| 1. |
- Alfredsson, Joakim, et al.
(författare)
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Predicting the risk of bleeding during dual antiplatelet therapy after acute coronary syndromes
- 2017
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Ingår i: Heart. - : BMJ PUBLISHING GROUP. - 1355-6037 .- 1468-201X. ; 103:15, s. 1168-1176
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Dual antiplatelet therapy (DAPT) with aspirin + a P2Y12 inhibitor is recommended for at least 12 months for patients with acute coronary syndrome (ACS), with shorter durations considered for patients with increased bleeding risk. However, there are no decision support tools available to predict an individual patients bleeding risk during DAPT treatment in the post-ACS setting. Methods To develop a longitudinal bleeding risk prediction model, we analysed 9240 patients with unstable angina/non-ST segment elevation myocardial infarction (NSTEMI) from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial, who were managed without revascularisation and treated with DAPT for a median of 14.8 months. Results We identified 10 significant baseline predictors of non-coronary artery bypass grafting (CABG)-related Global Use of Strategies to Open Occluded Arteries (GUSTO) severe/life-threatening/moderate bleeding: age, sex, weight, NSTEMI (vs unstable angina), angiography performed before randomisation, prior peptic ulcer disease, creatinine, systolic blood pressure, haemoglobin and treatment with beta-blocker. The five significant baseline predictors of Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding included age, sex, angiography performed before randomisation, creatinine and haemoglobin. The models showed good predictive accuracy with Therneaus C-indices: 0.78 (SE=0.024) for the GUSTO model and 0.67 (SE=0.023) for the TIMI model. Internal validation with bootstrapping gave similar C-indices of 0.77 and 0.65, respectively. External validation demonstrated an attenuated C-index for the GUSTO model (0.69) but not the TIMI model (0.68). Conclusions Longitudinal bleeding risks during treatment with DAPT in patients with ACS can be reliably predicted using selected baseline characteristics. The TRILOGY ACS bleeding models can inform riskbenefit considerations regarding the duration of DAPT following ACS.
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| 2. |
- Braun, Oscar, et al.
(författare)
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Enhanced active metabolite generation and platelet inhibition with prasugrel compared to clopidogrel regardless of genotype in thienopyridine metabolic pathways
- 2013
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 110:6, s. 1223-1231
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Tidskriftsartikel (refereegranskat)abstract
- Clopidogrel response varies according to the presence of genetic polymorphisms. The CYP2C19*2 allele has been associated with impaired response; conflicting results have been reported for CYP2C19*17, ABCB1, and PON1 genotypes. We assessed the impact of CYP2C19, PON1, and ABCB1 polymorphisms on clopidogrel and prasugrel pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Aspirin-treated patients (N=194) with coronary artery disease from two independent, prospective, randomised, multi-centre studies comparing clopidogrel (75 mg) and prasugrel (10 mg) were genotyped and classified by predicted CYP2C19 metaboliser phenotype (ultra metabolisers [UM] = *17 carriers; extensive metabolisers [EM] = *1/1 homozygotes; reduced metabolisers [RM] = *2 carriers). ABCB1 T/T and C/T polymorphisms and PON1 A/A, A/G and G/G polymorphisms were also genotyped. PD parameters were assessed using VerifyNow (R) P2Y12 and vasodilator stimulated phosphoprotein (VASP) expressed as platelet reactivity index (PR!) after 14 days of maintenance dosing. Clopi-, dogrel and prasugrel active metabolite (AM) exposure was calculated in a cohort of 96 patients. For clopidogrel, genetic variants in CYP2C19, but notABCB1 or PON1, affected PK and PD. For prasugrel, none of the measured genetic variants affected PK or PD. Compared with clopidogrel, platelet inhibition with prasugrel was greater even in the CYP2C19 UM phenotype. Prasugrel generated more AM and achieved greater platelet inhibition than clopidogrel irrespective of CYP2C19, ABCB1, and PON1 polymorphisms. The lack of effect from genetic variants on prasugrel AM generation or antiplatelet activity is consistent with previous studies in healthy volunteers and is consistent with improved efficacy in acute coronary syndrome patients managed with percutaneous coronary intervention.
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| 3. |
- Erlinge, David, et al.
(författare)
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Prasugrel 5-mg in the very elderly attenuates platelet inhibition but maintains non-inferiority to prasugrel 10-mg in non-elderly patients: The GENERATIONS trial, a pharmacodynamic and pharmacokinetic study in stable coronary artery disease patients.
- 2013
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 62:7, s. 577-583
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We assessed pharmacodynamic (PD) response for the reduced prasugrel 5-mg maintenance dose in very elderly (≥75y; VE) patients. BACKGROUND: In TRITON-TIMI 38, prasugrel 10-mg reduced ischemic events versus clopidogrel 75-mg, but increased bleeding in VE patients. METHODS: We examined PD and active-metabolite pharmacokinetics with prasugrel 5-mg and 10-mg and clopidogrel 75-mg in a three-period (12 days each), blinded, cross-over study in VE (n=73, mean 79±3y) or non-elderly (≥45-<65y, NE) (n=82, 56±5y) stable coronary artery disease (CAD) patients on background aspirin. Assays included light transmission aggregometry (LTA), VerifyNow(®) P2Y12 (VN-P2Y12), and VASP. The primary comparison was non-inferiority of maximum platelet aggregation (MPA) comparing the median for prasugrel 5-mg in VE versus the 75th percentile for prasugrel 10-mg in NE, using a prespecified one-sided 97.5% confidence interval for the difference <15%. RESULTS: Prasugrel 5-mg in VE met the primary pharmacodynamic non-inferiority criterion versus prasugrel 10-mg in NE. For prasugrel 5-mg, MPA was significantly lower (mean±SD, 57±14%) than clopidogrel (63±14%) (p<0.001) in VE, but higher than prasugrel 10-mg in NE (46±12%) (p<0.001). PD response by LTA, VN-P2Y12, and VASP during all treatments appeared similar between age cohorts. Prasugrel 5-mg resulted in fewer VE poor responders versus clopidogrel. Rates of mild bleeding were higher with prasugrel 10-mg, but similar for prasugrel 5-mg versus clopidogrel 75-mg. CONCLUSIONS: In aspirin-treated stable CAD patients, prasugrel 5-mg in VE attenuated platelet inhibition while meeting prespecified non-inferiority criterion versus prasugrel 10-mg in NE, with significantly better PD response and fewer poor responders compared to clopidogrel 75-mg in VE.
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| 4. |
- Erlinge, David, et al.
(författare)
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Prasugrel 5 mg in the Very Elderly Attenuates Platelet Inhibition But Maintains Noninferiority to Prasugrel 10 mg in Nonelderly Patients
- 2013
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 62:7, s. 577-583
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study assessed pharmacodynamic (PD) response to the reduced prasugrel maintenance dose of 5 mg in very elderly (VE) patients (andgt;= 75 years of age). less thanbrgreater than less thanbrgreater thanBackground In the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction 38) study prasugrel 10 mg reduced ischemic events versus clopidogrel 75 mg, but increased bleeding in VE patients. less thanbrgreater than less thanbrgreater thanMethods We examined PD and active metabolite pharmacokinetics (PKs) with prasugrel 5 and 10 mg and clopidogrel 75 mg in a 3-period (12 days each) blinded, crossover study in VE (n = 73; mean: 79 +/- 3 years of age) or (n 82) nonelderly (NE) (andgt;= 45 to andlt;65 years of age; mean: 56 +/- 5 years of age) stable coronary artery disease (CAD) patients receiving background aspirin. Assays included light transmission aggregometry (LTA), VerifyNow P2Y12 (VN-P2Y12), and vasodilator-associated stimulated phosphoprotein (VASP). The primary comparison was noninferiority of maximum platelet aggregation (MPA) comparing the median for prasugrel 5 mg in VE versus the 75th percentile for prasugrel 10 mg in NE, using a pre-specified 1-sided 97.5% confidence interval for the difference andlt;15%. less thanbrgreater than less thanbrgreater thanResults Prasugrel 5 mg in VE met the primary PD noninferiority criterion versus prasugrel 10 mg in NE. For prasugrel 5 mg, MPA was significantly lower (57 +/- 14%) than clopidogrel (63 +/- 14%; p andlt; 0.001) in VE but higher than prasugrel 10 mg in NE (46 +/- 12%; p andlt; 0.001). PD response by LTA, VN-P2Y12, and VASP during all treatments appeared similar between age cohorts. Prasugrel 5 mg resulted in fewer VE poor responders than clopidogrel. Rates of mild bleeding were higher with prasugrel 10 mg but similar for prasugrel 5 mg versus clopidogrel 75 mg. less thanbrgreater than less thanbrgreater thanConclusions In aspirin-treated stable CAD patients, prasugrel 5 mg in VE attenuated platelet inhibition while meeting pre-specified noninferiority criterion versus prasugrel 10 mg in NE, with significantly better PD response and fewer poor responders compared to clopidogrel 75 mg in VE. (Comparison of Prasugrel and Clopidogrel in Very Elderly and Non-Elderly Patients With Stable Coronary Artery Disease [GENERATIONS]; NCT01107912)
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| 5. |
- Gurbel, Paul A., et al.
(författare)
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The effect of CYP2C19 gene polymorphisms on the pharmacokinetics and pharmacodynamics of prasugrel 5-mg, prasugrel 10-mg and clopidogrel 75-mg in patients with coronary artery disease
- 2014
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Ingår i: Thrombosis and Haemostasis. - : Schattauer. - 0340-6245 .- 2567-689X. ; 112:3, s. 589-597
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Tidskriftsartikel (refereegranskat)abstract
- CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC([0-tlast])), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator-stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/*17 non-carriers). AUC((0-tlast)) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [Cl]: 0.86,1.17, p>0.99; and 0.97, 95% CI:0.85,1.12, p=0.71, respectively), but was lower among RMs receiving clopidogrel 75-mg (1.37, 95% CI:1.14,1.65, p<0.001). Platelet reactivity was not significantly affected by CYP2C19 metaboliser status for prasugrel 5-mg, or for prasugrel 10-mg by MPA and VN-PRU, but for clopidogrel 75-mg was significantly higher in reduced metabolisers (all measures p<0.01). Prasugrel 10-mg showed greater antiplatelet effects vs clopidogrel 75-mg (all comparisons p<0.001). Prasugrel 5-mg showed greater antiplatelet effects vs clopidogrel 75-mg in RMs (all p<0.001), and comparable effects in EMs (all p >= 0.37). In contrast to clopidogrel, prasugrel active metabolite PK was not influenced by CYP2C19 genotype. Antiplatelet effect for prasugrel 10-mg was greater irrespective of metaboliser status and for prasugrel 5-mg was greater for RMs and comparable for EMs as compared to clopidogrel 75-mg.
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| 6. |
- Jakubowski, Joseph A., et al.
(författare)
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The influence of body size on the pharmacodynamic and pharmacokinetic response to clopidogrel and prasugrel : A retrospective analysis of the FEATHER study
- 2014
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 134:3, s. 552-557
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Patients treated with clopidogrel who have higher body size exhibit greater platelet reactivity than patients with lower body size. In a retrospective analysis of the FEATHER trial, we examined the relationship between platelet response to thienopyridines clopidogrel 75 mg (Clop-75), prasugrel 5 mg (Pras-5), and prasugrel 10 mg (Pras-10) using 3 body size indices: body weight (BW), body mass index (BMI), and body surface area (BSA). Relationships were assessed as continuous variables and as 4 incremental body size groups. Materials and Methods: Aspirin-treated patients with stable coronary artery disease (N = 72) and a BW range of 45-134 kg received Clop-75, Pras-5, and Pras-10 in a 3-period, blinded, cross-over study. Platelet assays included maximum platelet aggregation (MPA) to 20 mu M ADP by light transmission aggregometry, VerifyNow-P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). Exposure to active metabolites (AMs) was also assessed. Results: Body size was a determinant of AM exposure and residual platelet reactivity regardless of type and dose of thienopyridine. BW and BSA demonstrated marginally stronger correlations with platelet reactivity; VASP-PRI demonstrated a stronger correlation with the body size than the other tests. Correlation coefficients ranged from a high of 0.64 (BW vs. PRI on Pras-5) to a low of 0.34 (BMI vs. MPA on Pras-10), but all were statistically significant (p < 0.01). Conclusions: Using a comprehensive selection of body size indices, AM exposures, platelet function tests, and thienopyridine doses, we demonstrated a consistent inverse relationship between body size and response to clopidogrel and prasugrel. (C) 2014 Elsevier Ltd. All rights reserved.
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| 7. |
- Jakubowski, Joseph A., et al.
(författare)
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The Rationale for and Clinical Pharmacology of Prasugrel 5 mg
- 2017
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Ingår i: American Journal of Cardiovascular Drugs. - : Springer Science and Business Media LLC. - 1175-3277 .- 1179-187X. ; 17:2, s. 109-121
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Tidskriftsartikel (refereegranskat)abstract
- Prasugrel is a third-generation thienopyridine platelet P2Y12 adenosine diphosphate (ADP) receptor antagonist administered with aspirin for the treatment of patients with acute coronary syndrome (ACS) with planned percutaneous coronary intervention. Prasugrel is administered periprocedurally at an oral loading dose of 60 mg followed by daily maintenance doses (MDs) of 10 mg for most patients and 5 mg for patients weighing <60 kg or aged ≥75 years. Data from a prasugrel phase III study, TRITON-TIMI 38, suggested that a lower MD might be more suitable for patients weighing <60 kg or aged ≥75 years; subsequent pharmacokinetic and pharmacodynamic studies have indicated that prasugrel 5 mg reduced platelet reactivity in these populations to an extent similar to that of prasugrel 10 mg in heavier or younger patients. Clinical experience with prasugrel 5 mg is limited, and additional studies are needed to verify the clinical efficacy and safety of this dose in these challenging populations.
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| 8. |
- Wagner, Henrik, et al.
(författare)
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Higher body weight patients on clopidogrel maintenance therapy have lower active metabolite concentrations, lower levels of platelet inhibition, and higher rates of poor responders than low body weight patients
- 2014
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 38:2, s. 127-136
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Tidskriftsartikel (refereegranskat)abstract
- Body weight is a predictor of clopidogrel response. However, no prospective studies have compared pharmacodynamic (PD) and pharmacokinetic (PK) data based on body weight. We compared PD and PK effects of clopidogrel 75 mg in low body weight (LBW, <60 kg) and higher body weight (HBW, >= 60 kg) patients with stable coronary artery disease. LBW (n = 34, 56.4 +/- 3.7 kg) and HBW (n = 38, 84.7 +/- 14.9 kg) aspirin-treated patients received clopidogrel 75 mg for 10-14 days. The area under the concentration-time curve of active metabolite (Clop-AM) calculated through the last quantifiable concentration up to 4 h postdose, AUC((0-tlast)), was calculated by non-compartmental methods. Light transmission aggregometry (LTA) (maximum platelet aggregation and inhibition of platelet aggregation to 20 mu M adenosine diphosphate (ADP), and residual platelet aggregation to 5 mu M ADP), VerifyNow (R) P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein phosphorylation platelet reactivity index (VASP-PRI) were performed. Mean AUC((0-tlast)) was lower in HBW than LBW patients: 12.8 versus 17.9 ng h/mL. HBW patients had higher platelet reactivity as measured by LTA (all p <= 0.01), PRU (207 +/- 68 vs. 152 +/- 57, p < 0.001), and VASP-PRI (56 +/- 18 vs. 39 +/- 17, p < 0.001). More HBW patients exhibited high on-treatment platelet reactivity (HPR) using PRU (35 vs. 9 %) and VASP-PRI (65 vs. 27 %). Body weight correlated with PRU and VASP-PRI (both p < 0.001), and inversely with log transformed AUC((0-tlast)) (p < 0.001). In conclusion, HBW patients had lower levels of Clop-AM, and higher platelet reactivity and rates of HPR than LBW subjects, contributing to their suboptimal response to clopidogrel.
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| 9. |
- Braun, Oscar, et al.
(författare)
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Greater reduction of platelet activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease
- 2008
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 100:4, s. 626-633
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Tidskriftsartikel (refereegranskat)abstract
- Prasugrel, a novel P2Y(12) ADP-receptor antagonist, has been reported to achieve greater inhibition of platelet aggregation compared to clopidogrel as assessed by light transmission aggregometry. It was the objective of this study to investigate the effect of prasugrel on alternative markers of platelet activation in comparison to a high loading dose and the approved maintenance dose of clopidogrel. One hundred ten aspirin-treated patients with stable coronary artery disease were randomized to a loading dose (LD, day 1)/ maintenance dose (MD, days 2-29) of prasugrel 60 mg/10 mg or clopidogrel 600 mg/75 mg. Platelet activation markers were analyzed by whole blood flow cytometry pre-dose and at 2 and 24 hours after LD and pre-dose at 14 and 29 days. After stimulation with 20 muM ADP, 2 hours after LD, significantly lower expression of activated GPIIb/IIIa (4.3 vs. 21.8 [mean fluorescent intensity (MFI)], p < 0.001) and P-selectin (2.0 vs. 11.7 MFI, p < 0.001) along with decreased formation of platelet-monocyte aggregates (16.4% vs. 29.6% positive cells, p < 0.001) was observed with prasugrel versus clopidogrel. All these effects were maintained through 24 hours and during the MD period. In conclusion, prasugrel 60 mg LD and 10 mg MD inhibit several markers of platelet activation and the formation of platelet-monocyte aggregates more effectively than a 600 mg LD and 75 mg MD of clopidogrel. Attenuated platelet aggregation and reduced expression of platelet pro-coagulant and pro-inflammatory markers with prasugrel suggest the potential to reduce cardiovascular events both in the acute setting and in long-term treatment.
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| 10. |
- Chan, Mark Y., et al.
(författare)
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Temporal biomarker profiling reveals longitudinal changes in risk of death or myocardial infarction in Non-ST-segment elevation acute coronary syndrome
- 2017
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 63:7, s. 1214-1226
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There are conflicting data on whether changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) concentrations between time points (delta NT-proBNP and hs-CRP) are associated with a change in prognosis. METHODS: We measured NT-proBNP and hs-CRP at 3 time points in 1665 patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). Cox proportional hazards was applied to the delta between temporal measurements to determine the continuous association with cardiovascular events. Effect estimates for delta NT-proBNP and hs-CRP are presented per 40% increase as the basic unit of temporal change. RESULTS: Median NT-proBNP was 370.0 (25th, 75th percentiles, 130.0, 996.0), 340.0 (135.0, 875.0), and 267.0 (111.0, 684.0) ng/L; and median hs-CRP was 4.6 (1.7, 13.1), 1.9 (0.8, 4.5), and 1.8 (0.8, 4.4) mg/L at baseline, 30 days, and 6 months, respectively. The deltas between baseline and 6 months were the most prognostically informative. Every 40% increase of delta NTproBNP (baseline to 6 months) was associated with a 14% greater risk of cardiovascular death (adjusted hazard ratio (HR) 1.14, 95% CI, 1.03-1.27) and with a 14% greater risk of all-cause death (adjusted HR 1.14, 95% CI, 1.04 -1.26), while every 40% increase of delta hs- CRP (baseline to 6 months) was associated with a 9% greater risk of the composite end point (adjusted HR 1.09, 95% CI, 1.02-1.17) and a 10% greater risk of myocardial infarction (adjusted HR 1.10, 95%, CI 1.00 -1.20). CONCLUSIONS: Temporal changes in NT-proBNP and hs-CRP are quantitatively associated with future cardiovascular events, supporting their role in dynamic risk stratification of NSTEACS.
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| 11. |
- Erlinge, David, et al.
(författare)
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Clopidogrel metaboliser status based on point-of-care CYP2C19 genetic testing in patients with coronary artery disease
- 2014
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 111:5, s. 943-950
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Tidskriftsartikel (refereegranskat)abstract
- We compared results obtained with the Nanosphere Verigene (R) System, a novel point-of-care (POC) genetic test capable of analysing 11, CYP2C19 variants within 3 hours, to an established, validated genotyping method (Affymetrix (TM) DMET+; reference assay) for identifying extensive and reduced metabolisers of clopidogrel. Based on genotyping, patients (N=82) with stable coronary artery disease on clopidogrel 75 mg daily were defined as extensive metabolisers (*1/*1, *1/*17,*17/*17), reduced metabolisers (*1/*2,*1/*8,*2/*2,*2/*3), or of indeterminate metaboliser status (*2/*17). Pharmacokinetic exposure to clopidogrel's active metabolite and pharmacodynamic measures with P2Y12 reaction units (PRU) (VerifyNow (R) P2Y12 assay), and VASP PRI (PRI) were also assessed. There was a 99.9% overall; concordance of marker-level data between the Nanosphere Verigene and DMET+ systems in identifying the CYP2C19 variants and 100% agreement in classifying the patients as extensive (n=59) or reduced metabolisers (n=15). Extensive metabolisers had significantly higher active metabolite exposure than reduced metabolisers (LS means 12.6 ng*h/ml vs 7.7 ng*h/ml; p<0.001). Extensive metabolisers also had lower PRU (LS means 158 vs 212; p=0.003) and VASP PRI (LS means 48% vs 63%, p=0.01) compared to reduced metabolisers. Rates of high on-treatment platelet reactivity were higher in reduced metabolisers compared to extensive metabolisers (VASP PRI >= 50%: 79% vs 47%; PRU >235: 33% vs 16%). The Nanosphere Verigene CBS system identified 11 CYP2C19 alleles in less than 3 hours with a high degree of accuracy when compared to a conventional method, and was further validated against pharmacokinetic and pharmacodynamic phenotypes.
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| 12. |
- Erlinge, David, et al.
(författare)
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Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo
- 2008
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 52:24, s. 1968-77
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We evaluated the prevalence and mechanism of poor responsiveness to clopidogrel and prasugrel in coronary artery disease patients with and without diabetes. BACKGROUND: Low platelet inhibition by clopidogrel is associated with ischemic clinical events. A higher 600-mg loading dose (LD) has been advocated to increase responsiveness to clopidogrel. METHODS: In this study, 110 aspirin-treated patients were randomized to double-blind treatment with clopidogrel 600 mg LD/75 mg maintenance dose (MD) for 28 days or prasugrel 60 mg LD/10 mg MD for 28 days. Pharmacodynamic (PD) response was evaluated by light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The PD poor responsiveness was defined with 4 definitions previously associated with worse clinical outcomes. Active metabolites (AM) of clopidogrel and prasugrel were measured. Clopidogrel AM was added ex vivo. RESULTS: The proportion of patients with poor responsiveness was greater in the clopidogrel group for all definitions at all time points from 1 h to 29 days. Poor responders had significantly lower plasma AM levels compared with responders. Patients with diabetes were over-represented in the poor-responder groups and had significantly lower levels of AM. Platelets of both poor responders and diabetic patients responded fully to AM added ex vivo. CONCLUSIONS: Prasugrel treatment results in significantly fewer PD poor responders compared with clopidogrel after a 600-mg clopidogrel LD and during MD. The mechanism of incomplete platelet inhibition in clopidogrel poor-responder groups and in diabetic patients is lower plasma levels of its AM and not differences in platelet P2Y(12) receptor function.
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| 13. |
- Ernest, C. Steven, et al.
(författare)
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Population pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in aspirin-treated patients with stable coronary artery disease
- 2008
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 35:6, s. 593-618
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the current analysis was to characterize the population PK of prasugrel and clopidogrel metabolites, the resulting PD response, and identification of covariates for key PK/PD parameters. Aspirin-treated subjects with coronary artery disease were randomized to double-blind treatment with clopidogrel 600 mg loading dose (LD) followed by daily 75 mg maintenance dose (MD) or prasugrel 60 mg LD and daily 10 mg MD for 28 days. Plasma concentrations of prasugrel active metabolite (Pras-AM) and prasugrel's inactive thiolactone metabolite (Pras-thiolactone) were simultaneously fit to a multicompartmental model; a similar model adequately described clopidogrel's active metabolite (Clop-AM) PK. By linking to the PK model through the active metabolite concentrations, the PK/PD model characterized the irreversible inhibition of platelet aggregation through a sigmoidal Emax model. Although dose, sex, and weight were identified as significant covariates in the prasugrel PK model, only the effect of body weight produced significant changes in Pras-AM exposure. Generally, these factors resulted in only minor changes in Pras-AM exposures such that, overall, the change in the resulting maximal platelet aggregation (MPA) was predicted to be < or =10% points on average. The clopidogrel PK model included dose as a covariate indicating that a significantly less-than-proportional increase in Clop-AM exposure is expected over the dose range of 75-600 mg, thus, the model-predicted PD response is lower than might be anticipated given an 8-fold difference in dose and lower than that typically achieved following prasugrel 60 mg LD. The greater PD response with prasugrel compared with clopidogrel was accounted for by greater conversion of dose to active metabolite.
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| 14. |
- Hagström, Emil, et al.
(författare)
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Association Between Very Low Levels of High-Density Lipoprotein Cholesterol and Long-term Outcomes of Patients With Acute Coronary Syndrome Treated Without Revascularization : Insights From the TRILOGY ACS Trial
- 2016
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Ingår i: Clinical Cardiology. - : Wiley. - 0160-9289 .- 1932-8737. ; 39:6, s. 329-337
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low levels of high-density lipoprotein cholesterol (HDL-C; < 40 mg/dL) are associated with increased risk of cardiovascular events, but it is unclear whether lower thresholds (< 30 mg/dL) are associated with increased hazard.Hypothesis: Very low levels of HDL-C may provide prognostic information in acute coronary syndrome (ACS) patients treated medically without revascularization.Methods: We examined data from 9064/9326 ACS patients enrolled in the TRILOGY ACS trial. Participants were randomized to clopidogrel or prasugrel plus aspirin. Study treatments continued for 6 to 30 months. Relationships between baseline HDL-C and the composite of cardiovascular death, myocardial infarction (MI), or stroke, and individual endpoints of death (cardiovascular and all-cause), MI, and stroke, adjusted for baseline characteristics through 30 months, were analyzed. The HDL-C was evaluated as a dichotomous variable-very low (< 30 mg/dL) vs higher (>= 30 mg/dL)-and continuously.Results: Median baseline HDL-C was 42mg/dL (interquartile range, 34-49mg/dL) with little variation over time. Frequency of the composite endpoint was similar for very low vs higher baseline HDL-C, with no risk difference between groups (hazard ratio [ HR]: 1.13, 95% confidence interval [ CI]: 0.95-1.34). Similar findings were seen for MI and stroke. However, risks for cardiovascular (HR: 1.42, 95% CI: 1.13-1.78) and all-cause death (HR: 1.36, 95% CI: 1.11-1.67) were higher in patients with very low baseline HDL-C.Conclusions: Medically managed ACS patients with very low baseline HDL-C levels have higher risk of long-term cardiovascular and all-cause death but similar risks for nonfatal ischemic outcomes vs patients with higher baseline HDL-C.
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| 15. |
- Jakubowski, Joseph A., et al.
(författare)
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Prasugrel: A novel thienopyridine antiplatelet agent : A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile
- 2007
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Ingår i: Cardiovascular Drug Reviews. - : Wiley. - 0897-5957 .- 1527-3466. ; 25:4, s. 357-374
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Forskningsöversikt (refereegranskat)abstract
- Prasugrel (CS-747, LY640315) is a novel member of the thienopyridine class of oral antiplatelet agents that includes ticlopidine and clopidogrel. Like other thienopyridines, prasugrel is a prodrug that is inactive in vitro. Prasugrel's distinct chemical structure permits efficient conversion to its active metabolite with a less rigorous dependence on specific cytochrome P-450 enzymes. Prasugrel is rapidly converted in vivo to an active metabolite (R-138727) that binds specifically and irreversibly to the platelet P2Y(12) purinergic receptor inhibiting ADP-mediated platelet activation and aggregation. Preclinical studies indicated that prasugrel is approximately 10- and 100-fold more potent at inhibiting ex vivo platelet aggregation and in vivo thrombus formation than clopidogrel and ticlopidine, respectively. Early clinical data in healthy subjects confirmed the greater platelet inhibition and consistency with prasugrel compared to clopidogrel. While the active metabolites of prasugrel and clopidogrel resulted in similar levels of platelet inhibition in vitro, the amount of each active metabolite generated in vivo was quite different-prasugrel (60 mg) resulting in an approximately 12-fold greater exposure to its active metabolite compared with clopidogrel (300 mg). This observation provides a mechanistic basis for the faster, greater, and more consistent inhibition of platelet aggregation observed with prasugrel. Clinical studies in patients with cardiovascular disease confirmed the potent antiplatelet effect of prasugrel compared with clopidogrel. Collectively, these phase 1/1b studies and a phase 2 study (JUMBO-TIMI 26) aided in dose selection for the recently completed phase 3 trial (TRITON-TIMI 38) in patients with acute coronary syndrome undergoing percutaneous coronary intervention.
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| 16. |
- Jernberg, Tomas, et al.
(författare)
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Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease
- 2006
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 27:10, s. 1166-1173
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: This study was designed to compare the degree of inhibition of platelet aggregation (IPA) of prasugrel with that of clopidogrel in stable aspirin-treated patients with coronary artery disease (CAD). METHODS AND RESULTS: Subjects (n=101) were randomly assigned to the following loading dose (LD) (day 1)/maintenance dose (MD) (days 2-28) combinations: prasugrel, 40 mg/5 mg; 40 mg/7.5 mg; 60 mg/10 mg; 60 mg/15 mg; or clopidogrel, 300 mg/75 mg. Turbidometric platelet aggregation was measured at multiple timepoints during the study. At 4 h after dosing, with 20 microM ADP, both prasugrel LDs achieved significantly higher mean IPA levels (60.6% and 68.4 vs. 30.0%, respectively; all P<0.0001) and lower percentage (3 vs. 52%, P<0.0001) of pharmacodynamic non-responders (defined as IPA <20%) than clopidogrel. Prasugrel 10 and 15 mg MDs achieved consistently higher mean IPA than clopidogrel 75 mg at day 28 (all P<0.0001). At pre-MD on day 28, there were no non-responders in the 10 and 15 mg prasugrel group, compared with 45% in the clopidogrel group (P=0.0007). CONCLUSION: In this population, prasugrel (40-60 mg LD and 10-15 mg MD) achieves greater IPA and a lower proportion of pharmacodynamic non-responders compared with the approved clopidogrel dosing.
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| 17. |
- Varenhorst, Christoph, et al.
(författare)
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Assessment of P2Y(12) inhibition with the point-of-care device VerifyNow P2Y12 in patients treated with prasugrel or clopidogrel coadministered with aspirin
- 2009
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 157:3, s. 562.e1-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Variability in response to thienopyridines has led to the development of point-of-care devices to assess adenosine diphosphate (ADP)-induced platelet aggregation. These tests need to be evaluated in comparison to reference measurements of P2Y(12) function during different thienopyridine treatments. METHODS: After a run-in on 75 mg aspirin, 110 subjects were randomized to double-blind treatment with clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD. Antiplatelet effects were evaluated by VerifyNow P2Y12 (VN-P2Y12) device (Accumetrics, San Diego, CA), vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay, and light transmission aggregometry (LTA). Prasugrel's and clopidogrel's active metabolite concentration were also determined. RESULTS: Dose- and time-dependent inhibition of P2Y(12) was evident with VN-P2Y12. There was strong correlation with VN-P2Y12 and VASP or LTA for all treatments through a wide range of P2Y(12) function. At high levels of P2Y(12) inhibition, platelet function measured by VN-P2Y12 was maximally inhibited and could not reflect further changes seen with VASP or LTA methods. Correlation was also observed between exposure to clopidogrel's active metabolite and VN-P2Y12 during MD and LD, whereas it was observed only with prasugrel MD. CONCLUSION: The VN-P2Y12 correlated strongly with inhibition of P2Y(12) function, as measured with either VASP or LTA. VN-P2Y12 also correlated to exposure to the active metabolite of prasugrel and clopidogrel up to levels associated with assumed saturation of the P2Y(12) receptor.
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| 18. |
- Varenhorst, Christoph, 1977-, et al.
(författare)
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Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease
- 2009
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 30:14, s. 1744-1752
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Tidskriftsartikel (refereegranskat)abstract
- Aims The metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. Methods and results Ninety-eight patients with coronary artery disease (CAD) taking either clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD were genotyped for variation in six CYP genes. Based on CYP genotype, patients were segregated into two groups: normal function (extensive) metabolizers (EM) and reduced function metabolizers (RM). Plasma active metabolite concentrations were measured at 30 min, 1, 2, 4, and 6 h post-LD and during the MD period on Day 2, Day 14, and Day 29 at 30 min, 1, 2, and 4 h. Vasodilator-stimulated phosphoprotein (VASP) and VerifyNow P2Y12 were measured predose, 2, and 24 +/- 4 h post-LD and predose during the MD period on Day 14 +/- 3 and Day 29 +/- 3. For clopidogrel, active metabolite exposure was significantly lower (P = 0.0015) and VASP platelet reactivity index (PRI, %) and VerifyNow P2Y(12) reaction unit (PRU) values were significantly higher (P < 0.05) in the CYP2C19 RM compared with the EM group. For prasugrel, there was no statistically significant difference in active metabolite exposure or pharmacodynamic response between CYP2C19 EM and RM. Variation in the other five genes demonstrated no statistically significant differences in pharmacokinetic or pharmacodynamic responses. Conclusion Variation in the gene encoding CYP2C19 in patients with stable CAD contributes to reduced exposure to clopidogrel's active metabolite and a corresponding reduction in P2Y(12) inhibition, but has no significant influence on the response to prasugrel.
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| 19. |
- Wallentin, Lars, 1943-, et al.
(författare)
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Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease
- 2008
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 29:1, s. 21-30
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: P2Y(12) receptor antagonism and platelet inhibition by prasugrel vs. clopidogrel were investigated in patients with stable coronary artery disease. METHODS AND RESULTS: One hundred and ten aspirin treated subjects were randomized to double-blind treatment with clopidogrel (n = 55) 600 mg loading dose (LD) and 75 mg maintenance dose (MD) or prasugrel (n = 55) 60 mg LD and 10 mg MD for 28 days. Concentrations of prasugrel and clopidogrel active metabolites were determined. Platelet aggregation to 20 microM adenosine diphosphate, measured by light transmission aggregometry, was reported as maximal platelet aggregation (MPA). P2Y(12) function was assessed by the vasodilator-stimulated phosphoprotein assay and reported as platelet reactivity index (PRI). The same pharmacodynamic measurements were performed after ex vivo addition of clopidogrel's active metabolite. At 2 h post-LD, mean MPA was 31 vs. 55%, and mean PRI 8.3 vs. 55.9% for prasugrel and clopidogrel, respectively (P < 0.001). During MD on day 14 and 28, mean MPA was 42 vs. 54% and mean PRI was 25 vs. 51%, respectively (P < 0.001). Peak level of the active metabolite and P2Y(12) inhibition occurred earlier and was greater with prasugrel (P < 0.001). Mean area under the time-concentration curve (AUC; microM.h) of the respective active metabolite was higher with prasugrel vs. clopidogrel post-LD (1.11 vs. 0.24) and post-MD (0.16 vs. 0.062). Ex vivo addition of clopidogrel's active metabolite further reduced PRI in all patients whose platelets were not already maximally inhibited. CONCLUSION: In aspirin-treated subjects with coronary artery disease, prasugrel 60/10 mg provides faster onset and greater inhibition of P2Y(12) receptor-mediated platelet aggregation than clopidogrel 600/75 mg, because of greater and more efficient generation of the active metabolite.
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