Prevalence Of High Platelet Reactivity Research Articles

Implication of diabetic status on platelet reactivity and clinical outcomes after drug-eluting stent implantation: results from the PTRG-DES consortium

BackgroundDiabetes mellitus (DM) is associated with thrombogenicity, clinically manifested with atherothrombotic events after percutaneous cutaneous intervention (PCI). This study aimed to investigate association between DM status and platelet reactivity, and their prognostic implication in PCI-treated patients.MethodsThe Platelet function and genoType-Related long-term Prognosis-Platelet Function Test (PTRG-PFT) cohort was established to determine the linkage of platelet function test (PFT) with long-term prognosis during dual antiplatelet therapy including clopidogrel in patients treated with drug-eluting stent (DES). We assessed platelet reactivity using VerifyNow and ‘high platelet reactivity (HPR)’ was defined as ≥ 252 P2Y12 reaction unit (PRU). Major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, myocardial infarction, stent thrombosis or stroke.ResultsBetween July 2003 and Aug 2018, DES-treated patients with available PFT were enrolled (n = 11,714). Diabetic patients demonstrated significant higher levels of platelet reactivity (DM vs. non-DM: 225.7 ± 77.5 vs. 213.6 ± 79.1 PRU, P < 0.001) and greater prevalence of HPR compared to non-diabetic patients (38.1% vs. 32.0%, P < 0.001). PRU level and prevalence of HPR were significantly associated with insulin requirement and HbA1c level, as well as diabetic status. DM status and HPR phenotype had a similar prognostic implication, which showed the synergistic clinical impact on MACCE. Association between PRU level and MACCE occurrence seemed higher in diabetic vs. non-diabetic patients. In non-DM patients, HPR phenotype did not significantly increase the risk of MACCE (adjusted hazard ratio [HRadj]: 1.073; 95% confidence interval [CI]: 0.869–1.325; P = 0.511), whereas HPR was an independent determinant for MACCE occurrence among diabetic patients (HRadj: 1.507; 95% CI: 1.193–1.902; P < 0.001).ConclusionThe levels of on-clopidogrel platelet reactivity are determined by diabetic status and the severity of DM. In addition, HPR phenotype significantly increases the risk of MACCE only in diabetic patients.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT04734028.

Impact of renal failure and high-platelet reactivity on major cardiovascular ischemic events among patients with acute coronary syndrome receiving dual antiplatelet therapy with ticagrelor.

No study has so far evaluated the impact of chronic kidney disease (CKD) on high-on treatment platelet reactivity (HRPR) with ticagrelor and their prognostic consequences, that were therefore the aim of the present study. Patients on dual antiplatelet therapy with ASA+ticagrelor (90mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30-90 days post-discharge. The primary study endpoint was defined as the occurrence of major cardiovascular events (a composite of cardiovascular death, recurrent acute coronary syndrome (MI), target vessel revascularization) at the longest available follow-up. We included 396 patients, that were divided according to CKD (eGFR <or≥ 60 mL/min). Mean platelet reactivity was comparable irrespective of renal function Prevalence of high platelet reactivity (HRPR) on Ticagrelor was similar among patients with or without CKD (9.7% vs. 11.8%, P=0.84). At a mean follow-up of 939±581.4 days, 21.2% of the patients experienced the primary composite endpoint, with a similar rate of events in patients CKD or normal renal function (22.2% vs. 21.2% HR [95%CI]= 0.92[0.52-1.61], P=0.77), and no difference in survival, ischemic and bleeding endpoints. After correction for baseline differences CKD did not emerge as an independent predictor of either HRPR (adjusted OR [95%CI]=0.47 [0.18;1.25], P=0.13) or MACE (adjusted HR [95%CI]=0.66 [0.34-1.29] P=0.18). In the present study we demonstrated that among ACS patients on DAPT with ASA and ticagrelor after PCI, renal failure is not associated with a higher rate of HRPR or to an increased risk of mortality or major ischemic and bleeding events.

The impact of mild therapeutic hypothermia on platelet reactivity in comatose survivors of cardiac arrest with acute myocardial infarction treated with ticagrelor.

The aim of the study was to assess the antiplatelet effect of ticagrelor in patients with myocardial infarction (MI) after out-of-hospital cardiac arrest (OHCA) treated with percutaneous coronary intervention (PCI) and mild therapeutic hypothermia (MTH) vs. MI patients without OHCA treated with PCI. The study was designed and performed as a phase IV, single-center, investigator-initiated, prospective, observational study assessing the early pharmacodynamic effect (within first 24 h) of a ticagrelor loading dose (180 mg) in both groups of patients (MTH group vs. MI group). For assessment of ticagrelor pharmacodynamics Multiple Electrode Aggregometry (MEA) was applied. Compared with the MTH group, platelet inhibition was persistently stronger in the MI group over the entire observation period (up to 24 h), with the highest differesnce at 4 hours after loading with ticagrelor (25.8 ± 26.4 vs. 75.8 ± 40.9 U, p = 0.002). As a consequence, there was a higher prevalence of high platelet reactivity in the MTH group, with the most explicit difference at 6 hours after the loading dose of ticagrelor (78% vs. 7%, p < 0.001). In comparison with patients treated with primary PCI for uncomplicated MI, the antiplatelet effect of ticagrelor in patients with MI complicated with OHCA, undergoing MTH and primary PCI, is attenuated and delayed.

727 Circadian variations of platelet reactivity on Clopidogrel in patients treated with elective percutaneous coronary intervention

Abstract Aims The potential diurnal variations of platelet reactivity in patients on clopidogrel treated with elective percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD) are currently unknown. Methods and results We prospectively enrolled 15 patients with stable CAD treated PCI and on clopidogrel therapy for at least eight days. All patients received their maintenance 75-mg clopidogrel dose at 8 AM. Platelet reactivity was assessed with the Verifynow P2Y12 assay at three different time points (10 AM, 6 PM, and 6 AM). Platelet reactivity is expressed as P2Y12 reaction units (PRU) and PRU thresholds ≥208 and ≥240 were used to define high platelet reactivity (HPR). A significant heterogeneity in diurnal levels of platelet reactivity was found (P = 0.0004), with a peak occurring at the 6 AM assessment. In addition, at the 6 AM evaluation patients showed the highest prevalence of HPR (53.3% of patients with PRU ≥240, 66.7% of patients with PRU ≥208). Conclusions Platelet reactivity in patients with stable CAD treated with PCI and taking clopidogrel in the morning follows a circadian rhythm, thus suggesting that platelet inhibition may not be constant and sufficient throughout the day. Whether an evening or a bis in die administration of clopidogrel may result in a constant and more reliable antiplatelet inhibition, should be investigated in dedicated studies.

Platelet reactivity and clinical outcomes following percutaneous coronary intervention in complex higher-risk patients.

To investigate the levels of platelet reactivity and the impact of high platelet reactivity (HPR) on long-term clinical outcomes of complex higher-risk and indicated patients (CHIP) with stable coronary artery disease (CAD) treated with elective percutaneous coronary intervention (PCI). We enrolled 500 patients undergoing elective PCI for stable CAD and treated with aspirin and clopidogrel. Patients were divided into four groups based on the presence of CHIP features and HPR. Primary endpoint was the occurrence of major adverse clinical events (MACE) at 5 years. The prevalence of HPR was significantly greater in the CHIP population rather than non-CHIP patients (39.9% vs 29.8%, P = 0.021). Patients with both CHIP features and HPR showed the highest estimates of MACE (22.1%, log-rank P = 0.047). At Cox proportional hazard analysis, the combination of CHIP features and HPR was an independent predictor of MACE (hazard ratio 2.57, 95% confidence interval 1.30-5.05, P = 0.006). Among patients with stable CAD undergoing elective PCI and treated with aspirin and clopidogrel, the combination of CHIP features and HPR identifies a cohort of patients with the highest risk of MACE at 5 years, who might benefit from more potent antiplatelet strategies.

Impact of smoking habit on platelet reactivity in a cohort of patients admitted due to an acute coronary syndrome

Abstract Background Several pharmacodynamic studies have shown the impact of smoking habit on platelet reactivity; with a reduction on platelet aggregation. Wether this inhibition in platelet reactivity is due to tobacco effects in platelet signaling pathways or due to a pharmacodynamic interaction with antiplatelet therapies is not well stablished. Purpose Our aim was to study the influence of smoking habit in platelet reactivity and in the response to P2Y12 inhibitors. Methods Patients admitted in four tertiary care hospitals due to an acute coronary syndrome that undergone percutaneous coronary intervention (PCI) were consecutively and prospectively recruited. All the patients received dual antiplatelet therapy with aspirin and a P2Y12 inhibitor following current European Guidelines. Platelet function was assessed at day 1 and day 30 post-PCI by VerifyNow P2Y12, VASP (Vasodilator-stimulated phosphoprotein) y MEA (Multiple electrode aggregometry). Results A total of 1000 patients were enrolled, of whom 12 had to be excluded due to inaccurate processing of blood samples. 372 patients (37,6%) had smoking habit. Non-smoking patients showed higher prevalence of high blood pressure [423 (68.7%) vs 196 (52.7%)] and diabetes mellitus [213 (34.6%) vs 81 (21.8%)]. Smoking patients were younger [57.3 (9,6) years old vs 68.4 (11.1)], with higher incidence of acute coronary syndrome with ST segment elevation [184 patients (49,5%) vs 241 (39.1%), p&amp;lt;0,001]. There were no differences in platelet function at day 1. When analysing platelet function 30 days post-PCI, a lower inhibition of platelet reactivity in non-smoking patients as compared with smoking patients was observed in those treated with clopidogrel, with higher prevalence of clopidogrel-resistance in non-smoking patients (VerifyNow, 51,2% prevalence of high platelet reactivity in non-smoking patients vs 34,9% 30 days after PCI, p=0,023). On the other hand, smoking patients that received ticagrelor did not show any differences. Patients with smoking habit treated with prasugrel showed a lower response of borderline statistical significance. Conclusion Smoking habit was associated with a lower response to prasugrel of borderline significance, and with higher response to clopidogrel, according with previous studies suggesting a pharmacodynamics interaction between tobacco use and P2Y12 inhibitors. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Fondo de Investigaciones Sanitarias (FIS)

A Multicenter, Randomized, Double-Blind, and Placebo-Controlled Study of the Effects of Tongxinluo Capsules in Acute Coronary Syndrome Patients with High On-Treatment Platelet Reactivity.

Background:High platelet reactivity (HPR) during clopidogrel treatment predicts postpercutaneous coronary intervention (PCI) ischemic events strongly and independently. Tongxinluo capsules (TCs) are a traditional Chinese medicine formulation used as antiplatelet treatment. However, its efficacy against HPR is not known. The aim of the present study was to evaluate the effects of TCs in acute coronary syndrome (ACS) patients with HPR.Methods:This multicenter, randomized, double-blind, placebo-controlled study prospectively analyzed 136 ACS patients with HPR who underwent PCI. The patients were enrolled from November 2013 to May 2014 and randomized to receive placebo or TCs in addition to standard dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. The primary end points were the prevalence of HPR at 30 days and the mean change in P2Y12 reaction units (PRUs) between baseline and 30 days. Survival curves were constructed with Kaplan-Meier estimates and compared by log-rank tests between the two groups.Results:Both groups had a significantly reduced prevalence of HPR at 30 days versus baseline, but the TC group, compared with the placebo group, had greater reduction (15.8% vs. 24.8%, P = 0.013), especially among patients with one cytochrome P450 2C19 loss of function (LOF) allele (χ2= 2.931, P = 0.047). The TC group also had a lower prevalence of HPR (33.3% vs. 54.2%, t = 5.284, P = 0.022) and superior performance in light transmittance aggregometry and higher levels of high-sensitivity C-reactive protein (hsCRP), but the composite prevalence of ischemic events did not differ significantly (χ2= 1.587, P = 0.208).Conclusions:In addition to standard DAPT with aspirin and clopidogrel, TCs further reduce PRU and hsCRP levels, especially in patients carrying only one LOF allele. The data suggest that TCs could be used in combination therapy for ACS patients with HPR undergoing PCI.

Abstract 19153: Morphine Delays and Attenuates Ticagrelor Exposure and Action in Patients With Myocardial Infarction: The Randomized, Double-blind, Placebo-controlled Impression Trial

Introduction: The currently available data from observational studies and a randomized trial on clopidogrel conducted in healthy volunteers suggest existence of drug-drug interactions between morphine and oral P2Y12 inhibitors, when administered together. Hypothesis: We aimed to test the hypothesis that morfine administered intravenously excerts the negative impact on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with myocardial infarction. Methods: In a single center, randomized, double-blind trial, participants were assigned in a 1:1 ratio to receive intravenously either morphine (5 mg) or placebo, followed by a 180 mg loading dose of ticagrelor. Pharmacokinetics was determined with liquid chromatography tandem mass spectrometry, while ticagrelor antiplatelet effect was measured with up to 3 different platelet function tests: vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay, multiple electrode aggregometry and VerifyNow P2Y12. Results: The pharmacokinetic and pharmacodynamic assessment was performed in 70 patients (35 in each study group). Morphine administration lowered the total exposure to ticagrelor and its active metabolite by 35.6% (AUC(0-12): 6307 vs. 9791 ng·h/mL; p=0.003) and 37.1% (AUC(0-12): 1503 vs. 2388 ng·h/mL; p=0.008), respectively, with a concomitant delay in maximal plasma concentration of ticagrelor (4 vs. 2 h; p=0.002) and AR-C124910XX (6 vs. 4 h; p=0.03) in morphine-treated patients. Multiple regression analysis showed that lower AUC(0-12) values for ticagrelor were associated with morphine administration (p=0.003) and the presence of ST-segment elevation myocardial infarction (p=0.010). All three methods of platelet reactivity assessment consistently showed a stronger antiplatelet effect of ticagrelor in the placebo group as reflected by a higher prevalence of high platelet reactivity in patients receiving morphine. Conclusions: Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction.

Prevalence and impact of high platelet reactivity in chronic kidney disease: results from the Assessment of Dual Antiplatelet Therapy with Drug-Eluting Stents registry.

Chronic kidney disease (CKD) is associated with increased rates of adverse events after percutaneous coronary intervention. We sought to determine the impact of CKD on platelet reactivity in clopidogrel-treated patients and whether high platelet reactivity (HPR) confers a similar or differential risk for adverse events among patients with CKD and non-CKD. We performed a post hoc analysis of the Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) registry, which included 8582 patients undergoing percutaneous coronary intervention with drug-eluting stents and platelet function testing using the VerifyNow assay. We compared HPR and its impact on ischemic and bleeding events >2 years among patients with CKD and non-CKD. Patients with CKD (n=1367) were older, more often female, diabetic, and had lower ejection fraction compared with their non-CKD counterparts (n=7043). Although HPR prevalence increased with worsening renal function in unadjusted analyses, these associations were no longer present after adjustment. Major adverse cardiac event rates at 2 years among those without CKD or HPR, HPR alone, CKD alone, and both CKD and HPR were 9.0%, 11.2%, 13.3%, and 17.5%, respectively (P<0.001). Associations between HPR and adverse events were uniform across CKD strata without evidence of interaction. HPR is more common among those with versus without CKD, an association that is attributable to confounding risk factors that are more prevalent in CKD. The impact of HPR on ischemic and bleeding events is similar irrespective of CKD status. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794.

Gender and Anti-thrombotic Therapy: from Biology to Clinical Implications

Cardiovascular diseases actually remain the leading cause of death and morbidity in Western countries, and it is the most common cause of death in American women accounting for about one third of all deaths. Women remain underrepresented in published trial literature relative to their disease prevalence. Strong evidence do exists demonstrating gender differences in efficacy (ischemic risk) and safety (bleeding risk) associated with antithrombotic treatment, mostly related to different values of body mass, and renal function in women than men. Several data show a higher platelet reactivity in females and a higher prevalence of high platelet reactivity on aspirin and clopidogrel therapy. In primary prevention, the use of aspirin is associated with a higher reduction of risk for ischemic stroke in females and for myocardial infarction in males. In the setting of ACS, female gender is associated with a significantly higher risk of bleeding. In summary, there are some gender-related aspects of guidance in the complex spectrum of the net clinical benefit related to antithrombotic treatment.

Decrease in high on-treatment platelet reactivity (HPR) prevalence on switching from clopidogrel to prasugrel: Insights from the switching anti-platelet (SWAP) study

The prevalence of high platelet reactivity (HPR) in patients who have switched from clopidogrel to prasugrel during maintenance phase after an acute coronary syndrome (ACS) event is unknown. Therefore, the effect of switching from clopidogrel to prasugrel on the prevalence of HPR was evaluated. This analysis from the previously reported SWAP (SWitching Anti Platelet) study assessed HPR at baseline, 2 and 24 hours, and seven days after switching from clopidogrel to prasugrel maintenance dose (MD), with or without a prasugrel loading dose (LD) using four definitions: maximum platelet aggregation (MPA) >65% (primary endpoint), MPA >50%, P2Y12 reaction units (PRU) >235, and platelet reactivity index (PRI) ≥ 50%. A total of 95 patients were available for analysis; 56 patients provided DNA for genetic assessments of cytochrome P450 (CYP) 2C19. There were 26 (27.4%) patients with HPR at the end of the clopidogrel run-in (defined as MPA >65%). The HPR prevalence varied by each definition and ranged from 19% (PRU >235) to 68% (PRI ≥ 50 %). A significantly higher HPR prevalence was observed during clopidogrel versus the combined prasugrel therapy groups at seven days as measured by MPA >65% (21.2% vs. 4.5%, p<0.05), PRU >235 (18.8% vs. 0%, p=0.001), and PRI ≥ 50 % (66.7% vs. 7.9%, p<0.0001). There was a significantly higher percentage of subjects carrying at least one reduced function allele with HPR measured by MPA >65% (p=0.02) or PRU >235 (p=0.05) than non-carriers with HPR. Switching ACS patients during maintenance clopidogrel therapy to prasugrel with or without an LD is associated with a reduced HPR prevalence and may provide an alternative strategy to treat patients with HPR, independent of CYP2C19 genotype.

Do statins influence platelet reactivity on acetylsalicylic acid therapy in patients with type 2 diabetes?

Type 2 diabetes (T2DM) patients are at increased risk of cardiovascular events despite long-term acetylsalicylic acid (ASA) therapy. This study was performed to establish the prevalence of high platelet reactivity (HPR) on ASA in T2DM and to identify its predictors. The study included 185 T2DM on chronic ASA therapy and to assess platelet reactivity during long-term ASA therapy, we applied the point-of-care method VerifyNow(®) aspirin test (Accumetrics, San Diego, CA, USA). Compared with the low platelet reactivity (LPR) group, patients with HPR had higher triglyceride levels (145 vs. 118 mg/dL, p = 0.041), were less frequently treated with statins (57.1% vs. 75.3%; p = 0.038) and tumor necrosis factor-alpha (TNF-α) concentrations were higher (2.15 vs. 1.74 pg/mL; p = 0.052). In a multivariate analysis only statin therapy (OR 0.375; 95% CI 0.15-0.91; P = 0.030) and lower concentrations of TNF-α (for each 1.0 pg/ml: or 1.3; 95% ci 1.00-1.72; p = 0.046) were predictive of LPR. Our study provides indirect evidence that the beneficial effect of statins on platelet activity may be related to their non-lipid-mediated, pleiotropic mechanisms of action. This might have been partly related to decreased platelet reactivity in patients receiving statin therapy. In our study in patients with T2DM, platelet reactivity on ASA therapy measured with VerifyNow(®) was associated with TNF-α concentrations and statin therapy. These results may imply a role for subclinical systemic inflammation and a beneficial effect of statins in the development of HPR in T2DM.

The gain‐of‐function variant allele CYP2C19*17: a double‐edged sword between thrombosis and bleeding in clopidogrel‐treated patients

A large number of clinical studies have documented that a loss-of-function variant CYP2C19*2 affects clinical profiles of clopidogrel (efficacy and safety). However, data on the impact of a gain-of-function variant CYP2C19*17 on the response to that drug seem to be less consistent. To systematically summarize all available clinical data assessing the role of the CYP2C19*17 variant in patients taking clopidogrel. A literature search was conducted and a meta-analysis was performed for 11 eligible studies. The endpoints included the major adverse cardiovascular events (MACE, representing non-fatal myocardial infarction, stroke, revascularization, or death), bleeding events, mortality, stent thrombosis and high platelet reactivity (HPR). Data from six clinical studies demonstrated that carriers of the CYP2C19*17 variant had a marked protection against recurrent cardiovascular events in patients with coronary artery disease compared with non-carriers, as measured by a 16% decrease in the incidence of MACE (10.0% vs. 11.9%; OR, 0.82; 95% CI, 0.72-0.94; P = 0.005). On the other hand, carriers had an increased risk of developing bleeding as expected (8.0% vs. 6.5%; OR, 1.25; 95% CI, 1.07-1.47; P = 0.006; four studies). Moreover, the presence of the CYP2C19*17 variant might lead to increased response to clopidogrel, as shown by a marked lower prevalence of HPR in carriers than in non-carriers (37.9% vs. 50.8%; OR, 0.60; 95% CI, 0.45-0.79; P = 0.0003; three studies). Carriers of the CYP2C19*17 variant have greater therapeutic responsiveness to clopidogrel than non-carriers, but they have an increased risk of developing bleeding as well.

Inter-patient variability and impact of proton pump inhibitors on platelet reactivity after prasugrel

Although there is considerable variability of platelet reactivity among patients treated with clopidogrel, little is known about inter-individual differences and possible role of proton pump inhibitors (PPIs) after prasugrel. We defined the extent of inter-patient variability, and evaluated the impact of PPI interaction in prasugrel-treated patients with acute coronary syndrome (ACS). Between January 2010 and May 2011, 104 prospective, high-risk patients with ACS were recruited into this multicentre, prospective, observational study. Twelve to 24 hours after receiving 60 mg loading dose of prasugrel, light transmission aggregometry (LTA) and whole blood impedance aggregometry (Multiplate) were used to assess platelet activity. Platelet function measurements were repeated during maintenance phase on reduced (5 mg) or on conventional (10 mg) doses of prasugrel. High platelet reactivity (HPR) was defined according to the consensus document of the Working Group on High On-Treatment Platelet Reactivity (LTA:>46%; Multiplate:>47U). Compared to maintenance doses, 60 mg loading dose of prasugrel provided significantly greater platelet reactivity inhibition (p<0.05). There were no significant differences between the conventional and reduced maintenance doses. Notably, a remarkable inter-patient variability was present in platelet reactivity after all doses of prasugrel, and the prevalence of HPR was significantly higher during the maintenance doses (p<0.05). Although median platelet reactivity values were consistently higher when prasugrel was used in combination with PPIs, these differences were not significant (p≥0.17). Despite potent platelet inhibition, inter-patient variability is present after all tested doses of prasugrel. The 60 mg loading dose is superior to conventional and reduced maintenance doses in terms of platelet reactivity inhibition and regarding the prevention of HPR.

The relation between CYP2C19 genotype and phenotype in stented patients on maintenance dual antiplatelet therapy

Both high platelet reactivity (HPR) and CYP2C19 genotyping have been proposed to stratify cardiovascular event risk and to personalize maintenance dual antiplatelet therapy (DAPT) in stented patients. However, how well CYP2C19 genotype correlates with HPR in patients on maintenance DAPT is less clear. We determined the association of CYP2C19 loss-of-function (*2) and gain-of-function (*17) allele status with platelet reactivity in 118 stented patients on DAPT ≥2 weeks and in 143 patients with stable coronary artery disease on aspirin therapy alone. Thirty-three percent and 39% carried at least 1 copy of *2 and *17 alleles, respectively. Neither allele was associated with platelet reactivity in patients on aspirin therapy alone. On DAPT, platelet aggregation was higher in those with *2 allele than noncarriers (P ≤ .01) but did not differ between those with the *17 allele and noncarriers. The prevalence of HPR using the 20 μM adenosine diphosphate-induced aggregation cutpoint was 34% in the total population: 26% in *1/*1 homozygotes, 49% in those with the *2 allele, and 20% in those with the *17 allele (P = .006). Determination of diplotype status enhanced identification of HPR. However, platelet function on DAPT is highly variable within diplotype groups. Therefore, CYP2C19 genotype and HPR are imperfect correlates of each other. Because both predict cardiovascular events with similar risk ratios, CYP2C19 genotyping and HPR may provide complementary information to stratify risk and personalized DAPT in stented patients than either alone.

Platelet function profiles in the elderly: Results of a pharmacodynamic study in patients on clopidogrel therapy and effects of switching to prasugrel 5 mg in patients with high platelet reactivity

Studies specifically designed to assess clopidogrel response in the elderly as well as treatment alternatives to improve platelet inhibition in this high-risk population are lacking. This study aimed to define pharmacodynamic (PD) profiles, including high platelet reactivity (HPR) rates, among elderly patients on maintenance clopidogrel therapy and to assess the PD effects of prasugrel 5 mg/day in elderly with HPR. This was a prospective observational PD study enrolling consecutive ≥ 75-year-old patients on maintenance clopidogrel therapy (75 mg/day) who were tested for clopidogrel response by the VerifyNow P2Y12 assay and light transmittance aggregometry (LTA). HPR rates were estimated using multiple definitions. HPR patients identified by the VerifyNow P2Y12 assay [P2Y12 reaction unit (PRU) ≥ 230] were switched to prasugrel 5 mg/day, and platelet function testing was performed after 15 days of treatment. PD testing was completed in 100 patients. The HPR prevalence varied between 25% and 32%, depending on the definition used. A PRU ≥ 230 was observed in 25 patients; of these, 20 switched to prasugrel 5 mg/day. This resulted in significant reduction in PRU mean values (279.8 ± 45.1 vs. 171.7 ± 65.2, p=0.0002) with an absolute between-treatment difference of 108.1 (95% confidence intervals 75.2-140.9). Accordingly, switching to prasugrel 5 mg/day overcame HPR in most (80%) patients. Consistently, all LTA measures were significantly lower after prasugrel compared with clopidogrel. In conclusion, a considerable proportion of elderly patients exhibit HPR while on standard clopidogrel therapy. Switching to 5 mg/day prasugrel in elderly patients with HPR is associated with enhanced platelet inhibition and overcomes HPR in the majority of these patients.

Antiplatelet effect of once- or twice-daily aspirin dosage in stable coronary artery disease patients with diabetes

The aim of this pilot study was to compare the effect of two different regimens of aspirin dosage on platelet of coronary artery disease (CAD) diabetic patients. Twenty-five CAD diabetic patients were included. Initially, all patients received aspirin 100 mg/day for 10 days. At day 10, aspirin antiplatelet effect was determined by measuring the collagen/epinephrine closure time (CT) 2 h after the last aspirin dosage and the next morning at 8 a.m.. The aspirin regimen was modified to 100 mg twice daily for patients showing a non-optimal platelet-inhibitory effect (CT < 298 s at 8 a.m.). Persistent high platelet reactivity (HPR) was defined by a CT < 160 s. During the 100 mg/day aspirin regimen, the prevalence of HPR at 8 a.m. was 48%, and only 7 patients (28%) had showed an optimal platelet-inhibitory effect. Bridging to the twice-daily regimen, the HPR was significantly reduced (p=0.025), and the optimal platelet-inhibitory effect was reached for 3 other patients. Our results showed that 100 mg aspirin twice-daily dosing rather than a once-daily dose significantly improves the aspirin effect on platelet of CAD diabetic patients. However, large prospective studies were needed to confirm whether this strategy will be clinically relevant and safe.

The relation between platelet reactivity and glycemic control in diabetic patients with cardiovascular disease on maintenance aspirin and clopidogrel therapy

High platelet reactivity (HPR) during aspirin and clopidogrel therapy in patients with diabetes has been reported and may affect outcomes. However, the relation of platelet reactivity to glycemic control is less studied in patients on dual antiplatelet therapy. Platelet aggregation (PA) in response to 5 and 20 micromol/L adenosine diphosphate (ADP) was compared in type 2 diabetic (n = 36) and nondiabetic patients (n = 35) undergoing elective stenting on aspirin and clopidogrel maintenance therapy. The relation of glycosylated hemoglobin (HbA(1c)) <7 g/dL (n = 16) and HbA(1c) > or =7 g/dL (n = 20) on PA was examined. High platelet reactivity was defined as >46% for 5 micromol/L ADP-induced and >59% for 20 micromol/L ADP-induced PA. Diabetic patients had higher 5 and 20 micromol/L ADP-induced PA than nondiabetic patients (45 +/- 17 vs 33 +/- 12, P = .009 and 52 +/- 19 vs 40 +/- 12, P = .004, respectively). Diabetic patients with HbA(1c) > or =7.0 g/dL had significantly higher 5 and 20 micromol/L ADP-induced PA versus patients with diabetes with HbA(1c) <7.0 g/dL (54 +/- 15 vs 34 +/- 14, P < .001 and 62 +/- 14 vs 40 +/- 17, P < .001, respectively). Among diabetic patients with HbA(1c) > or =7 g/dL, the prevalence of HPR was 65% and 60%; and among diabetic patients with HbA(1c) <7 g/dL, the prevalence of HPR was 19% and 13% as measured by 5 and 20 micromol/L ADP-induced PA, respectively. A correlation was present between 5 and 20 micromol/L ADP-induced PA and HbA(1c) (r = 0.60 and 0.62, P = .0001, respectively). An important relation exists between glycemic control and platelet reactivity in patients with type 2 diabetes mellitus treated with dual antiplatelet therapy. Poorly controlled patients with diabetes have the greatest platelet reactivity and may require alternative antiplatelet strategies, and further clinical investigations are warranted.