Residual Platelet Research Articles

MRP4 over-expression has a role on both reducing nitric oxide-dependent antiplatelet effect and enhancing ADP induced platelet activation

The impact of inhibition of multidrug resistance protein 4 (MRP4) on nitric oxide (NO) resistance and on ADP-induced platelet aggregation is unknown. The aim of this investigation was to verify whether platelet NO resistance correlates with MRP4 expression and evaluate whether this can be reduced by in vitro MRP4 inhibition mediated by cilostazol. Moreover, we assessed if inhibition of MRP4-mediated transport reduces ADP-induced platelet reactivity. The inhibitory effect of sodium nitroprusside (SNP), a NO-donor that enhances cyclic guanosine monophosphate (cGMP) cytosolic concentration, was assessed in platelets obtained from aspirin treated patients and in a control population. The inhibitory effect of SNP was evaluated by ADP-induced aggregation in SNP-treated platelets. The impact of MRP4 on ADP-induced platelet aggregation was performed in high on aspirin residual platelet reactivity (HARPR) patients and compared to healthy volunteers (HV), and a control cohort (CTR). In aspirin-treated patients with high levels of MRP4, reduced SNP inhibition was found compared to those with low levels of MRP4. MRP4 inhibition by cilostazol significantly reduced ADP-induced platelet aggregation in HARPR population, and to a lesser extent in HV and CTR populations. In conclusion, cilostazol can mitigate the hyper-reactive platelet phenotype of HARPR patients by reducing residual ADP-induced platelet aggregation and increasing NO-dependent endothelial antiplatelet effects.

Serum uric acid level negatively correlated with the prevalence of clopidogrel low response in patients undergoing antiplatelet treatment with aspirin and clopidogrel

Background and aimsIt has been reported that elevated serum uric acid (SUA) is related to inflammation and potentially to platelet hyper-reactivity. However, the relationship between elevated SUA and residual platelet reactivity is uncertain in patients on dual antiplatelet treatment (DAPT) with aspirin and clopidogrel. Methods and resultsA cross-sectional cohort study was conducted on 2569 patients undergoing DAPT with aspirin and clopidogrel. Patients' SUA levels, residual platelet aggregation, routine blood tests and clinical characteristics were recorded. The relationship between SUA level and residual platelet aggregation was assessed by correlation analysis, and the relationship between SUA level and the prevalence of clopidogrel low response (CLR) was assessed by multivariate logistic regression analysis. Adenosine diphosphate (ADP) induced platelet aggregation (PLADP) was higher in normal-SUA group than that in hyperuricemia group [30(21, 40) % vs. 27(19, 39) %, p = 0.032]. No significant difference was found for arachidonic acid (AA) induced platelet aggregation (PLAA) between the two groups [4(2, 5) % vs. 3(2, 5) %, p = 0.557]. The correlation between SUA and PLADP was statistically significant(r = −0.115, p < 0.001), while that between SUA and PLAA was non-significant (r = −0.012, p = 0.643). Using the multivariate logistic regression analysis, higher SUA concentration was associated with a decreased risk of clopidogrel low response (CLR) (OR [95%CI] = 0.997 [0.995–0.999], p = 0.001). ConclusionThis is the largest study to date showing that in patients receiving DAPT with aspirin and clopidogrel, SUA is independently and negatively associated with the prevalence of clopidogrel low response. Clinical trial registrationURL: http://www.clinicaltrials.gov Unique Identifier: NCT01955200.

Mean Corpuscular Volume Predicts Adverse Outcomes Following Peripheral Angioplasty With Stenting and Is Associated With On-Treatment Platelet Reactivity.

Structural aspects of red blood cells have been associated with cardiovascular disease. No data linking mean corpuscular volume (MCV) to clinical outcomes and on-treatment platelet reactivity in patients with peripheral artery disease (PAD) are available. We investigated a composite of atherothrombotic events and target vessel restenosis or reocclusion following infrainguinal stenting for stable PAD. Residual platelet reactivity was measured by light transmission aggregometry (LTA) and the VerifyNow assays. We included 104 patients receiving dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. In receiver-operating characteristic analysis, MCV effectively discriminated between patients with and without adverse outcomes and identified a MCV ≤90.8 fL as optimal cutoff. Adverse outcomes occurred significantly more often in patients with low MCV (log-rank P = .002). In univariable Cox regression analysis, low MCV was associated with an increased risk of future adverse outcomes (hazard ratio [HR]: 2.662 [95%CI: 1.304-5.434]; P = .007) and remained significantly associated after adjustment (HR: 2.591 [95%CI: 1.242-5.403]; P = .011). Mean corpuscular volume was inversely correlated with arachidonic acid (AA)- and adenosine diphosphate (ADP)-inducible platelet reactivity by LTA and with the VerifyNow aspirin assay. Low MCV is associated with adverse outcomes over 2 years following infrainguinal stenting. Mean corpuscular volume correlates inversely with AA- and ADP-inducible platelet reactivity during DAPT.

Higher neutrophil-to-lymphocyte ratio (NLR) increases the risk of suboptimal platelet inhibition and major cardiovascular ischemic events among ACS patients receiving dual antiplatelet therapy with ticagrelor

BackgroundNeutrophil to lymphocyte ratio (NLR) has emerged as a useful and easy-to-assess prognostic tool and biomarker of cardiovascular risk. However, few studies have evaluated its role on platelet inhibition among patients on dual antiplatelet therapy (DAPT), and especially in the settings of acute coronary syndromes (ACS). We aimed at assessing the impact of NLR on platelet reactivity and the risk of major ischemic events at long-term follow-up among ACS patients on DAPT with ticagrelor. MethodsPatients on dual antiplatelet therapy with ASA + ticagrelor (90 mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30–90 days post-discharge. Aggregation tests were performed by Multiple Electrode Aggregometry (MEA). Suboptimal platelet inhibition (HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min). The primary study endpoint was defined as the occurrence of major cardiovascular events (a composite of cardiovascular death, recurrent acute coronary syndrome, target vessel revascularization) at longest available follow-up. ResultsWe included 397 patients, that were divided according to NLR tertiles. Patients with higher NLR were older (p < .001), less frequently smokers (p = .03), with higher rates of renal failure (p = .001), previous bypass surgery (p = .05) and use of statins (p = .03) and diuretics (p = .01). Higher white blood cells count and C-reactive protein (p < .001) and lower haemoglobin (p = .001) were associated with NLR. Mean platelet reactivity and the prevalence of high platelet reactivity (HRPR) on ticagrelor were significantly associated to higher NLR tertiles values (7% vs 12% vs 14.3%, p = .04), with a significant relationship between NLR and platelet reactivity being confirmed for all the different activating stimuli.At a mean follow-up of 939 ± 581.4 days, 21.2% of the patients experienced the primary composite endpoint, with a trend for a higher risk of events across NLR tertiles (15.4% vs 24.2% vs 24.4%, p = .09), that became statistically significant after correction for baseline confounders (adjusted HR[95%CI] = 1.13[1.008–1.26], p = .036). Moreover, NLR was significantly associated to overall mortality and recurrent ACS (adjusted p = .008, p = .06 and p = .02 respectively). ConclusionsIn the present study we found that among ACS patients treated with ASA and ticagrelor after PCI, suboptimal platelet inhibition despite DAPT was significantly increased for higher values of Neutrophil-to-Lymphocyte Ratio. Moreover, mortality and the risk of recurrent major ischemic events at long-term were associated to NLR.

Open-label multicenter registry on the outcomes of peripheral arterial disease treated by balloon angioplasty with optical frequency domain imaging in superficial femoral artery and popliteal artery (OCEAN-SFA study).

Although balloon angioplasty for femoropopliteal artery lesions has been associated with restenosis rates of up to 60% at 12months, the mechanism of restenosis has not been fully evaluated. The aim of this study was to evaluate the relationship between the vascular features observed on optical frequency domain imaging (OFDI) before and after balloon angioplasty of femoropopliteal artery lesions, and restenosis at 6months. This study was a prospective multicenter single arm study. OFDI was performed before and after balloon angioplasty and plaque characteristics and vascular features, along with de novo lesions, were assessed. The primary outcome was the presence or absence of restenosis 6months after balloon angioplasty. Residual platelet reactivity was assessed according to VerifyNow platelet reactivity units (PRUs). The number of patients completing 6months of follow-up was 47, of which 14 had developed restenosis. Maximum thickness of the dissection flap (odds ratio (OR) 2.71; 95% confidence interval [0.9-8.0]; p = 0.071) and lesion length were identified as risk factors for restenosis (OR 1.015; 95% confidence interval [0.001-0.029]; p = 0.039). The mean PRU at the time of treatment in patients with restenosis was significantly higher than in those without restenosis (286.3 ± 82.6 vs. 208.5 ± 03.6, p = 0.026). Long lesions and major dissection on OFDI after balloon angioplasty for femoropopliteal artery lesions increase restenosis at 6months. In addition, high residual platelet reactivity at the time of EVT may also be a risk factor for restenosis.Clinical Trial Registration Number UMIN000021120.

Screening on platelet LncRNA expression profile discloses novel residual platelet reactivity biomarker.

Double antiplatelet therapy (DAPT) has wide inter-individual variabilities in coronary heart disease (CHD) patients' responses, which undermines the prognosis effect in clinical practice. Long noncoding RNAs (lncRNAs) have been reported to be widely existed in platelets, albeit their potential roles in platelet responses to DAPT largely remains in the realm of the unknown. This study aims to screen differentially expressed lncRNAs responsible for high residual platelet reactivities under DAPT. We enrolled 144 CHD patients that received DAPT and assigned them to high platelet reactivity (HPR) group and baseline group according to their residual platelet reactivities. Statistical analysis and a series of experiments including microarray analysis, platelet reactivity screening, RNA isolation and lncRNA microarray analysis were explored to the research. We detected a total of 22,424 kinds of co-expressed lncRNAs in three pairs of patients between the HPR and baseline groups. We identified twenty differentially expressed lncRNAs and successfully validated three of them in the 144 patients. Ultimately, the expression of ensemble transcript ENST00000433442 was demonstrated as significantly correlated with high platelet reactivity (OR=0.487, P=.035) by logistic regression analysis. There is a considerable amount of lncRNAs in platelets, and the downregulated expression of ENST00000433442 is an independent risk factor for high residual platelet reactivity in CHD patients under DAPT.

The role of clopidogrel in the current treatment of acute coronary syndrome

In the article, a review is given of the facts that determined contemporary views of the role of clopidogrel in the treatment of acute coronary syndrome. The author described a history of the clinical studies of clopidogrel in acute coronary syndrome (ACS), analysed its role in the current approaches to the treatment of the disease during the widespread use of other platelet P2Y 12 receptor antagonists (ticagrelor and prasugrel). The article discusses circumstances, when clopidogrel may have additional advantages, particularly the role of adherence to prolonged double antiplatelet therapy, as well as situations, when sever suppression of platelet function can be decreased (treatment de-escalation). According to a prospective randomized open-label PoPular Age study, clopidogrel combined with acetylsalicylic acid in patients with ACS without persistent ST segment elevations at the age of ≥70 years showed better adherence to treatment over the coming year as compared with clopidogrel combined with ticagrelor or prasugrel. As a result, these two approaches had comparable efficacy. Today, treatment de-escalation is a necessary measure to extend the double antiplatelet therapy in cases, when continued administration of prasugrel or ticagrelor appears unacceptable. There is insufficient evidence for the routine implementation of de-escalation in stented patients with ACS, although a small prospective, one-centre randomized open-label ToPIC study shows that this approach is safe. The author provides a review of the results of recently presented prospective studies on the choice of a platelet P2Y 12 receptor antagonist for long-term treatment of acute coronary syndrome, taking into account the residual platelet reactivity and cytochrome p450 2c19 genetic polymorphisms. Among them are multicenter open randomized clinical TRoPICAL-ACS study, multicenter randomized open-label PoPular Genetics and TAILoR PCI studies. According to the study results, the long-term outcomes in stented patients with ACS with a good response to clopidogrel assessed by the residual functional activity of platelets or by studying cytochrome p450 2c19 genetic polymorphisms may not be worse than those during use of prasugrel or ticagrelor.

Effects of colchicine on platelet aggregation in patients on dual antiplatelet therapy with aspirin and clopidogrel.

Platelets aggregation leading to thrombosis plays a pivotal role in the pathophysiology of acute coronary syndrome (ACS) and of stent thrombosis. Antiplatelet therapy with aspirin plus an ADP-receptor inhibitor (ticagrerol, prasugrel or clopidogrel) is recommended to reduce the risk of other platelet-mediated events. Clopidogrel is recommended in patients with Chronic Coronary Syndromes (CCS) or in ACS patients at high bleeding risk. Unfortunately, up to 30% of patients are non-responders to clopidogrel and show residual high platelet reactivity (HPR). Colchicine (COLC) is a drug with cardiovascular effects. We have demonstrated that COLC might exert protective cardiovascular effects by interfering with cytoskeleton rearrangement, a phenomenon involved in platelet aggregation. Here, we investigate in vitro the effects of colchicine on platelet aggregation of patients on DAPT with clopidogrel. Platelets obtained from 35 CCS patients on therapy with clopidogrel were pre-incubated with COLC 10 µM before being stimulated with ADP (20 µM), or TRAP (25 µM) at 0, 30, 60 and 90 min to measure max aggregation by LTA. Platelets not COLC-preincubated served as controls. Seven patients were pre-selected as clopidogrel non-responders. COLC significantly reduced TRAP-induced platelet aggregation in clopidogrel responders and non-responders. Interestingly, COLC inhibited ADP-induced platelet aggregation in clopidogrel non-responders in which ADP still caused activation despite DAPT. We demonstrate that COLC inhibits platelet aggregation in clopidogrel non-responders with HPR despite DAPT with this ADP receptor-inhibitor. Further in vivo studies should be designed to evaluate the opportunity to prescribe colchicine after ACS/CCS to overcome the clopidogrel limitations in the DAPT therapy.

Antiplatelet Therapy in Acute Coronary Syndromes. Lights and Shadows of Platelet Function Tests to Guide the Best Therapeutic Approach.

The key role of platelets in pathophysiology of Acute Coronary Syndromes (ACS) has been well recognized. Platelet activation and aggregation, together with tissue factor-pathway activation, lead to acute thrombus formation in the coronary vessels at sites of plaque rupture. Thus, antiplatelet therapy with drugs able to interfere with platelet activation/aggregation represents a cornerstone of ACS treatment in intensive care units and catheterisation labs. Several observational studies have described that residual high platelet reactivity, despite antiplatelet therapy, is associated with increased risk of nonfatal Myocardial Infarction (MI), definite/probable stent thrombosis and cardiovascular mortality. Thus, assessment of platelet function with reliable and reproducible platelet function tests might be crucial to identify patients at high risk of thrombosis or not responding to ongoing antiplatelet strategies. However, despite this promising background, some randomized clinical trials have failed to demonstrate improvement in outcomes when using platelet function tests for clinical decision-making. This review, after describing platelet biology and pathophysiology of ACS, briefly considers the drugs currently approved for use in patients with ACS or treated by the percutaneous coronary intervention (PCI). Finally, we provide an updated overview of the current methods to evaluate platelet reactivity in the clinical setting of ACS illustrating their potential advantages/limitations in current clinical practice.

Residual platelet reactivity, thrombus burden and myocardial reperfusion in patients treated by PCI after successful pre-hospital fibrinolysis compared to primary PCI.

We compared residual platelet reactivity and post PCI atherothrombotic burden using OFDI in patients successfully treated by primary PCI versus pharmacoinvasive approach (PI) defined as PCI after successful pre-hospital fibrinolysis. Despite pre-hospital P2Y12-inhibitor loading dose, high rates of high on-treatment platelet reactivity were found at the time of PCI in both groups. Primary PCI patients had higher post stenting thrombus burden and lower rates of final normal myocardial blush grade compared to PI. These findings support the use of a pharmacoinvasive reperfusion strategy especially when primary PCI cannot be timely performed.

Facilitation Through Aggrastat or Cangrelor Bolus and Infusion Over PrasugreL: a MUlticenter Randomized Open-label Trial in PatientS with ST-elevation Myocardial InFarction Referred for PrimAry PercutaneouS InTERvention (FABOLUS FASTER) Trial: Design and Rationale : The FABOLUS FASTER Trial.

Antithrombotic therapy is a critical component of the management of ST-elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PCI). Rapid and profound inhibition of platelet reactivity has been shown to mitigate the ischemic risks and improve myocardial salvage. High residual platelet reactivity (HRPR) has been reported up to 4 or 6h after loading dose of prasugrel or ticagrelor; therefore, multiple alternative strategies, including crushed or chewed oral tables or intravenous agents, have been investigated to provide a more rapid and sustained inhibition of platelet function and bridge the initial treatment gap. The FABOLUS FASTER is the first investigator-initiated, multicentre, open-label, prospective, randomized study to directly compare the pharmacodynamics effects of cangrelor, tirofiban, chewed or integer prasugrel. This study will add new insights in the management of antiplatelet therapy in patients with STEMI undergoing primary PCI and might be hypothesis-generating for future clinical trials in this field. The trial is registered on clinicaltrials.gov NCT02978040, and EudraCT 2017-001065-24.

Reduction of Preoperative Waiting Time before Urgent Surgery for Patients on P2Y12 Inhibitors Using Multiple Electrode Aggregometry: A Retrospective Study.

P2Y12 inhibitor discontinuation is essential before most surgical interventions to limit bleeding complications. Based on pharmacodynamic data, fixed discontinuation durations have been recommended. However, as platelet function recovery is highly variable among patients, a more individualized approach based on platelet function testing (PFT) has been proposed. The aim of this retrospective single-centre study was to determine whether PFT using whole blood adenosine diphosphate–multiple electrode aggregometry (ADP–MEA) was associated with a safe reduction of preoperative waiting time. Preoperative ADP–MEA was performed for 29 patients on P2Y12 inhibitors. Among those, 17 patients underwent a coronary artery bypass graft. Twenty one were operated with an ADP–MEA ≥ 19 U (quantification of the area under the aggregation curve), and the waiting time was shorter by 1.6 days (median 1.8 days, IQR 0.5–2.9), by comparison with the current recommendations (five days for clopidogrel and ticagrelor, seven days for prasugrel). Platelet function recovery was indeed highly variable among individuals. With the 19 U threshold, high residual platelet inhibition was associated with perioperative platelet transfusion. These results suggest that preoperative PFT with ADP–MEA could help reduce waiting time before urgent surgery for patients on P2Y12 inhibitors.

Ticagrelor Inhibits Toll-Like and Protease-Activated Receptor Mediated Platelet Activation in Acute Coronary Syndromes

PurposeSince ticagrelor inhibits the cellular uptake of adenosine, thereby increasing extracellular adenosine concentration and biological activity, we hypothesized that ticagrelor has adenosine-dependent antiplatelet properties. In the current study, we compared the effects of ticagrelor and prasugrel on platelet activation in acute coronary syndrome (ACS).MethodsPlatelet surface expression of P-selectin and activated glycoprotein (GP) IIb/IIIa in response to adenosine diphosphate (ADP), the toll-like receptor (TLR)-1/2 agonist Pam3CSK4, the TLR-4 agonist lipopolysaccharide (LPS), the protease-activated receptor (PAR)-1 agonist SFLLRN, and the PAR-4 agonist AYPGKF were measured by flow cytometry in blood from 80 ticagrelor- and 80 prasugrel-treated ACS patients on day 3 after percutaneous coronary intervention. Residual platelet aggregation to arachidonic acid (AA) and ADP were assessed by multiple electrode aggregometry and light transmission aggregometry.ResultsADP-induced platelet activation and aggregation, and AA-induced platelet aggregation were similar in patients on ticagrelor and prasugrel, respectively (all p ≥ 0.3). Further, LPS-induced platelet surface expression of P-selectin and activated GPIIb/IIIa did not differ significantly between ticagrelor- and prasugrel-treated patients (both p > 0.4). In contrast, Pam3CSK4-induced platelet surface expression of P-selectin and activated GPIIb/IIIa were significantly lower in ticagrelor-treated patients (both p ≤ 0.005). Moreover, SFLLRN-induced platelet surface expression of P-selectin and activated GPIIb/IIIa were significantly less pronounced in patients on ticagrelor therapy compared to prasugrel-treated patients (both p < 0.03). Finally, PAR-4 mediated platelet activation as assessed by platelet surface expression of activated GPIIb/IIIa following stimulation with AYPGKF was significantly lower in patients receiving ticagrelor (p = 0.02).ConclusionTicagrelor inhibits TLR-1/2 and PAR mediated platelet activation in ACS patients more strongly than prasugrel.

Cost-effectiveness of Platelet Function-Guided Strategy with Clopidogrel or Ticagrelor.

Some patients treated with dual antiplatelet therapy (DAPT) following acute coronary syndrome (ACS) can still exhibit heightened residual platelet reactivity (HRPR), which is potentially linked to adverse vascular outcomes. Better tailored DAPT strategies are needed to address this medical need. Aim: To assess the cost-effectiveness of guided DAPT with clopidogrel or ticagrelor in addition to aspirin when using VerifyNow P2Y12 testing in post-ACS patients. Methods: The costs were calculated per 1,000 patients aged >55 years. It was assumed that all patients received either generic clopidogrel or ticagrelor for 1 year, and underwent VerifyNow P2Y12 assay testing before DAPT maintenance. Results: Guided DAPT will prevent five more MIs and six more deaths per 1,000 patients than a standard prescription of generic clopidogrel. The total predictive value of costs per patient is 32% lower if a guided strategy is used than if ticagrelor is given to all patients. Conclusion: Assessment of heightened residual platelet reactivity with P2Y12 assay in triaging DAPT post-ACS patients for 1 year is a cost-effective strategy that would reduce financial burden compared to routine administration of more expensive antiplatelet agents.

A novel approach of platelet function test for prediction of attenuated response to clopidogrel.

BACKGROUND:Elevated mean platelet volume (MPV) and immature platelet fraction (IPF) are predictive for vascular risk. Both can be associated with residual platelet reactivity. We aimed to explore associations among platelet characteristics and responder status in stroke patients on clopidogrel.METHODS:Blood samples from 46 patients and 15 healthy subjects were analyzed for platelet count, MPV, IPF, large cell ratio (LCR) and high-fluorsecent immature platelet fraction (H-IPF). As a novelty, not only whole blood, but upper and lower half blood samples after 1-hour gravity sedimentation were analyzed. Platelet aggregometry was used for the whole blood and separated samples to explore area under the curve (AUC) in patients and controls.RESULTS:The AUC of the whole blood showed significant differences compared to the upper and lower samples separated after 1-hour sedimentation in patients and controls (p < 0.001 and p = 0.005 respectively). Remarkably, AUC measured in the upper samples in 59% of patients on clopidogrel were exceeding the therapeutic range suggesting that ascending platelets exert aggregation in the presence of ADP. This observation was associated with increased MPV and LCR in the upper samples (both p = 0.04). Patients on clopidogrel were characterized as responders and non-responders and the percentage of H-IPF was significantly higher among non-responders compared to controls in the upper samples (p = 0.04).CONCLUSIONS:The modified platelet function test may help to stratify patients with high residual platelet reactivity.

Comparison of Age (

Elderly patients may have increased platelet reactivity and adverse events after percutaneous coronary intervention. Whether age is an independent predictor of worse outcomes after accounting for platelet reactivity is unknown. We sought to determine the relation between age and platelet reactivity on 2-year outcomes after percutaneous coronary intervention with drug-eluting stents (DES). ADAPT-DES was a prospective observational registry comprising 8,582 DES-treated patients. Patients were categorized with an age cutoff of 75 years. On-clopidogrel platelet reactivity was evaluated with VerifyNow P2Y12 testing. Multivariable Cox proportional hazards regression models were used to describe the relation between increasing age and 2-year clinical outcomes. Patients ≥75 old were more likely to be women and had more cardiovascular risk factors and more extensive coronary artery disease than younger patients. Residual platelet reactivity on-clopidogrel increased slightly with age (adjusted r = 0.05, p <0.0001). Age ≥75 years was associated with greater all-cause mortality (adjusted HR 1.64, 95% CI 1.25 to 2.15, p <0.001), myocardial infarction (adjusted HR 1.33, 95% CI 1.01 to 1.74, p = 0.04) and clinically relevant bleeding (adjusted HR 1.33, 95% CI 1.10 to 1.61 p = 0.003). In contrast, the risk of stent thrombosis was independent of age (adjusted HR 0.83, 95% CI 0.46 to 1.52, and p = 0.55). Considered as a continuous variable, age was directly related to clinically relevant bleeding, cardiac and all-cause mortality, was inversely related to stent thrombosis, and was not related to myocardial infarction. There was no significant interaction between age and on-treatment platelet reactivity for the risk of 2-year clinical outcomes. In conclusion, increasing age had a stronger association with the risk of death and bleeding than of thrombotic events. Despite being associated with older age, higher residual platelet reactivity did not modify the adjusted relative risks of ischemic and bleeding events associated with age.

Double Layer Micromesh Stents Versus Closed Cell Stents for the Endovascular Treatment of Carotid Stenosis in the Current Era

Introduction: Although several randomized control studies showed increase incidence of adverse neurological events in the 30-day post-procedure outcomes in patients with carotid stenosis treated with carotid stenting (CAS) versus endarterectomy (CEA), recent guidelines suggests promising results with CAS in high volume centres with expert surgeons1. Based on this findings, companies that produce medical devices are multiplying their efforts to design new stents structure that can better protect carotid plaque during carotid stenosis endovascular treatment to avoid plaque prolapse or micro-debris embolization. The role of real effectiveness of Anti-platelet therapy on neurological complication of CAS remains unclear. The aim of this study is to examine the incidence of new ischaemic lesions, stroke o TIA, in patients treated in our centre using a new double-layer micromesh stent versus a closed cell stent. Methods: A Prospective randomized 1:1 trial was conducted from 1st January 2016 on going to compare the outcomes of carotid stenosis treatment with double-layer micromesh stents VS closed cell stents. The primary end point was the occurrence of death and neurological adverse events (TIA /Stroke) within 30 days. Secondary end point was the occurrence major adverse cardiovascular events (MACEs), defined as MI or severe arrhythmias. 88 patients were enrolled in both arm of the study. A distal protection device was used in all cases. All patient were treated preoperatively, and for 3 months post-operatively, with double anti-aggregation therapy and underwent multiplate platelet function testing using ADP test in order to assess clopidogrel resistance and therefore shifted to ticagrelor antiplatelet therapy. Statistical analysis was conducted with SAS software, version 9.4 (SAS Institute, Inc., Cary, NC). Results: There was 41 females (46,6%) and 47 males (53,4%) In group 1 and 38 females (43.2%) and 50 males in group 2 (56,8%). No stroke or death was observed in both groups of patients. No statistical differences were observed in terms of minor neurological adverse events (TIA) within 30 days: 2 (2.7%) patient experienced peri-operative TIA, with prompt recovery, and no new findings were seen in the neuroimaging in both arm of the trial. Patients symptomatic for pre-operative TIA within 30-days were treated in 2 cases (2.7%) in Group A and in 3 case (3.4%) in group B with no neurological post-operative complications. In terms of major adverse cardiovascular events (MACEs) no MI were observed in both groups. No statistical differences were defined for severe arrhythmias compared intra-operatively in 5 patients (5.7%) in group 1 vs 2 patients (2.7%) in group B (P 0.43). Overall the to groups, 20% of the patients showed high residual platelet reactivity after clopidogrel therapy ant thus shifted to ticagrelor for effective double anti-platelet therapy. Conclusion: Primary Carotid stenting with double-layer micromesh stents showed safe and feasible results. A tendency of a slightly higher incidence of intraoperative severe arrhythmias with the double layer micromesch stent may be due to higher radial force caused by the stent structure. Real effective antiplatelet therapy may partially explain similar results with both types of stents for the treatment of internal carotid artery stenosis.

Reasons for the Failure of Platelet Function Testing to Adjust Antiplatelet Therapy: Pharmacodynamic Insights From the ARCTIC Study.

In the ARCTIC trial (Assessment by a Double Randomization of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption Versus Continuation One Year After Stenting), treatment adjustment following platelet function testing failed to improve clinical outcomes. However, high-on-treatment platelet reactivity (HPR) is considered as a predictor of poor ischemic outcome. This prespecified substudy evaluated clinical outcomes according to the residual platelet reactivity status after antiplatelet therapy adjustment. We analyzed the 1213 patients assigned to the monitoring arm of the ARCTIC trial in whom platelet reactivity was evaluated by the VerifyNow P2Y12 test before percutaneous coronary intervention and during the maintenance phase (at 14 days). HPR was defined as platelet reaction unit≥235U. The primary ischemic end point, a composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization and the safety end point of major bleeding were assessed according to the platelet reactivity status. Before percutaneous coronary intervention, 35.7% of patients displayed HPR (n=419). During the acute phase, between percutaneous coronary intervention and the 14-day platelet function testing, ischemic (adjusted hazard ratio, 0.94 [95% CI, 0.74-1.18]; P=0.58) and safety outcomes (hazard ratio, 1.28 [95% CI, 0.22-7.59]; P=0.78) were similar in HPR and non-HPR patients. During the maintenance phase, the proportion of HPR patients (n=186, 17.4%) decreased by 56%. At 1-year, there was no difference for the ischemic end point (5.9% versus 6.0%; adjusted hazard ratio, 0.79 [95% CI, 0.40-1.58]; P=0.51) and a nonsignificant higher rate of major bleedings (2.7% versus 1.0%, hazard ratio, 2.83 [95% CI, 0.96-8.41]; P=0.06) in HPR versus non-HPR patients. The proportion of HPR was halved after platelet function testing and treatment adjustment but without significant ischemic benefit at 1 year. HPR seems more as a modifiable risk marker than a risk factor of ischemic outcome. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00827411.

Does the use of high dose atorvastatin in combination with dual antiplatelet therapy modify residual platelet activity in patients with acute coronary syndrome?

Does the use of high dose atorvastatin in combination with dual antiplatelet therapy modify residual platelet activity in patients with acute coronary syndrome?

Homocysteine levels and platelet reactivity in coronary artery disease patients treated with ticagrelor

Background and aimRecurrent atherothrombotic events have been reported in certain higher risk subsets of patients even with ticagrelor, a potent first-line antiplatelet agent for the management of patients with acute coronary syndrome (ACS). Hyperhomocysteinemia is a known determinant of platelet function abnormalities. Therefore, the aim of our study was to evaluate the impact of homocysteine (Hcy) levels on platelet reactivity in patients receiving Ticagrelor. Methods and resultsPatients with ACS undergoing percutaneous coronary revascularization and on dual antiplatelet therapy with ASA + Ticagrelor (90mg/twice a day) were scheduled for platelet function assessment 30–90 days post-discharge. Aggregation tests were performed by Multiple Electrode Aggregometry (MEA). Suboptimal platelet inhibition HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min).We included 432 patients, divided according to Hcy tertiles. Higher Hcy levels were associated with age, renal failure, creatinine levels and use diuretics (p < 0.001).Patients with higher Hcy levels displayed a higher platelet reactivity at COL test (p = 0.002), and ADP test (p = 0.04), with a linear relationship between Hcy and platelet aggregation after stimulation with collagen (r = 0.202, p < 0.001), thrombin receptor peptide (r = 0.104, p = 0.05) and ADP (r = 0.145, p = 0.006).However, Hcy levels did not significantly affect the rate of HRPR with Ticagrelor (9.9% vs 13.7% vs 10.7%, p = 0.89; adjusted OR [95% CI] = [0.616–1.51], p = 0.99). ConclusionsAmong patients with ACS, despite the elevated platelet reactivity associated to hyperhomocysteinemia, DAPT with ticagrelor could overcome such phenomenon, achieving an adequate platelet inhibition in the majority of the patients.