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Optimum duration of dual antiplatelet treatment (DAPT) after coronary stenting remains uncertain, with an unknown efficacy to safety ratio of extended treatment leading to discrepancies between international guidelines and clinical practice. We assessed whether DAPT continuation beyond 1 year after coronary stenting is beneficial. This analysis was a planned extension of the previously published ARCTIC-Monitoring trial, in which we randomly allocated 2440 patients to a strategy of platelet function testing with antiplatelet treatment adjustment or a conventional strategy after coronary stenting with drug-eluting stent (DES). We recruited patients (aged 18 years or older) scheduled for planned DES implantation at 38 centres in France. After 1 year of follow-up, patients without contraindication to interruption of DAPT were eligible for a second randomisation to this second phase of the study (ARCTIC-Interruption). Using a computer-generated randomisation sequence (1:1; stratified by centre), we allocated patients to a strategy of interruption of DAPT where the thienopyridine was interrupted and single aspirin antiplatelet treatment was maintained (interruption group) or a strategy of DAPT continuation for 6–18 months (continuation group). The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularisation, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00827411. Between Jan 4, 2011, and March 3, 2012, 1259 eligible patients were randomly allocated to treatment in ARCTIC-Interruption: 624 to the interruption group and 635 to the continuation group. After a median follow-up of 17 months (IQR 15–18), the primary endpoint occurred in 27 (4%) patients in the interruption group and 24 (4%) patients in the continuation group (hazard ratio [HR] 1·17 [95% CI 0·68–2·03]; p=0·58). STEEPLE major bleeding events occurred more often in the continuation group (seven [1%] patients) compared with the interruption group (one [<0·5%] patient; HR 0·15 [0·02–1·20]; p=0·073). Major or minor bleedings were also more common in the continuation group compared with the interruption group (12 [2%] patients vs three [1%] patients; HR 0·26 [0·07–0·91]; p=0·04). Our finding suggests no apparent benefit but instead harm with extension of DAPT beyond 1 year after stenting with DES when no event has occurred within the first year after stenting. No conclusion can be drawn for high-risk patients who could not be randomised. The consistency between findings from all trials of such interruption suggests the need for a reappraisal of guidelines for DAPT after coronary stenting towards shorter duration of treatment. Allies in Cardiovascular Trials Initiatives and Organized Networks (ACTION Study Group), Fondation de France, Sanofi-Aventis, Cordis, Medtronic, Boston Scientific, Fondation SGAM.

In the context of interventional cardiology, platelet function testing may identify patients treated with P2Y12-inhibitors at an increased risk of mortality, thrombosis and bleeding. Several whole blood point-of-care platelet function analyzers are available; however, inter-device differences have not been examined systematically. To compare three platelet function tests under standardized in vitro conditions. Healthy volunteer (n = 10) blood samples were spiked with increasing concentrations of ticagrelor (0–7500 ng/mL) and/or ASA (0–3280 ng/mL), measured on three platelet function analyzers (TEG®6s, Multiplate®, and VerifyNow®) and respective Effective Concentration (EC) levels EC10, EC50 and EC90 were calculated. Repeatability was assessed in a separate group of pooled blood samples (n = 10) spiked with ticagrelor at EC10, EC50 and EC90. ASA had no impact on ADP-activated channels for all three devices. TEG®6s was able to distinguish (p ≤ 0.05) between all ticagrelor EC zones; VerifyNow® and Multiplate® were able to distinguish between three and two zones, respectively. Multiplate® showed the largest window between EC10 and EC90 (19–9153 ng/mL), followed by TEG®6s (144–2589 ng/mL), and VerifyNow® (191–1100 ng/mL). Drug effect models distribution of disagreements were identified for TEG®6s (5.0%), VerifyNow® (8.3%), and Multiplate® (13.3%). TEG®6s showed the smallest average coefficient of variation between EC conditions (5.1%), followed by Multiplate® (14.1%), and VerifyNow® (17.7%). Linear models could be generated between TEG®6s and Multiplate®, but not VerifyNow®. Significant differences were found between whole blood point-of-care platelet function analyzers and the clinical impact of these differences needs to be further investigated.

Abstract Background Platelet function testing may be warranted to assess response to aspirin and clopidogrel. Hypothesis/Objectives To evaluate the effects of aspirin, clopidogrel, or combination therapy using 3 platelet function tests: Multiplate Analyzer (MP), Platelet Function Analyzer-200 (PFA), and Plateletworks (PW). Animals Six healthy laboratory Beagles. Methods Randomized double-blind placebo-controlled study (crossover design). Dogs were given aspirin 1 mg/kg, clopidogrel 2 mg/kg, or combination therapy for 1 week each, with a washout period of 2 weeks. Platelet function was assessed on days 0 and 7 of each phase using MP (adenosine diphosphate [ADP], arachidonic acid [AA], collagen [COL] agonists), PFA (P2Y, COL-ADP [CADP], COL-Epinephrine [CEPI] cartridges), and PW (ADP, AA, COL agonists). Platelet counts were obtained with impedance and optical counters. Results For MP, mean aggregation was decreased for COL and AA with combination therapy and for ADP with all treatments. For PFA, mean CT was increased for the CEPI cartridge with aspirin; and for the P2Y and CADP cartridges with clopidogrel or combination therapy. More dogs receiving clopidogrel showed an increase in PFA CT using the P2Y than the CADP cartridge. For PW, mean aggregation was decreased for AA with all treatments; for ADP with clopidogrel or combination therapy; and for COL with clopidogrel. The PW results with the 2 hematology counters showed almost perfect agreement. Conclusion and Clinical Importance All platelet function tests detected treatment effects in some dogs and may have utility for monitoring therapy.

Prolonged use of dual antiplatelet therapy (DAPT) post-percutaneous coronary intervention (PCI) has been shown to reduce the risk of major adverse cardiovascular events (MACE), but with increased bleeding. It remains unknown whether biomarkers of platelet activation may be useful for identifying patients at increased risk of MACE. The DAPT study was a randomized trial of 12 versus 30 months of DAPT in patients who underwent PCI. Serum biomarkers [myeloid-related protein (MRP)-8/14, P-selectin, soluble CD-40 ligand (sCD40L)] were assessed in 1399 patients early post-PCI. On-treatment platelet reactivity index (PRI) using VASP phosphorylation was assessed in 443 patients randomized to continued DAPT at 1 year. MACE was defined as CV death, MI, or ischemic stroke. Multivariable models were adjusted for baseline characteristics, index event, and stent type. A stepwise increase in the risk of MACE was observed with increasing tertiles of both MRP-8/14 and P-selectin (p-trend = 0.04 for both). After multivariable adjustment, the adjusted HR (95% CI) for MACE in patients in the top tertile was 1.94 (1.14–3.30) for MRP-8/14 and 1.62 (0.99–2.64) for P-selectin. In contrast, baseline sCD40L was not associated with CV risk. Among patients randomized to continued DAPT, higher on-treatment platelet reactivity was not significantly associated with risk of MACE (p-trend = 0.32; adj-HR T3 vs. T1 1.54, 95% CI 0.20–12.18) or bleeding (P-trend = 0.17; adj-HR 0.25, 95% CI 0.05–1.21). MRP-8/14 and soluble P-selectin may be useful for identifying patients at increased risk of MACE after PCI. The utility of on-treatment platelet function testing requires further study.Clinical Trial Registrationhttps://www.clinicaltrials.gov. Unique identifier NCT00977938.

Purpose Current treatment guidelines do not recommend different antiplatelet treatments for patients in different coronary risk categories; nor do they consider ethnic differences in responses to individual drugs. Objectives We performed a prospective, single-blind, randomized, comparative study of Taiwanese patients with stable angina and scheduled stent implantation for intermediate-to-highly complex coronary lesions and compared the platelet reactivity unit (PRU) levels and 24-month outcomes of groups receiving three different antiplatelet treatments. Methods Patients ( N  = 334) were randomized into three treatment groups (aspirin + clopidogrel, aspirin + ticagrelor, or aspirin + clopidogrel + cilostazol) for 6 months of treatment and were then switched to aspirin only. PRU levels were determined 24 h, 7 days, and 1 month after stent implantation. Clinical outcomes and adverse events were recorded over 24 months. Results Clopidogrel treatment reached full effect after 1 month. Ticagrelor decreased PRU levels more than did clopidogrel but often to levels that increased the risk of hemorrhage. The addition of cilostazol to clopidogrel decreased PRU levels earlier and more strongly than clopidogrel alone but not as strongly as did ticagrelor. Ticagrelor treatment caused fewer major adverse cardiovascular events (MACEs) and more episodes of minor bleeding than the other two treatments. Conclusions Clopidogrel appears safer than ticagrelor in Taiwanese patients with stable angina after stent implantation for intermediate-to-highly complex coronary lesions. The addition of cilostazol to clopidogrel may provide a more rapid decrease in PRU to therapeutic levels without increasing the risk of hemorrhage. Clinical trial registration number NCT02101411.

In physiological hemostasis a prompt recruitment of platelets on the vessel damage prevents the bleeding by the rapid formation of a platelet plug. Qualitative and/or quantitative platelet defects promote bleeding, whereas the high residual reactivity of platelets in patients on antiplatelet therapies moves forward thromboembolic complications. The biochemical mechanisms of the different phases of platelet activation - adhesion, shape change, release reaction, and aggregation - have been well delineated, whereas their complete translation into laboratory assays has not been so fulfilled. Laboratory tests of platelet function, such as bleeding time, light transmission platelet aggregation, lumiaggregometry, impedance aggregometry on whole blood, and platelet activation investigated by flow cytometry, are traditionally utilized for diagnosing hemostatic disorders and managing patients with platelet and hemostatic defects, but their use is still limited to specialized laboratories. To date, a point-of-care testing (POCT) dedicated to platelet function, using pertinent devices much simpler to use, has now become available (ie, PFA-100, VerifyNow System, Multiplate Electrode Aggregometry [MEA]). POCT includes new methodologies which may be used in critical clinical settings and also in general laboratories because they are rapid and easy to use, employing whole blood without the necessity of sample processing. Actually, these different platelet methodologies for the evaluation of inherited and acquired bleeding disorders and/or for monitoring antiplatelet therapies are spreading and the study of platelet function is strengthening. In this review, well-tried and innovative platelet function tests and their methodological features and clinical applications are considered.

Platelet storage pool disease (SPD) is a platelet function disorder characterized by a reduction in the number or content of α-granules, dense granules, or both, and is diagnosed by specialized tests. Patients with SPD often present with prolonged bleeding time (BT), but the sensitivity and reproducibility of this test have limitations, often resulting in false negatives. It has recently been reported that an automated microchip flow-chamber system (T-TAS ® ) is useful in the assessment of anti-platelet therapy, and could have potential as a screening test for SPD. We examined the utility of T-TAS in three individuals from one family diagnosed with δ-SPD. The propositus had a mildly prolonged BT, and the standard tests for platelet function were close to the normal range. Whole blood samples were anti-coagulated with hirudin and applied to T-TAS microchips coated with collagen (PL-chips) at shear rates of 1000 and 2000 s −1 . Platelet thrombus formation (PTF) was monitored with a pressure sensor. Markedly depressed PTF was observed in all cases at both shear rates. These findings indicate that T-TAS is highly sensitive to the defect in these patients with SPD, and may represent a good candidate screening test for a wide range of platelet function disorders.

Background Proton-pump inhibitors (PPIs) are often prescribed to patients receiving dual antiplatelet therapy (DAPT). However, this class of medication, especially omeprazole, has been associated with a reduction in clopidogrel efficacy, leading many clinicians to substitute omeprazole with ranitidine. Objectives Our objective was to compare the antiplatelet effect of clopidogrel before and after the addition of omeprazole or ranitidine. Methods We measured platelet aggregability at baseline and after 1 week of clopidogrel 75 mg daily. Subjects were then randomized in a double-blinded, double-dummy fashion to omeprazole 20 mg twice daily (bid) or ranitidine 150 mg bid. We repeated aggregability tests after 1 additional week, using VerifyNow P2Y12™ (Accumetrics; San Diego, CA, USA), depicting aggregability as percent inhibition of platelet aggregation (IPA). Results We enrolled 41 patients in the omeprazole group and 44 in the ranitidine group. IPA was significantly decreased after the addition of omeprazole to clopidogrel (from 26.3 ± 32.9 to 17.4 ± 33.1 %; p  = 0.025), with no statistical significant changes observed in the ranitidine group (from 32.6 ± 28.9 to 30.1 ± 31.3 %; p  = 0.310). The comparison of IPA in both groups at the end of the follow-up showed a trend toward significance ( p  = 0.07, 95 % confidence interval [CI] −1.19 to 26.59); after excluding homozygous patients for 2C19*2 genotype, the comparison of IPA between the groups reached statistical significance (32.7 ± 30.8 vs. 17.7 ± 33.4 %, respectively, for ranitidine and omeprazole groups; p  = 0.04). Conclusions Unlike omeprazole, ranitidine did not influence platelet aggregability response to clopidogrel. Clinical Trial Registration NCT01896557.

Various platelet function tests are currently used to measure responsiveness to antiplatelet therapy. We sought to compare 2 point-of-care platelet function tests, VerifyNow Assay (Accumetrics, San Diego, CA) and Multiple Electrode Platelet Aggregometry (MEA) (Dynabyte, Munich, Germany), for predicting early clinical outcomes after percutaneous coronary intervention. Platelet reactivity in the arachidonic acid–induced and adenosine diphosphate (ADP)–induced platelet aggregation was measured simultaneously with the VerifyNow Assay and MEA in 222 patients undergoing percutaneous coronary intervention between August and October 2009. We investigated the correlations between the 2 tests and performed receiver operating characteristic curve analysis for major adverse cardiovascular events (MACE), a composite of death, myocardial infarction (MI), stroke, and target vessel revascularization, at 30 days. Major adverse cardiovascular events occurred in 19 patients (8.6%), including 14 patients with periprocedural MI and 5 patients with stroke. Correlations were weak between the 2 tests in the arachidonic acid–induced (Spearman r = 0.189, P = .006) and ADP-induced platelet reactivity (Spearman r = 0.390, P < .001). Although the VerifyNow P2Y12 Assay (Accumetrics) was able to predict periprocedural MI (area under the aggregation curve 0.680, P = .024) and 30-day MACE (area under the aggregation curve 0.649, P = .032), VerifyNow Aspirin Assay (Accumetrics), MEA ASPI test, and MEA ADP test failed to predict such clinical events. Hyporesponsiveness to clopidogrel based on the VerifyNow Assay was associated with about a 6-fold increased risk of MACE at 30 days. Hyporesponsiveness to clopidogrel measured by VerifyNow Assay was able to identify patients with dual antiplatelet therapy who were at higher risk for periprocedural MI and MACE at 30 days. Further randomized studies are required to validate the effectiveness of different platelet function tests for predicting long-term clinical outcomes.

Accurate assessment of blood haemostasis is essential for the management of patients who use extracorporeal devices, receive anticoagulation therapy or experience coagulopathies. However, current monitoring devices do not measure effects of haemodynamic forces that contribute significantly to platelet function and thrombus formation. Here we describe a microfluidic device that mimics a network of stenosed arteriolar vessels, permitting evaluation of blood clotting within small sample volumes under pathophysiological flow. By applying a clotting time analysis based on a phenomenological mathematical model of thrombus formation, coagulation and platelet function can be accurately measured in vitro in patient blood samples. When the device is integrated into an extracorporeal circuit in pig endotoxemia or heparin therapy models, it produces real-time readouts of alterations in coagulation ex vivo that are more reliable than standard clotting assays. Thus, this disposable device may be useful for personalized diagnostics and for real-time surveillance of antithrombotic therapy in clinic. The current hemostasis assays are unable to predict thrombotic or bleeding risk in clinics. Here, Jain et al . present a novel microfluidic device mimicking stenosed arterioles that determines clotting times in vitro and in extracorporeal circuits, offering a simple and reliable monitoring of blood homeostasis and platelet function.