Prasugrel but not high dose clopidogrel overcomes the lansoprazole neutralizing effect of P2Y12 inhibition: Results of the randomized DOSAPI study.

AIMS: The potential negative metabolic interaction between proton pump inhibitors and clopidogrel is an unsolved issue. We hypothesized that doubling the clopidogrel maintenance dose (150 mg) would be less effective than switching to prasugrel 10 mg maintenance dose (MD) to overcome this negative interaction. METHOD AND RESULTS: In a randomized study with a factorial design, 82 stable coronary artery disease patients treated with 75 mg clopidogrel MD and aspirin were assigned to receive in a double blind fashion lansoprazole (30 mg/day) or placebo and to receive in an open fashion 150 mg clopidogrel MD or 10 mg prasugrel MD. The primary endpoint was the relative change in residual platelet reactivity over the 14-day study period [(RPA14day-RPAbaseline)/RPAbaseline]. The effect of doubling the clopidogrel MD on relative change in RPA was neutralized by lansoprazole (-53.6±48.4% versus +0.8±53.7% without and with lansoprazole, respectively, p = 0.02) whereas 10 mg of prasugrel MD dramatically reduced RPA irrespective of lansoprazole co-administration (-81.8 %±24.8% vs. -72.9%±32.9% without and with lansoprazole, respectively, p = NS). Lansoprazole exposure was the only parameter with a significant interaction with RPA among subgroups. CONCLUSION: The higher platelet inhibitory effect obtained by doubling the clopidogrel MD was totally neutralized by the co-administration of lansoprazole. This drug interaction was not observed with prasugrel 10 mg.

Intravenous Clopidogrel (MDCO-157) Compared with Oral Clopidogrel: The Randomized Cross-Over AMPHORE Study.

BACKGROUND: The extent of P2Y12 inhibition during coronary intervention is an important determinant of ischemic complications. The currently available oral P2Y12 inhibitors are limited by a relatively slow onset of action and variable on-treatment response. OBJECTIVE: Our objective was to determine the pharmacodynamic (PD) dose-antiplatelet response relationship and the pharmacokinetics of MDCO-157, an intravenous formulation of clopidogrel complexed with sulphobutylether betacyclodextrin, and to identify the dose level of MDCO-157 that matches the PD effect of oral clopidogrel 300 mg. METHODOLOGY: A randomized open-label crossover study was performed in 33 healthy adult volunteers to determine the pharmacokinetic (clopidogrel and clopidogrel H4 thiol active metabolite) and the PD (vasodilator-stimulated phosphoprotein [VASP]) effects of MDCO-157 at doses of 75, 150, and 300 mg and of oral clopidogrel 300 mg. RESULTS: Data are presented as %, mean (standard deviation). The maximum effect of P2Y12 receptor inhibition assessed by flow cytometry using VASP was 70.42 (6.7), 69.45 (7.1), and 65.58 (12.6) for intravenous MDCO-157 at doses of 75, 150, and 300 mg, respectively, compared with 56.6 (17.5) with oral clopidogrel 300 mg administration (p < 0.0001). Intravenous administration of MDCO-157 led to a stepwise increase in plasma exposure of clopidogrel, higher than with administration of an oral dose of 300 mg (p < 0.0001). Plasma exposure of H4-thiol also increased with intravenous dose (3.6 ± 2.6, 6.9 ± 4.6, and 12.4 ± 9.1 h·ng/ml for intravenous 75, 150, and 300 mg, respectively) but was lower than with oral administration of a 300-mg dose (34.0 ± 16.0 h.ng/ml; pairwise p < 0.0001). CONCLUSIONS: MDCO-157, an intravenous formulation of clopidogrel complexed with sulphobutylether betacyclodextrin, did not show significant platelet inhibition when administered at doses up to 300 mg. Higher doses with longer infusion may be needed to reach a sufficient threshold of active metabolite generation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01860105.

A unique, low dose of intravenous enoxaparin in elective percutaneous coronary intervention.

OBJECTIVES: This study was designed to examine a unique and low dose of intravenous enoxaparin in elective percutaneous coronary intervention (PCI) that would be applicable to an unselected population regardless of age, weight, renal function, or use of glycoprotein IIb/IIIa inhibitors. BACKGROUND: There is limited experience of anticoagulation using intravenous (IV) low-molecular-weight heparin in PCI, which has been obtained with high doses causing elevated anticoagulation levels and delayed sheath withdrawal. METHODS: A total of 242 consecutive patients undergoing elective PCI were treated with a single IV bolus of enoxaparin (0.5 mg/kg), and 26% of patients (n = 64) also received eptifibatide. Sheaths were removed immediately after the procedure in patients treated with enoxaparin only, and 4 h after the procedure in those also treated with eptifibatide. RESULTS: A peak anti-Xa >0.5 IU/ml was obtained in 97.5% of the population, and 94.6% of patients had their peak anti-Xa level in the predefined target range of 0.5 to 1.5 IU/ml. Advanced age, renal failure, being overweight, and eptifibatide use did not alter the anticoagulation profile. At one-month follow-up, six patients (2.5%) had died, had a myocardial infarction, or undergone an urgent revascularization; all the patients had an anti-Xa level >0.5 IU/ml during PCI. Patients without an ischemic event and without a creatine kinase rise, but with a detectable troponin release in the next 24 h of PCI (>2 microg/ml, n = 21), had similar anti-Xa levels as those without troponin elevation. There were one major and three minor bleeding events that were not associated with anti-Xa overshoot. CONCLUSIONS: Low-dose (0.5 mg/kg) IV enoxaparin allows a prespecified target level of anticoagulation (anti-Xa >0.5 IU/ml) in the vast majority of patients undergoing PCI, appears to be safe and effective, allows immediate sheath removal when used alone, and does not require dose adjustment when used with eptifibatide.

Eptifibatide provides additional platelet inhibition in non-ST-elevation myocardial infarction patients already treated with aspirin and clopidogrel. Results of the platelet activity extinction in non-Q-wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE) study.

OBJECTIVES: The present study hypothesis was that eptifibatide offered further antiplatelet efficacy above clopidogrel in non-ST-elevation myocardial infarction (NSTEMI) patients before an expeditive coronary intervention. BACKGROUND: Although thienopyridines and glycoprotein (GP) IIb/IIIa antagonists are often co-prescribed in the context of NSTEMI, the antiplatelet interaction of these agents is poorly described and the superiority of GP IIb/IIIa antagonists above thienopyridine treatment alone is not clear. METHOD: Thirty-two NSTEMI patients treated with aspirin and enoxaparin were studied using flow cytometry to define parameters of platelet activation with a panel of agonists before clopidogrel, after clopidogrel, and during an eptifibatide infusion following the clopidogrel load. RESULTS: After platelet activation with adenosine diphosphate, thrombin receptor-activating peptide, or U46-619, relative reductions in conformationally activated GP IIb/IIIa receptor expression (evaluated with PAC-1) of 48%, 43%, and 33%, respectively (all p < 0.0001), were seen with clopidogrel, but further 80%, 78%, and 72% (all p < 0.0001) reductions were seen with eptifibatide. With the same agonists, fibrinogen binding was significantly reduced after clopidogrel by 70%, 64%, and 81% (all p < 0.0001) and again further reduced with eptifibatide by 90%, 95%, and 69% (all p < 0.0001). The total number of GP IIb/IIIa receptors (measured as P2 expression) and P-selectin expression fell after clopidogrel, after ex vivo stimulation with the same agonists; however, both parameters increased slightly during the eptifibatide infusion. CONCLUSIONS: The activated GP IIb/IIIa expression and fibrinogen binding findings indicate that eptifibatide provides significant potent antiplatelet activity above aspirin and clopidogrel, suggesting additive immediate protection in the treatment of NSTEMI. The P2 and P-selectin findings suggest the possibility of a partial agonist and/or pro-inflammatory effect.

High doses of clopidogrel to overcome genetic resistance: the randomized crossover CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2).

OBJECTIVES: This study sought to determine whether the pharmacokinetic (PK) and pharmacodynamic (PD) responses to high or standard clopidogrel loading doses (LDs) differ according to CYP2C19*2 allele. BACKGROUND: CYP2C19 loss-of-function alleles are associated with reduced responsiveness to standard clopidogrel doses. METHODS: Young post-myocardial infarction patients heterozygous (wild type [wt]/*2, n = 43) or homozygous (*2/*2, n = 8) for the CYP2C19*2 genetic variant were matched with patients not carrying the variant (wt/wt, n = 58). All patients were randomized to a 300- or 900-mg clopidogrel LD. The relative reduction in residual platelet aggregation (RR-RPA, %) and the area under the plasma concentration time curve of active metabolite from baseline to 6 h after loading (AUC(0-6)) were compared according to both LD and CYP2C19*2 carriage. RESULTS: The 300-mg LD led to a gene-dose effect for RR-RPA (-65.7% ± 35.9% in wt/wt vs. -48.0% ± 38.4% in wt/*2 vs. -14.6% ± 32.4% in *2/*2; overall p value = 0.003, p = 0.03 for wt/wt versus wt/*2, p = 0.04 for wt/*2 versus *2/*2) with minor effect in *2/*2 carriers. After the 900-mg LD, the effect of the CYP2C19*2 variant on platelet inhibition was fully compensated in wt/*2 carriers but not in *2/*2 carriers (-83.6% ± 25.8% in wt/wt vs.-77.2% ± 26.9% in wt/*2 vs. -29.5% ± 26.8% in *2/*2; overall p value = 0.0003, p = 0.20 for wt/wt versus wt/*2, p < 0.001 for wt/*2 versus *2/*2). A similar pattern was observed for the active metabolite AUC(0-6) according to carriage of CYP2C19*2 for both LDs. There was a significant correlation between PK and PD responses irrespective of the LD. CONCLUSIONS: Carriers of CYP2C19*2 display significantly lower responses to clopidogrel with a gene-dose effect. Clopidogrel resistance can be overcome by increasing the dose in heterozygous carriers but not in homozygous carriers. (Clopidogrel and Response Variability Investigation Study 2 [CLOVIS-2]; NCT00822666).

Enoxaparin anticoagulation monitoring in the catheterization laboratory using a new bedside test.

OBJECTIVES: This study evaluated the ability of the bedside test Hemochron Jr. Hemonox (International Technidyne Corporation, Edison, New Jersey) to identify patients with insufficient anti-Xa activity level in the catheterization laboratory. BACKGROUND: Inadequate anticoagulation in patients undergoing percutaneous coronary intervention (PCI) is associated with increased periprocedural ischemic events. METHODS: In 296 unselected patients undergoing catheterization and/or PCI, whole blood Hemonox clotting time (CT) and activated partial thromboplastin time (aPTT) were measured at baseline (T1) and 10 min after the intravenous administration of enoxaparin (T2) in patients receiving additional enoxaparin and compared with plasma chromogenic anti-Xa activity level. RESULTS: Median values were 0.1 IU/ml (interquartile range [IQR]: 0.1 to 0.1 IU/ml) and 0.87 IU/ml (IQR: 0.74 to 1.03 IU/ml) for anti-Xa; 74 s (IQR: 70 to 81 s) and 143 s (IQR: 114 to 206 s) for Hemonox CT; and 44 s (IQR: 39 to 50 s) and 72 s (IQR: 58 to 93 s) for aPTT at T1 and T2, respectively. When using Hemonox CT to discriminate patients with anti-Xa level <0.5 IU/ml, the area under the receiver operating characteristic curve was 0.95 +/- 0.01 (95% confidence interval [CI]: 0.93 to 0.97) versus 0.89 +/- 0.01 (95% CI: 0.86 to 0.92) for aPTT. The threshold value of 120 s was associated with a 94.9% (95% CI: 91.1% to 97.4%) sensitivity and a 73.3% (95% CI: 67.6% to 78.5%) specificity to detect patients with inadequate anti-Xa level (<0.5 IU/ml) and positive predictive and negative predictive values of 73.9% (95% CI: 68.7% to 79.0%) and 94.78% (95% CI: 91.8% to 97.8%), respectively. CONCLUSIONS: Hemonox CT appears to be a fast and reliable bedside test for detecting patients insufficiently anticoagulated and needing adjustment of anticoagulation therapy with enoxaparin before PCI.