Predictors of Heightened Platelet Reactivity Despite Dual-Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention
ABSTRACT Small studies have indicated that drug-drug interactions and such clinical characteristics as diabetes mellitus may increase residual platelet reactivity in patients on clopidogrel therapy. The independent contribution of these variables to high residual platelet reactivity (HRPR) is not well studied. Residual platelet reactivity was assessed using the VerifyNow P2Y12 assay (Accumetrics Inc., San Diego, California) in 377 patients with stable coronary artery disease on maintenance clopidogrel therapy. HRPR was defined using a threshold previously shown to predict adverse clinical outcomes. Residual platelet reactivity was significantly higher in women (220 +/- 82 vs 200 +/- 77 P2Y12 reaction units [PRU]; p = 0.041), non-Caucasians (229 +/- 79 vs 202 +/- 78 PRU; p = 0.047), patients with diabetes mellitus (220 +/- 73 vs 196 +/- 80 PRU; p = 0.005), and those treated with nitrates (233 +/- 70 vs 200 +/- 80 PRU; p = 0.018) or proton-pump inhibitors (218 +/- 79 vs 198 +/- 78 PRU; p = 0.02), whereas residual platelet reactivity was significantly lower in active smokers (168 +/- 82 vs 208 +/- 77 PRU; p = 0.006). Independent predictors of HRPR were female gender (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.14 to 3.19, p = 0.014), non-Caucasian ethnicity (OR 3.05, 95% CI 1.49 to 6.28, p = 0.002), use of proton-pump inhibitors (OR 1.64, 95% CI 1.03 to 2.59, p = 0.035), and active smoking (OR 0.37, 95% CI 0.14 to 0.94, p = 0.037). HRPR was associated with increased 6-month mortality rates (3.0% vs 0%; p = 0.016). In conclusion, our findings support the hypothesis that clopidogrel nonresponsiveness is primarily the result of genetic mechanisms and factors that may influence activity of the cytochrome P-450 system.
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ABSTRACT: High on-treatment platelet reactivity (HPR) has been identified as an independent risk factor for ischaemic events. The randomised, double-blind, TRIPLET trial included a pre-defined comparison of HPR in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) following a placebo/600-mg clopidogrel loading dose (LD) immediately before a subsequent prasugrel 60-mg or 30-mg LD. Platelet reactivity was assessed using the VerifyNow® P2Y12 assay (P2Y12 Reaction Units, PRU) within 24 hours (h) following the placebo/clopidogrel LD (immediately prior to prasugrel LD), and at 2, 6, 24, 72 h following prasugrel LDs. The impact of CYP2C19 predicted metaboliser phenotype (extensive metabolizers [EM] and reduced metabolisers [RM]) on HPR status was also assessed. HPR (PRU ≥240) following the clopidogrel LD (prior to the prasugrel LD) was 58.5% in the combined clopidogrel LD groups. No significant difference was noted when stratified by time between the clopidogrel and prasugrel LDs (≤6 hs vs>6 h). At 6 h following the 2nd loading dose in the combined prasugrel LD groups, HPR was 7.1%, with 0% HPR by 72 h. There was no significant effect of CYP2C19 genotype on pharmacodynamic (PD) response following either prasugrel LD treatments at any time point, regardless of whether it was preceded by a clopidogrel 600-mg LD. In conclusion, in this study, patients with ACS intended for PCI showed a high prevalence of HPR after clopidogrel 600-mg LD regardless of metaboliser status. When prasugrel LD was added, HPR decreased substantially by 6 h, and was not seen by 72 h.Thrombosis and Haemostasis 04/2014; 112(2). DOI:10.1160/TH13-09-0747 · 5.76 Impact Factor
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ABSTRACT: Introduction: Antiplatelet effects of clopidogrel appear to be affected by various factors including genetic polymorphism. So far, there has been little information about the response of clopidogrel in Asians, whose prevalence of a CYP2C19 loss-of-function (LOF) allele is high. Methods and Results: We investigated background and clinical factors affecting on-clopidogrel platelet reactivity in Japanese patients undergoing coronary stent implantation (n = 114). In univariate analysis, antiplatelet effects of clopidogrel in a steady state were associated with not only CYP2C19 genotypes but also several factors including dyslipidemia. In addition, we developed an algorithm that can estimate P2Y12 Reaction Units (PRU) in a steady state by multiple regression analysis and evaluated the adequacy of the algorithm by the Akaike Information Criterion. Conclusions: We revealed several factors influencing on-clopidogrel platelet reactivity in Japanese patients. We also succeeded in developing an algorithm that estimates PRU in a steady state, although it is uncertain whether the algorithm can be applied to other populations.Thrombosis Research 08/2014; 134(4). DOI:10.1016/j.thromres.2014.07.018 · 2.43 Impact Factor
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ABSTRACT: High on-treatment platelet reactivity (HTPR) on clopidogrel correlates with adverse outcomes in patients treated with percutaneous coronary intervention (PCI). Whether HTPR is a modifiable risk factor for future events is not clear. We evaluated the effect of serial clopidogrel dose adjustment based on platelet function testing (PFT) during 12 months of dual antiplatelet therapy (DAPT) using Multiplate(®) analyzer in patients with HTPR after PCI in acute coronary syndrome on clinical outcome. Eighty-seven patients were randomized to interventional (n = 43) and control group (n = 44). Blood samples for PFT were drawn at day 1, 2, 3, 7, 30 and at month 2, 3, 6, 9 and 12. Clopidogrel dose was modified at each point of PFT in the interventional group with patients taking up to two additional 600 mg loading doses and a range of 75-300 mg maintenance dose to achieve and maintain optimal platelet reactivity (19-46 U). The incidence of the primary endpoint (composite of cardiovascular death, non-fatal myocardial infarction, target vessel revascularization and ischemic stroke) was significantly higher in the control group (36.3 vs 16.2 %; p = 0.034). There were no differences in total bleeding events (6.8 vs 4.6 %, p = ns). Patients in the interventional group maintained better P2Y12 inhibition during follow-up. We hypothesize that targeting the therapeutic window of platelet reactivity continuously throughout DAPT by dose adjustment of P2Y12 inhibitor may lead to better platelet reactivity control, and thus reduce the rate of ischemic complications in this high risk group of patients.Journal of Thrombosis and Thrombolysis 05/2014; DOI:10.1007/s11239-014-1087-0 · 1.99 Impact Factor