VerifyNow System Research Articles

Early detection of resistance to dual antiplatelet therapy in patients who have undergone percutaneous coronary intervention using the VerifyNow test and associated factors.

Resistance to dual antiplatelet therapy (DAPT), including aspirin and clopidogrel, in patients who have undergone percutaneous coronary intervention (PCI) leads to the inability to prevent thrombotic complications. The present study aimed to evaluate early resistance to aspirin and clopidogrel in patients following PCI using the VerifyNow test and associated factors. A total of 50 patients diagnosed with acute coronary syndromes (ACS) who underwent emergency PCI and received DAPT were recruited in the present study. The detection of resistance to aspirin and clopidogrel was performed using the VerifyNow system. Resistance to aspirin was determined with VerifyNow Aspirin >550 aspirin reaction units (ARU). Resistance to clopidogrel was determined with VerifyNow P2Y12 >208 P2Y12 reaction units (PRU). The resistance rate to aspirin was 14%, while the resistance rate to clopidogrel was higher, at 34%. There were 2 patients with resistance to aspirin and clopidogrel (4%). Univariable logistic regression analysis revealed that diabetes, the use of β-blockers, and low levels of hemoglobin and hematocrit were associated with resistance to clopidogrel. Following multivariable logistic regression analysis, only the use of β-blockers was truly associated with resistance to clopidogrel. On the whole, the results of the present study may also prove to be helpful in the selection of therapeutic drugs for patients undergoing PCI and who are diagnosed with ACS.

Clinical impact of high platelet reactivity in patients with atrial fibrillation and concomitant percutaneous coronary intervention on dual or triple antithrombotic therapy

Abstract Background High platelet reactivity (HPR) on clopidogrel is an established thrombotic risk factor after percutaneous coronary intervention (PCI). The introduction of more potent antiplatelet drugs has partially surpassed this issue. However, in the setting of concomitant atrial fibrillation (AF) and PCI clopidogrel is still the most adopted P2Y12 inhibitor. Purpose We sought to evaluate the possible clinical relevance of genetic and platelet function testing (PFT) in a real-world population with concomitant AF and PCI on dual (DAT) or triple (TAT) antithrombotic therapy. Methods All consecutive patients with history of AF discharged from our cardiology ward with DAT or TAT after a PCI from April 2018 to March 2021 were enrolled in an observational registry. For all subjects, blood serum samples were collected and tested for platelet reactivity by arachidonic acid and ADP (VerifyNow system) and genotyping of the CYP2C19*2 loss-of-function polymorphism. We recorded at 3 and 12-months follow-up: (1) major adverse cardiac and cerebrovascular events (MACCE), (2) major hemorrhagic or clinically relevant non-major bleeding and (3) all-cause mortality. Results A total of 147 patients were included (91, 62% on TAT). In 93.4% of patients, clopidogrel was chosen as P2Y12 inhibitor. P2Y12 dependent HPR resulted an independent predictor of MACCE both at 3 and 12 months (HR 2.93, 95% C.I. 1.03 to 7.56, p=0.027 and HR 1.67, 95% C.I. 1.20 to 2.34, p=0.003, respectively). At 3-months follow-up the presence of CYP2C19*2 polymorphism was independently associated with MACCE (HR 5.21, 95% C.I. 1.03 to 26.28, p=0.045). Conclusions In a real-world unselected population on TAT or DAT, the entity of platelet inhibition on P2Y12 inhibitor is a potent predictor of thrombotic risk, suggesting the clinical utility of this laboratory evaluation for a tailored antithrombotic therapy in this high-risk clinical scenario.

Clopidogrel-Related High Residual Platelet Reactivity Associated with Estimated Glomerular Filtration Rate in Patients with Acute Ischemic Stroke

Introduction: There are few studies on the relationship between the occurrence of clopidogrel-related high residual platelet reactivity (HRPR) and estimated glomerular filtration rate (eGFR) at admission in patients with ischemic stroke. The aim of this study was to investigate the possible relationship between the two. Methods: Patients who were hospitalized and diagnosed with acute ischemic stroke were recruited from July 1, 2017, to June 30, 2018, at Shanghai TCM-Integrated Hospital. Renal function was measured within 24 h of enrollment and eGFR was calculated. Patients were tested for platelet reactivity using the VerifyNow system after 7 days of antiplatelet therapy with clopidogrel 75 mg/d alone, and patients with P2Y12 reaction unit values ≥230 were diagnosed with HRPR. The association between HRPR and eGFR was analyzed. Results: A total of 274 patients were enrolled in the study, of whom 91 (33.21%) had HRPR. Multivariate logistic regression analysis suggested that an increased risk of HRPR was independently associated with female sex and reduced eGFR (female sex: OR = 2.24, 95% CI: 1.26–3.99, p = 0.006; mild chronic kidney disease [CKD]: OR = 2.95, 95% CI: 1.47–5.93, p = 0.002; moderate CKD: OR = 3.07, 95% CI: 1.08–8.75, p = 0.04). Conclusion: Decreased eGFR is an independent risk factor for the occurrence of HRPR in patients with ischemic stroke.

Impact of renal function on Ticagrelor-induced antiplatelet effects in coronary artery disease patients.

Chronic renal failure (CKD) is associated with the presence of increased platelet reactivity and lower clinical benefit of clopidogrel. Ticagrelor has a more favorable pharmacodynamic and pharmacokinetic profile compared to clopidogrel, which has translated into better clinical outcomes in patients with acute coronary syndrome (ACS). We conducted a prospective mechanistic cohort study in order to investigate the impact of renal failure on the pharmacokinetics and pharmacodynamics of ticagrelor in patients with acute ACS. Patients were divided into two groups based on their estimated renal clearances (eGFR≥60mL/min and eGFR<60mL/min). Platelet function was determined using the VerifyNow system at baseline, after the ticagrelor loading dose and at discharge. In addition, levels of ticagrelor and its active metabolite (AR-C124910XX) were determined in the first hour after loading dose. 48 patients were recruited (eGFR≥60mL/min: 35 and eGFR<60mL/min: 13). There were no significant differences between the groups in terms of platelet inhibition after the loading or after 7days of treatment (p=0.219). However, the levels of ticagrelor and its active metabolite were lower in subjects with normal renal function than in CKD, especially at 4 (p=0.02 and 0.04 respectively) and 6h of loading (p=0.042 and 0.08 respectively). No differences in platelet inhibition were observed after treatment with ticagrelor in patients with different renal function, although patients with renal impairment showed higher levels of ticagrelor and AR-C124910XX after 4h of the loading dose.

Baseline P2Y12 reactivity, kidney function, and CYP2C19 genotype determine clopidogrel responsiveness in acute stroke

Clopidogrel is the most-widely used platelet P2Y12-inhibitor for secondary-prevention of ischemic stroke. Platelet P2Y12 reactivity before and after inhibitors can be measured with blood sampling by commercialized system. We aimed to evaluate (1) whether high-on-clopidogrel platelet P2Y12 reactivity (HCPR) is associated with short-term vascular events and (2) the predictors of HCPR in acute stroke. The inclusion criterion was patients with acute stroke who received clopidogrel within 12–48 h after the onset. Platelet reactivity was assayed at baseline and after clopidogrel treatment using the VerifyNow system. The primary endpoint was recurrent ischemic events within 21 days after stroke. Among 190 patients, 32(16.9%) had recurrent ischemic stroke. Multivariate analyses showed that HCPR was significantly associated with the short-term events with an odds-ratio of 2.5 (95% CI 1.1–5.7, p = 0.027). Patients with HCPR had significantly higher frequencies of high baseline platelet P2Y12 reactivity, impaired kidney function, and carrying one or two CYP2C19 loss-of-function alleles. A poor clopidogrel response score combining these factors was developed. Ten percent of patients with score 0, 20.3% of those with score 1, 38.3% of those with score 2, and 66.7% of those with score 3 had HCPR (χ2-test, p < 0.001). Multivariate analyses showed that, compared with the score-0 group, the score-2 and -3 groups had higher risks of HCPR with hazard-ratios of 5.4 (95% CI 1.5–20.3, p = 0.012) and 17.4 (95% CI 3.4–88.9, p = 0.001) for developing recurrent ischemic strokes. The study emphasized the role of HCPR in ischemic stroke. We also developed an HCPR risk score, which could be used in clinical practice or trials, potentially with more precision, to weigh the clinical benefit of a tailored antiplatelet-strategy for patients with stroke.

Altered platelet reactivity, coagulation, endothelial and inflammatory markers early after smoking cessation verified with cotinine plasma concentration

Background/Introduction: Cigarette smoking is a potent modifiable risk factor for coronary artery disease (CAD). However, little is known about alterations to prothrombotic state and platelet reactivity early after smoking cessation following percutaneous coronary interventions (PCI). Purpose: We investigated alterations to platelet reactivity, coagulation and markers of platelet, endothelial, inflammatory and coagulation activation in clopidogrel-treated patients with CAD after PCI before and after smoking cessation. Methods: Smoking patients aged 18 years or older at least 30 days after PCI were recruited and encouraged to quit the habit. At baseline and at 30 days, we measured platelet reactivity with VerifyNow system, thrombomodulin, P-selectin, platelet factor 4 (CXCL4/PF4), citrullinated histone H3 (H3cit) and cotinine level. Results: Among 117 patients, 84 patients (72%) at a median age of 60.5 years (40 [interquartile range 30–47] pack-years) completed a 30-day follow-up. At day 30, 30 (35.7%) patients stopped smoking with cotinine level < 50 ng/ml. Baseline characteristics were similar in both groups. In smoking quitters a change in platelet reactivity was larger (Δ platelet reactivity units (PRU) 19 [2, 43] vs. -6 [-32, 37], p = 0.018), along with a change in P-selectin concentration (-11.82 [-23.62, 1.34] vs. 7.19 [-14.24, 17.19] ng/ml, p = 0.005). Positive correlations was noticed between cotinine and both P-selectin ( r = 0.23, p = 0.045) and CXCL4 (r = 0.27, p = 0.02). Conclusion: After smoking cessation in CAD patients following PCI an increase in platelet reactivity and a decrease in P-selectin levels were observed. The risk of thrombotic complications post PCI might be paradoxically enhanced among patients who stopped smoking.

Clinical impact of high platelet reactivity in patients with atrial fibrillation and concomitant percutaneous coronary intervention on dual or triple antithrombotic therapy

High platelet reactivity (HPR) on clopidogrel is an established thrombotic risk factor after percutaneous coronary intervention (PCI). The introduction of more potent antiplatelet drugs has partially surpassed this issue. However, in the setting of concomitant atrial fibrillation (AF) and PCI clopidogrel is still the most adopted P2Y12 inhibitor. In the present study all consecutive patients with history of AF discharged from our cardiology ward with dual (DAT) or triple (TAT) antithrombotic therapy after a PCI from April 2018 to March 2021 were enrolled in an observational registry. For all subjects, blood serum samples were collected and tested for platelet reactivity by arachidonic acid and ADP (VerifyNow system) and genotyping of the CYP2C19*2 loss-of-function polymorphism. We recorded at 3 and 12-months follow-up: (1) major adverse cardiac and cerebrovascular events (MACCE), (2) major hemorrhagic or clinically relevant non-major bleeding and (3) all-cause mortality. A total of 147 patients were included (91, 62% on TAT). In 93.4% of patients, clopidogrel was chosen as P2Y12 inhibitor. P2Y12 dependent HPR resulted an independent predictor of MACCE both at 3 and 12 months (HR 2.93, 95% C.I. 1.03 to 7.56, p = 0.027 and HR 1.67, 95% C.I. 1.20 to 2.34, p = 0.003, respectively). At 3-months follow-up the presence of CYP2C19*2 polymorphism was independently associated with MACCE (HR 5.21, 95% C.I. 1.03 to 26.28, p = 0.045). In conclusion, in a real-world unselected population on TAT or DAT, the entity of platelet inhibition on P2Y12 inhibitor is a potent predictor of thrombotic risk, suggesting the clinical utility of this laboratory evaluation for a tailored antithrombotic therapy in this high-risk clinical scenario.Graphical abstractThe present analysis was performed in patients with AF undergoing PCI on dual or triple antithrombotic therapy. At 1 year follow-up MACCE incidence was consistent, and it was not different in different antithrombotic pattern groups. P2Y12 dependent HPR was a potent independent predictor of MACCE both at 3- and 12-months follow-up. In the first 3 months after stenting the carriage of CYP2C19*2 allele was similarly associated with MACCE. Abbreviation: DAT, dual antithrombotic therapy; HPR, high platelet reactivity; MACCE, major adverse cardiac and cerebrovascular events; PRU, P2Y12 reactive unit; TAT, triple antithrombotic therapy. Created with BioRender.com.

Perioperative Antiplatelet Therapy for the Stent-Assisted Coil Embolization: Results of the Questionnaire Survey.

This study aimed to determine the status of perioperative antiplatelet therapy in stent-assisted coil embolization (SAC) in Japan. The questionnaire consisted of 13 questions and used Google forms, and was sent to institutions where endovascular specialists were employed. The results were analyzed. The responses from 307 centers indicated that the timing of initiation of antiplatelet therapy was 14 days-1 month before treatment in half of centers, and 7-14 days before treatment in the other half. Platelet function tests were performed at 165 centers (56.2%), of which 136 centers (46.3%) performed these tests for all patients, with the VerifyNow system being the most widely used tool. The duration of postoperative dual antiplatelet therapy was 6, 3, and 12 months in 169 (57.7%), 70 (23.5%), and 42 (14.3%) centers, respectively. The antiplatelet agents used for monotherapy were P2Y12 receptor antagonists or aspirin, with a postoperative period of up to 12 months in 139 centers (47.3%), 24 months in 68 centers (23.1%), and longer than 24 months in 50 centers (17%). Current antiplatelet therapy for SAC in Japan varies widely among institutions. Moreover, each center has its own empirical rules for SAC. Therefore, the findings of this survey suggest the need to establish guidelines for optimal periprocedural antiplatelet therapy for SAC.

Altered platelet reactivity, coagulation, endothelial and inflammatory markers early after smoking cessation verified with cotinine plasma concentration

Abstract Background/Introduction Cigarette smoking is a potent modifiable risk factor for coronary artery disease (CAD) including patients after percutaneous coronary interventions (PCI). Cigarette smoking is associated with major changes in platelet, endothelial, inflammatory, and coagulation responses. The early period after PCI witnesses the highest risk of thrombotic events. However, data regarding alterations of prothrombotic state and platelet reactivity early after smoking cessation are scarce. Purpose We investigated alterations to platelet reactivity, coagulation and markers of platelet, endothelial and neutrophil activation in clopidogrel-treated patients with CAD after PCI before and after smoking cessation. Methods Patients aged 18 years or older, who smoked at least 10 cigarettes per day, at least 30 days after successful PCI with stent placement, and those treated with 75 mg clopidogrel and 75 mg acetylsalicylic acid (ASA) once daily, were included in the study and were encouraged to quit the habit. Platelet reactivity was measured with VerifyNow system and the concentrations of cotinine, thrombomodulin, P-selectin, platelet factor 4 (CXCL4/PF4), citrullinated histone H3 (H3cit), were assessed in blood samples at baseline and at the 30-day follow-up visit. Smoking cessation was defined as cotinine concentrations of &amp;lt;50 ng/ml. Results Among 117 patients, being current smokers, who attended the baseline visit, 84 patients completed a 30-day follow-up. The median [interquartile range] age of patients was 50 [55–65] years, median body mass index was 27.55 [25.2–30.9] kg/m2, and a median load of smoking was 40 [30–47] pack-years. At the follow-up visit, 30 patients stopped smoking as confirmed by cotinine concentrations (study group) and 54 patients continued smoking (control group). Baseline characteristics were similar in both groups. In the study group as compared to the control group, at day 30 a change in platelet reactivity was larger (Δ platelet reactivity units (PRU) 19 [2, 43] vs −6 [−32, 37], p=0.018), along with a change in P-selectin concentration (−11.82 [−23.62, 1.34] vs 7.19 [−14.24, 17.19] ng/ml), p=0.005). The change in the concentrations of thrombomodulin, CXCL4/PF4, and citH3 did not differ significantly between groups. Conclusion In the early period after smoking cessation in coronary artery disease patients following PCI treated with clopidogrel and ASA, an increase in platelet reactivity with a decrease in P-selectin levels was observed. No significant changes in other markers were noticed. It might be speculated that the risk of thrombotic complications might be paradoxically enhanced among such patients after smoking cessation despite dual antiplatelet therapy. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Centre of Postgraduate Medical Education

Evaluation of Stent Apposition in the LVIS Blue Stent-Assisted Coiling of Distal Internal Carotid Artery Aneurysms : Correlation with Clinical and Angiographic Outcomes.

To evaluate the stent apposition of a low-profile visualized intraluminal support (LVIS) device in distal internal carotid artery (ICA) aneurysms, examine its correlation with clinical and angiographic outcomes, and determine the predictive factors of ischemic adverse events (IAEs) related to stent-assisted coiling. We retrospectively analyzed a prospectively maintained database of 183 patients between January 2017 and February 2020. The carotid siphon from the cavernous ICA to the ICA terminus was divided into posterior, anterior, and superior bends. The anterior bends were categorized into angled (V) and non-angled (C, U, and S) types depending on the morphology and measured angles. Complete stent apposition (CSA) and incomplete stent apposition (ISA) were evaluated using unsubtracted angiography and flat-panel detector computed tomography. Dual antiplatelet therapy with aspirin 200 mg and clopidogrel 75 mg was administered. Clopidogrel resistance was defined as fewer responders (≥10%, <40%) and non-responders (<10%) based on the percent inhibition (%INH) of the VerifyNow system. These were counteracted by a dose escalation to 150 mg for fewer responders or substitution with cilostazol 200 mg for non-responders. IAEs included intraoperative in-stent thrombosis, transient ischemic attack, cerebral infarction, and delayed in-stent stenosis. A multivariate logistic regression analysis was used to determine the predictive factors for ISA and IAEs. There were 33 ISAs (18.0%) and 27 IAEs (14.8%). The anterior bend angle was narrower in ISA (-4.16°±25.18°) than in CSA (23.52°±23.13°) (p<0.001). The V- and S-types were independently correlated with the ISA (p<0.001). However, treatment outcomes, including IAEs (15.3% vs. 12.1%), aneurysmal complete occlusion (91.3% vs. 88.6%), and recanalization (none of them), did not differ between CSA and ISA (p>0.05). The %INH of 27 IAEs (13.78%±14.78%) was significantly lower than that of 156 non-IAEs (26.82%±20.23%) (p<0.001). Non-responders to clopidogrel were the only significant predictive factor for IAEs (p=0.001). The angled and tortuous anatomical peculiarity of the carotid siphon caused ISA of the LVIS device; however, it did not affect clinical and angiographic outcomes, while the non-responders to clopidogrel affected the IAEs related to stent-assisted coiling.

High on-treatment platelet reactivity is associated with poor outcomes after ischemic stroke: A meta-analysis.

High on-treatment platelet reactivity (HTPR) determined by platelet function assays is present in certain patients with ischemic stroke or transient ischemic attack (TIA). However, it is unclear whether HTPR is associated with poor clinical outcomes. Our study aimed to investigate the relationship of HTPR with recurrent vascular events in ischemic stroke or TIA. Pubmed (MEDLINE), EMBASE, and Cochrane Library were searched for eligible studies from inception to January 1, 2022. Stata 17.0 software was used to calculate the risk ratio (RR). Subgroup and sensitivity analyses were conducted to assess the source of heterogeneity. A random-effects model was used when heterogeneity was present. Primary endpoint of the meta-analysis was the risk ratio of recurrent vascular events in HTPR Patients. While stroke and TIA, all-cause death, early neurological deterioration, early new ischemic lesions, and stroke severity measured by National Institute of Health Stroke Scale (NIHSS) scores at admission were also pooled. Thirty articles (7995 patients) were eligible including 28 cohort studies and 2 prospective case-control studies. The prevalence of HTPR varied from 5.9% to 60%. HTPR was associated with an increased risk of recurrent vascular events (RR=2.94, 95% CI 2.04-4.23), stroke recurrence (RR=2.05; 95% CI 1.43-2.95), and all-cause mortality (RR=2.43; 95% CI 1.83-3.22). Subgroup analysis showed that HTPR determined by optical aggregometry, Verify-Now system and 11dh TXB2 is related to a higher risk of recurrent vascular events (RR=3.53, 95% CI 1.51-9.40; RR=2.16, 95% CI 1.02-4.56; RR=3.76, 95% CI 1.51-9.40, respectively). Moreover, patients with HTPR had an increased incidence of early neurological deterioration (RR=2.75; 95% CI 1.76-4.30) and higher NIHSS scores at admission (Mean difference 0.19, 95% CI 0.01-0.36). This meta-analysis demonstrates HTPR is associated with higher risk of recurrent vascular events, early neurological deterioration and increased severity in patients with ischemic stroke and TIA. HTPR measured by platelet function assays may guide the use of antiplatelet agents in ischemic stroke and TIA.

Comparative Study of Ex Vivo Antiplatelet Activity of Aspirin and Cilostazol in Patients with Diabetes and High Risk of Cardiovascular Disease.

Background The role of aspirin in primary cardiovascular disease prevention in patients with diabetes remains controversial. However, some studies have suggested beneficial effects of cilostazol on cardiovascular disease in patients with diabetes. We prospectively investigated the antiplatelet effects of cilostazol compared with aspirin in patients with diabetes and cardiovascular risk factors.Methods We randomly assigned 116 patients with type 2 diabetes and cardiovascular risk factors but no evident cardiovascular disease to receive aspirin at a dose of 100 mg or cilostazol at a dose of 200 mg daily for 14 days. The primary efficacy outcome was antiplatelet effects of aspirin and cilostazol assessed with the VerifyNow system (aspirin response units [ARU]) and PFA-100 (closure time [CT]). Secondary outcomes were changes of clinical laboratory data (ClinicalTrials.gov Identifier: NCT02933788).Results After 14 days, there was greater decrease in ARU in aspirin (–28.9%±9.9%) compared cilostazol (–0.4%±7.1%, P<0.001) and was greater increase in CT in aspirin (99.6%±63.5%) compared cilostazol (25.7%±54.1%, P<0.001). The prevalence of aspirin resistance was 7.5% according to VerifyNow (defined by ARU ≥550) and 18.9% according to PFA-100 (CT <192 seconds). Compared with aspirin, cilostazol treatment was associated with increased high density lipoprotein cholesterol (7.1%±12.7% vs. 4.2%±18.0%, P=0.006) and decreased triglycerides (–9.4%±33.7% vs. 4.4%±17.57%, P=0.016). However, there were no significant changes in total and low density lipoprotein cholesterol, C-reactive protein level, and cluster of differentiation 40 ligand between cilostazol and aspirin groups.Conclusion Aspirin showed better antiplatelet effects assessed with VerifyNow and PFA-100 compared with cilostazol. However, there were favorable changes in atherogenic dyslipidemia only in the cilostazol.

Influence of Clinically Significant Genes on Antiplatelet Effect of Clopidogrel and Clinical Outcomes in Patients with Acute Coronary Syndrome and Atrial Fibrillation

Introduction: The interindividual variability of the antiplatelet effect of clopidogrel is determined by multiple clinical and genetic factors. A lot of genotype-oriented studies have concentrated on the impact of CYP2C19 gene polymorphisms on platelet aggregation in patients receiving clopidogrel. However, the influence of this polymorphism may be only 12–20%, so other genetic markers should also be investigated. The aim of this work was to study the impact of carriage of CES1, PON1, ABCG2, CYP4F2, CYP3A4, IGTB3, P2Y12, PEAR1, and B4GALT2 polymorphisms on antiplatelet effect of clopidogrel and clinical outcomes in patients with acute coronary syndrome (ACS) and atrial fibrillation (AF). Methods: 103 patients who underwent ACS with or without percutaneous coronary intervention and concomitant nonvalvular AF were included in an open multicenter prospective study to assess efficacy and safety of combined antithrombotic therapy. The study assessed the frequency of different primary clinical outcomes (incidence of major bleeding, hospital mortality, cardiovascular mortality, stroke and transient ischemic attacks (TIAs), renal mortality) and secondary outcomes (resistance to therapy – high residual platelet reactivity, excessive platelet suppression). Residual platelet reactivity was examined using the VerifyNow system (Accumetrics, Latham, NY, USA). Results: None of the studied genetic markers had no statistically significant effect on the antiaggregant response to clopidogrel in patients with ACS and AF. However, CYP4F2 C(Val433Met) T, PEAR1 rs41273215 C>T were statistically significantly associated with an increased frequency of bleeding on antithrombotic therapy. B4GALT2 rs1061781 was statistically significantly associated with increased frequency of strokes and TIA. Conclusion: In our study, we determined that carriers of CYP4F2 gene polymorphisms C(Val433Met)T, PEAR1 rs41273215 C>T (CT+TT) were associated with lower safety of antithrombotic therapy in patients with ACS and AF. And, the B4GALT2 rs1061781 gene polymorphism was associated with a greater risk of insufficient efficacy of the therapy. The data obtained in our study may improve the understanding of the effect of less studied genetic markers on the efficacy and safety of antithrombotic therapy in patients with ACS and AF.

Impact of Calcium Channel Blockers on Aspirin Reactivity in Patients with Coronary Artery Disease.

Calcium channel blockers (CCBs) do not reduce the risk of initial or recurrent myocardial infarction (MI) in patients diagnosed with stable coronary artery disease (CAD). The aim of this current study was to evaluate the association between CCBs and aspirin resistance in patients with CAD. Patients with stable CAD who were regularly taking aspirin (75-100 mg qd) for at least 1 month prior to enrollment in the study were included. The VerifyNow system was used for platelet function testing with high on-aspirin platelet reactivity (HAPR) defined as aspirin reaction units (ARU) >550. We compared patients treated with CCBs versus control group. Five hundred three patients with CAD were included in this study, and 88 were treated with CCBs. Mean age (67.9±9.7 in the CCB group vs. 66.5±11.4 in the control group), gender (77.3 male vs. 82.9%), rates of diabetes mellitus (34.7 vs. 36.9%), rates of CKD (23.5 vs. 23.5%), dyslipidemia (85.1 vs. 85.3%), and statin therapy (89.5 vs. 90.7%) were similar. The mean ARU was 465.4±70.0 for patients treated with CCBs versus 445.2±60.0 in controls (p=0.006). Similarly, 15.9% of CCB patients demonstrated HAPR compared to 7.0% (p=0.006). The administration of CCBs was independently associated with HAPR in a multivariate analysis (OR 1.72, 95% CI: 1.04-8.91, p=0.047) as well as in propensity score matched analysis (OR 1.56; CI: 1.22-1.93; p<0.001). Usage of CCBs is positively correlated with aspirin resistance. These findings may suggest an adverse pharmacologic effect of CCBs among patients with stable CAD treated with aspirin.

Hyperacute postprocedural high platelet reactivity: a novel predictor for in-hospital adverse events in acute coronary syndrome with prasugrel loading

Abstract Introduction Postprocedural High platelet reactivity (HPR) seems to associate long term adverse cardiovascular events, mainly intrastent thrombosis. However, the relationship between hyper-acute postprocedural HPR with prasugrel loading and clinical outcomes in acute coronary syndrome (ACS) is still unclear. Moreover, factors contributing HPR in ACS with prasugrel loading are also unknown. Purpose This study aimed to assess the impact of hyper-acute postprocedural HPR with prasugrel loading on clinical outcomes in ACS during hospitalization, as well as to define appropriate cut-off values and identify contributing factors of HPR. Methods We performed a single-centre, retrospective observational study that enrolled 207 patients who underwent emergent PCI for ACS with prasugrel loading. The P2Y12reaction unit (PRU) value was measured immediately after PCI with the VerifyNow System. The primary endpoint was major adverse cardiac events (MACE, defined as the composite of death, myocardial infarction, stroke, heart failure, ventricular arrhythmia needing defibrillation). Results Mean patient age (standard deviation) was 70.5 (±13.0) years, 78.7% were male, and average time from prasugrel intake to PRU calculation was 98.3 (±49.1) min. During a mean hospital stay of 15.9 (±9.3) days, there were 34 in-hospital MACE (16.4%) and 10 deaths (4.8%). Thrombosis events, didn't stand out and mechanical complications, such as cardiac rupture and cardiac tamponade occupies most of cardiovascular death which occurred before 10 days on admission. PRU was significantly higher in MACE group than Non-MACE group (279±65 vs 227±72, p&amp;lt;0.001 respectively). The ROC curve analysis of PRU for discriminating significant in-hospital MACE showed the cut off value of 293 (sensitivity:52.9%, specificity:83.2% [AUC=0.709, p&amp;lt;0.0001]). 47patients (29.4%) were thus categorized as HPR (PRU&amp;gt;293) immediately after emergent PCI. Kaplan-Meyer curve showed MACE events occurred in HPR group than non-HPR group (38.2% vs 10.0%, p&amp;lt;0.001). Multiple cox analysis demonstrated that HPR was independent predictors of MACE in patients with ACS underwent PCI (OR 5.416, 95% CI 2.157–13.598, p&amp;lt;0.0001). Multiple logistic regression model showed female sex, low haemoglobin value, and large mean platelet volume were independent predictors of HPR. Conclusion PRU was significantly higher in MACE group, and appropriate cut-off value of HPR in this study was 293. HPR was independent predictor of MACE during hospitalization, however thrombosis event was not significant. Evidence of clinical impact with postprocedural HPR within 120 minutes after prasugrel loading is scarce. This study shows post-procedural HPR, even without sufficient time after prasugrel intake, can be a useful predictive marker of adverse events during hospitalization. Funding Acknowledgement Type of funding sources: None. PRU between Non-MACE and MACE groupKaplan-Meyer curve

High On-Treatment Platelet Reactivity as Predictor of Long-term Clinical Outcomes in Stroke Patients with Antiplatelet Agents.

The purpose was to explore the value of high on-treatment platelet reactivity (HTPR) in predicting long-term clinical outcomes for stroke patients. The platelet reactivity was assayed after being treated with either 75mg clopidogrel or 100mg aspirin daily with VerifyNow System in stroke patients. HTPR for clopidogrel was defined as PRU ≥ 208, and that for aspirin was defined as ARU ≥ 550. CYP2C19 genotyping was performed using the Sequenom MassARRAY iPLEX platform. The primary endpoint was a composite of recurrent ischemic stroke, transient ischemic attack, myocardial infarction, or ischemic vascular death. The safety endpoint was bleeding. In the clopidogrel group, among 345 patients recruited, 174 of them were categorized as HTPR. A total of 270 patients were followed up for 54months. There was a significant association between HTPR and the primary endpoint (HRadj 2.13 [95% CI, 1.43-3.15], p < 0.001). Among the 314 participants genotyped for CYP2C19, 187 (59.6%) were classified as CYP2C19 loss-of-function allele carriers. Patients with at least 1 loss-of-function allele were more likely to present with HTPR (ORadj 2.61 [95%CI, 1.43-4.77], p = 0.008), and had a higher risk of the primary endpoint (HRadj 2.05 [95% CI, 1.30, 3.25], p = 0.002). In the aspirin group, among 140 patients recruited, 28 of them were categorized as HTPR. A total of 121 patients were followed up for 30months. Similarly, there was a significant association between HTPR and the primary endpoint (HRadj 3.28 [95% CI, 1.52-7.71], p = 0.002). HTPR is an independent risk factor for ischemic events during long-term follow-up in stroke patients. Platelet function testing is helpful to evaluate the effect of antiplatelet therapy for stroke patients.

Platelet-Derived Thrombogenicity Measured by Total Thrombus-Formation Analysis System in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

Prompt and potent antiplatelet effects are important aspects of management of ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI). We evaluated the association between platelet-derived thrombogenicity during PPCI and enzymatic infarct size in STEMI patients. Platelet-derived thrombogenicity was assessed in 127 STEMI patients undergoing PPCI by: (1) the area under the flow-pressure curve for the PL-chip (PL18-AUC10) using the total thrombus-formation analysis system (T-TAS); and (2) P2Y12reaction units (PRU) using the VerifyNow system. Patients were divided into 2 groups (High and Low) based on median PL18-AUC10during PPCI. PRU levels during PPCI were suboptimal in both the High and Low PL18-AUC10groups (median [interquartile range] 266 [231-311] vs. 272 [217-317], respectively; P=0.95). The percentage of final Thrombolysis in Myocardial Infarction (TIMI) 3 flow was lower in the High PL18-AUC10group (75% vs. 90%; P=0.021), whereas corrected TIMI frame count (31.3±2.5 vs. 21.0±2.6; P=0.005) and the incidence of slow-flow/no-reflow phenomenon (31% vs. 11%, P=0.0055) were higher. The area under the curve for creatine kinase (AUCCK) was greater in the High PL18-AUC10group (95,231±7,275 IU/L h vs. 62,239±7,333 IU/L h; P=0.0018). Multivariate regression analysis identified high PL18-AUC10during PPCI (β=0.29, P=0.0006) and poor initial TIMI flow (β=0.37, P<0.0001) as independent determinants of AUCCK. T-TAS-based high platelet-derived thrombogenicity during PPCI was associated with enzymatic infarct size in patients with STEMI.

Antiplatelet effects of citalopram in patients with ischaemic stroke: A randomized, placebo-controlled, double-blind study

We evaluated the effect of SSRI treatment on platelet aggregation in patients with ischaemic stroke and included patients from the randomized double-blind controlled study of citalopram in acute ischaemic stroke (TALOS). Patients on clopidogrel were included 6 months after acute ischaemic stroke. Platelet parameters, including P2Y12 platelet reactivity using the VerifyNow System, were measured at the last day of study treatment and repeated after a 14-day wash-out period. A total of 60 patients were included (n = 32 randomized to citalopram). Platelet aggregation levels did not differ between the citalopram group (mean 116, 95% CI 89 to 143) and the placebo group (mean 136, 95% CI 109 to 163) (On-treatment, p = 0.14). Similarly, there was no significant change in platelet aggregation in the citalopram group from on-treatment to post-treatment (mean difference 2.0; 95% CI −18 to 14). Platelet count, size and turnover were not affected by SSRI treatment. In conclusion, SSRI therapy did not lead to statistically significant inhibition of platelet aggregation in ischaemic stroke patients treated with clopidogrel.

255Impact of the type of acute coronary syndrome on the pharmocodynamic response to P2Y12 inhibitors in the acute and maintenance phase of therapy

Abstract Background The presence of an acute coronary syndrome (ACS) is per se a predictor of reduced responsiveness to clopidogrel; in particular, patients with ST-elevation myocardial infarction (STEMI) have impaired clopidogrel-induced platelet inhibition than those with other forms of ACS. However, the impact of the type of ACS on the pharmocodynamic efficacy of more potent P2Y12 antagonists such as prasugrel or ticagrelor has not been fully elucidated to date. Purpose To assess the impact of the type of ACS on platelet inhibition mediated by P2Y12 receptor antagonists in the acute and the maintenance phase of therapy in a contemporary cohort of ACS patients undergoing percutaneous coronary intervention (PCI). Methods Substudy of a prospective, national, multicentre, pharmacodynamic registry conducted in a population of ACS patients undergoing PCI and treated with dual antiplatelet therapy including aspirin and a P2Y12 inhibitor as per clinical indication. Patients were classified according to the ACS diagnosis into groups: a) STEMI, b) non-ST-elevation ACS (NSTEACS), c) unstable angina (UA), and d) other (excluded from the present analysis). Platelet function tests (PFT) were performed at day 1 and day 30 (±5) after PCI and included: 1) VerifyNow P2Y12 assay, expressed as P2Y12 reaction units (PRUs); 2) Vasodilator-stimulated phosphoprotein (VASP) assay; and 3) Multiple electrode aggregometry (MEA). Results A total of 965 patients (372 with STEMI, 395 with NSTEACS and 198 with UA) were included in the present substudy. At day 1, the proportions of patients with each type of ACS according to the P2Y12 inhibitor received were: 1) clopidogrel (n=317): STEMI 35.0%, NSTEACS 34.4% and UA 30.6%; 2) prasugrel (n=192): STEMI 70.3%, NSTEACS 17.7% and UA 12.0%; 3) ticagrelor (n=456): STEMI 27.6%, NSTEACS 55.3% and UA 17.1%. A statistically significant reduced platelet inhibition, measured with the VerifyNow system, was observed in STEMI patients compared with the other forms of ACS in patients receiving clopidogrel (STEMI: 217.3±8.1, NSTEACS: 157.1±7.9 and UA: 164.9±8.6 PRUs; p for STEMI vs. NSTEACS &lt;0.001 and p for STEMI vs. UA &lt;0.001) and ticagrelor (STEMI: 57.7±3.8, NSTEACS: 45.2.1±2.6 and UA: 40.6±4.9 PRUs; p for STEMI vs. NSTEACS 0.008 and p for STEMI vs. UA 0.007), while a numerical trend towards greater platelet reactivity in STEMI compared to UA was observed in subjects receiving prasugrel (Figure). Remarkably, at day 30, no significant differences on platelet inhibition were observed according to the ACS type with any of the P2Y12 inhibitors. Similar results were observed with MEA and VASP assays. PD response according to the ACS type Conclusions Patients presenting with STEMI have impaired platelet inhibition mediated by P2Y12 antagonists compared to other types of ACS during the acute phase of therapy, whereas no difference is observed during the maintenance phase of treatment. Acknowledgement/Funding Funded by Instituto de Salud Carlos III through the project PI13/01012 (co-funded by European Regional Development Fund. ERDF, a way to build Europe)

Antiplatelet Resistance in Patients with Atherosclerosis

Abstract Variable platelet response to aspirin and clopidogrel is a well-known phenomenon in patients with coronary artery disease and ischemic cerebral stroke. The objective of the present study was to evaluate the frequency and possible risk factors of antiplatelet resistance in patients with cerebrovascular and cardiovascular diseases. The VerifyNow system was used to evaluate adenosine-5-diphosphate and platelet P2YI2 receptor function in patients with cerebrovascular and cardiovascular disease, who received dual antiplatelet therapy. Aspirin resistance was defined as aspirin reaction units (ARU) ≥ 550. Clopidogrel resistance was defined as Platelet Reaction Units (PRU) &gt; 230. In the group of cerebrovascular diseases there were 13.2% (n = 27) patients with aspirin and 24.5% (n = 50) with clopidogrel resistance. However, in the cardiovascular group there were 20% (n = 9) aspirin and 11.1% (n = 5) clopidogrel resistant patients. In the cerebrovascular group, aspirin resistant patients had a lower triglyceride level (p = 0.001, r = 0.26) than aspirin sensitive patients. Clopidogrel resistant patients had a significantly higher level of glycated haemoglobin (HbA1C) (p = 0.016, r = 023), triglycerides (p = 0.033, r = 0.16) and lower level of high-density lipoproteins (p = 0.027, r = 0.16) than clopidogrel sensitive patients. In the cardiovascular group, patients who were resistant to aspirin had a significantly higher high-density lipoprotein level (p = 0.038, r = 0.31). No other factors differed significantly between the aspirin or clopidogrel resistant and sensitive patients in the cardiovascular group. Aspirin resistance was more common in patients with cardiovascular disease, and clopidogrel resistance in patients with cerebrovascular disease, although the difference was not significant. Our findings indicate that diabetes mellitus and an elevated level of lipoproteins could be risk factors for aspirin or clopidogrel resistance in patients with cerebrovascular diseases. Further studies should be conducted using larger patient cohorts with balanced groups of patients to investigate clinical aspects of antiplatelet resistance.