 ± 4.1% in 34 patients not receiving Clopidogrel and 61.1 ± 17.0% in 33 patients treated with Clopidogrel (P < 0.0001). In the Clopidogrel group, the PRI values were widely dispersed (from 6.6 to 85.8%) and more than 30% of these patients had a PRI equivalent of values in patients not receiving Clopidogrel. The flow cytometric analysis of VASP phosphorylation seems to be a suitable test to evaluate the efficacy of Clopidogrel treatment. This assay demonstrated a wide interindividual variability of the inhibitory response of platelets to Clopidogrel and showed that one-third of the patients treated appeared to be ‘unprotected’ by this therapy.

  • flow cytometric analysis of intraplatelet vasp phosphorylation for the detection of Clopidogrel resistance in patients with ischemic cardiovascular diseases
    Journal of Thrombosis and Haemostasis, 2005
    Co-Authors: Boris Aleil, Catherine Ravanat, J P Cazenave, G Rochoux, A Heitz, Christian Gachet
    Abstract:

    Summary.  Interindividual variability of the inhibitory effect of Clopidogrel on platelet functions leading to Clopidogrel resistance has been described in some patients with ischemic cardiovascular disease. A reliable laboratory test is therefore needed to identify patients insufficiently protected by this antiplatelet treatment. The phosphorylation of vasodilator-stimulated phosphoprotein (VASP), an intraplatelet actin regulatory protein, is dependent on the level of activation of the platelet P2Y12 receptor, which is targeted by Clopidogrel. The aim of this study was to use a flow cytometric VASP phosphorylation assay to evaluate the efficacy of Clopidogrel therapy. The platelet reactivity index (PRI), expressed as a percentage, is the difference in VASP fluorescence intensity between resting (+PGE1) and activated (+ADP) platelets. In vitro, the PRI was strongly correlated with the inhibition of platelet aggregation induced by specific blockade of the P2Y12 receptor by the competitive antagonist AR-C69931MX (R = 0.72, P < 0.0001). Ex vivo, the PRI was 78.3 ± 4.6% in 47 healthy donors, 79.0 ± 4.1% in 34 patients not receiving Clopidogrel and 61.1 ± 17.0% in 33 patients treated with Clopidogrel (P < 0.0001). In the Clopidogrel group, the PRI values were widely dispersed (from 6.6 to 85.8%) and more than 30% of these patients had a PRI equivalent of values in patients not receiving Clopidogrel. The flow cytometric analysis of VASP phosphorylation seems to be a suitable test to evaluate the efficacy of Clopidogrel treatment. This assay demonstrated a wide interindividual variability of the inhibitory response of platelets to Clopidogrel and showed that one-third of the patients treated appeared to be ‘unprotected’ by this therapy.

Eric R Bates - One of the best experts on this subject based on the ideXlab platform.

  • contribution of hepatic cytochrome p450 3a4 metabolic activity to the phenomenon of Clopidogrel resistance
    Circulation, 2004
    Co-Authors: Paul A Gurbel, Kirk E. Guyer, Paul B Watkins, Charlene Neer, Amy S Hopp, David G M Carville, Alan R Tait, Eric R Bates
    Abstract:

    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 μmol/L)–indu...

  • atorvastatin reduces the ability of Clopidogrel to inhibit platelet aggregation a new drug drug interaction
    Circulation, 2003
    Co-Authors: Lucy Waskell, Kirk E. Guyer, Paul B Watkins, Charlene Neer, Amy S Hopp, David G M Carville, Alan R Tait, Kevin Horowitz, Eric R Bates
    Abstract:

    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±1...

Gilles Montalescot - One of the best experts on this subject based on the ideXlab platform.

  • cyp2c19 but not pon1 genetic variants influence Clopidogrel pharmacokinetics pharmacodynamics and clinical efficacy in post myocardial infarction patients
    Circulation-cardiovascular Interventions, 2011
    Co-Authors: Jeansebastien Hulot, Jeanphilippe Collet, Johanne Silvain, Guillaume Cayla, Frederick Allanic, Anne Bellemainappaix, Stuart A Scott, Gilles Montalescot
    Abstract:

    Background—Reduced concentrations of Clopidogrel active metabolite have been associated with diminished platelet inhibition and higher rates of adverse cardiovascular events. Paraoxonase-1 (PON1) has recently been proposed as a key enzyme for Clopidogrel metabolic activation. We tested the effects of PON1 polymorphisms on Clopidogrel pharmacokinetics and pharmacodynamics and the occurrence of cardiovascular outcomes in young post–myocardial infarction (MI) patients treated with Clopidogrel. Methods and Results—We genotyped PON1 (Q192R and L55M) and CYP2C19 variants in 106 patients enrolled in the PK/PD CLOVIS-2 trial. Patients were randomly exposed to a 300-mg or 900-mg Clopidogrel loading dose in a crossover study design. Clopidogrel active metabolite isomer H4 (clopi-H4) and platelet function testing were measured serially after loading dose. There was no significant association between PON1 Q192R or L55M and clopi-H4 formation or antiplatelet response to Clopidogrel after either loading dose. Using mul...

  • upstream Clopidogrel use and the efficacy and safety of early eptifibatide treatment in patients with acute coronary syndrome an analysis from the early glycoprotein iib iiia inhibition in patients with non st segment elevation acute coronary syndrom
    Circulation, 2011
    Co-Authors: Tracy Y Wang, Uwe Zeymer, Robert A. Harrington, Robert P. Giugliano, Gilles Montalescot, Stefan James, Jennifer A White, Pierluigi Tricoci, Frans Van De Werf, Paul W. Armstrong
    Abstract:

    Background-In the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial, routine preangiography eptifibatide use was not superior to delayed provisional use but led to more bleeding. This analysis examines efficacy and safety of early eptifibatide in the setting of concurrent upstream Clopidogrel use. Methods and Results-In EARLY-ACS, Clopidogrel use and timing were determined by treating physicians, but randomization to early eptifibatide versus placebo was stratified by the intent to use upstream Clopidogrel. Among 9166 non-ST-elevation acute coronary syndrome patients who underwent coronary angiography, intent to use upstream Clopidogrel was declared in 6895 (75%), and 7068 (77%) received upstream Clopidogrel. After multivariable adjustment, intended upstream Clopidogrel use did not differentially influence the effect of early eptifibatide on the primary end point of 96-hour death/myocardial infarction/recurrent ischemia requiring urgent revascularization/thrombotic bailout (interaction P = 0.988). Early eptifibatide use reduced 30-day death/myocardial infarction among patients with intended upstream Clopidogrel (adjusted odds ratio 0.85; 95% confidence interval 0.73 to 0.99) but not among those without intended upstream Clopidogrel use (adjusted odds ratio 1.02; 95% confidence interval 0.80 to 1.30). However, the Clopidogrel by randomized treatment interaction term was not significant (P = 0.23). Thrombolysis in Myocardial Infarction major bleeding risk was increased with early eptifibatide in the setting of upstream Clopidogrel use. Results were similar using actual Clopidogrel treatment strata. Conclusions-Routine early eptifibatide use, compared with delayed provisional use, may be associated with lower 30-day ischemic risk in non-ST-elevation acute coronary syndrome patients also treated with Clopidogrel before angiography. The benefit-risk ratio of intensive platelet inhibition with combined early use of antiplatelet agents needs further evaluation in prospective randomized trials.

  • prasugrel compared with high dose Clopidogrel in acute coronary syndrome the randomised double blind acapulco study
    Thrombosis and Haemostasis, 2009
    Co-Authors: Gilles Montalescot, Georgios Sideris, Remy Cohen, Catherine Meuleman, Claire Bal Dit Sollier, Olivier Barthelemy, Patrick Henry, Pascal Lim, Farzin Beygui, Jeanphilippe Collet
    Abstract:

    Compared with the approved dose regimen of Clopidogrel (300-mg loading dose [LD], 75-mg maintenance dose [MD]), prasugrel has been demonstrated to reduce ischaemic events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). In ACS, antiplatelet effects of a prasugrel MD regimen have not been previously compared with either a higher Clopidogrel MD or after switching from a higher Clopidogrel LD. The objective of this study was to evaluate the antiplatelet effect of a prasugrel 10-mg MD versus a Clopidogrel 150-mg MD in patients with ACS who had received a Clopidogrel 900-mg LD. Patients with non-ST elevation ACS, treated with aspirin and a Clopidogrel 900-mg LD, were randomised within 24 hours post-LD to receive a prasugrel 10-mg or Clopidogrel 150-mg MD. After 14 days of the initial MD, subjects switched to the alternative treatment for 14 days. The primary endpoint compared maximum platelet aggregation (MPA, 20 µM adenosine diphosphate [ADP]) between prasugrel and Clopidogrel MDs for both periods. Responder analyses between treatments were performed using several platelet-function methods. Of 56 randomised subjects, 37 underwent PCI. MPA was 26.2% for prasugrel 10 mg and 39.1% for Clopidogrel 150 mg (p<0.001). The prasugrel MD regimen reduced MPA from the post-900-mg LD level (41.2% to 29.1%, p=0.003). Poor response ranged from 0% to 6% for prasugrel 10 mg and 4% to 34% for Clopidogrel 150 mg. Thus, in ACS patients a prasugrel 10-mg MD regimen resulted in significantly greater platelet inhibition than Clopidogrel at twice its approved MD or a 900-mg LD.

  • Clopidogrel 150 mg day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention results from the vasp 02 vasodilator stimulated phosphoprotein 02 randomized study
    Jacc-cardiovascular Interventions, 2008
    Co-Authors: Boris Aleil, Gilles Montalescot, Jeanphilippe Collet, L Jacquemin, Fabien De Poli, Michel Zaehringer, Jeanpierre Cazenave, Marieclaude Dickele, J P Monassier, Christian Gachet
    Abstract:

    Objectives We investigated whether maintenance therapy with Clopidogrel 150 mg/day produces greater platelet inhibition than the standard 75-mg/day dose and whether the higher maintenance dose increases platelet inhibition in low responders to Clopidogrel 75 mg/day. Background Patients show interindividual variability in their platelet response to Clopidogrel. Low responders could potentially obtain greater clinical benefit from greater doses of Clopidogrel. Methods One hundred fifty-three elective percutaneous coronary intervention patients were randomized to Clopidogrel 150 mg/day (n = 58) or 75 mg/day (n = 95) for 4 weeks, with vasodilator-stimulated phosphoprotein assay-guided switching to Clopidogrel 150 mg/day after 2 weeks in low responders (platelet reactivity index ≥69%). All patients received aspirin 75 mg/day. Results After 2 weeks, Clopidogrel 150 mg/day produced a significantly lower platelet reactivity index than Clopidogrel 75 mg/day (43.9 ± 17.3% vs. 58.6 ± 17.7%; p l 0.0001). The proportion of low responders was significantly lower in patients randomized to Clopidogrel 150 mg/day than in those randomized to Clopidogrel 75 mg/day (8.6% vs. 33.7%; p = 0.0004). In the Clopidogrel 75 mg/day group, 64.5% (20 of 31) of low responders became responders after switching to Clopidogrel 150 mg/day for 2 weeks. No major bleeds occurred during the study; the incidence of minor bleeds was similar in each treatment group. Conclusions In elective percutaneous coronary intervention patients, a 150-mg/day Clopidogrel maintenance dose produces greater inhibition of platelet function than Clopidogrel 75 mg/day. In low responders to Clopidogrel 75 mg/day, switching to Clopidogrel 150 mg/day overcomes low responsiveness in a majority of patients. These findings warrant further clinical evaluation. (VASP-02; EudraCT number: 2004-005230-40).