Measuring high on-treatment platelet reactivity in clinical practice; should we use a panel of platelet function tests?

: High on-treatment platelet reactivity (HPR) on P2Y12-inhibitors in patients treated with dual antiplatelet therapy is strongly associated with adverse ischaemic events. Studies have shown conflicting results with regard to the correlation and agreement between the different tests. Several assays are available to establish HPR. A composite advice based on more than one test might be a better way to identify HPR patients. To compare HPR rates and agreement between individual platelet function tests and a panel of three tests In our large percutaneous coronary intervention centre, all patients who suffered a stent thrombosis were invited back to a dedicated clinic. Platelet function testing was performed in all patients and matched control patients. HPR rates were compared between individual tests and with a composite comprised of three tests. A total of 242 patients were included, of whom in 193 patients all tests were available. HPR rates ranged from 14.6% [VerifyNow cut-off >235 platelet reactivity units (PRU)] to 49.7% (Vasodilator-Stimulated Phosphoprotein Assay). HPR according to the composite advice (≥2 out of 3 tests indicating HPR) was present in 29.8% of patients. The best correlation with the composite advice was observed with light transmittance aggregometry (kappa = 0.78) and VerifyNow (lower cut-off >208 PRU; kappa = 0.68). VerifyNow with cut-off more than 235 PRU identified the smallest proportion of patients with HPR, whereas Vasodilator-Stimulated Phosphoprotein Assay seemed to 'over-identify' HPR. In this real life patient cohort, a large variability was observed between four different platelet function tests. The use of a composite advice based on three tests is a promising alternative.

Tailored P2Y12 inhibitor treatment in patients undergoing non-urgent PCI-the POPular Risk Score study.

PURPOSE: The POPular Risk Score was developed for the selective intensification of P2Y12 inhibitor treatment with prasugrel instead of clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI) with stent implantation. This score is based on platelet reactivity (VerifyNow P2Y12 assay), CYP2C19 genotyping, and clinical risk factors. Our aim was to determine if the use of this score in clinical practice is associated with a reduction in thrombotic events without increasing bleeding events. METHODS: In a single-center prospective cohort study, patients with a high risk score were treated with prasugrel and patients with a low risk score with clopidogrel. The risk score-guided cohort was compared with a historic cohort of clopidogrel-treated patients. The endpoint consisted of all-cause death, myocardial infarction, stroke, or stent thrombosis during 1 year of follow-up. TIMI major and minor bleeding events were also analyzed. RESULTS: The guided cohort contained 1127 patients, 26.9% of whom were switched to prasugrel according to the POPular Risk Score. The historic cohort contained 893 patients. The incidence of the combined thrombotic endpoint was significantly lower in the guided cohort as compared with the historic cohort (8.4% versus 3.7%, p < 0.001). This strategy was safe with respect to bleeding (4.0% versus 1.3%, p < 0.001, for TIMI major or minor bleeding). Results were comparable after multivariate and propensity score matched and weighted analysis. CONCLUSION: Selective intensification of P2Y12 inhibitor treatment after non-urgent PCI based on the POPular Risk Score is associated with a reduction in thrombotic events without an increase in bleeding events.

Neoatherosclerosis in Patients With Coronary Stent Thrombosis: Findings From Optical Coherence Tomography Imaging (A Report of the PRESTIGE Consortium).

OBJECTIVES: The purpose of this study was to assess neoatherosclerosis in a registry of prospectively enrolled patients presenting with stent thrombosis using optical coherence tomography. BACKGROUND: In-stent neoatherosclerosis was recently identified as a novel disease manifestation of atherosclerosis after coronary stent implantation. METHODS: Angiography and intravascular optical coherence tomography were used to investigate etiologic factors of neoatherosclerosis in patients presenting with stent thrombosis >1 year after implantation (very late stent thrombosis [VLST]). Clinical data were collected according to a standardized protocol. Optical coherence tomographic acquisitions were analyzed in a core laboratory. Cox regression analysis was performed to identify factors associated with the formation of neoatherosclerosis and plaque rupture as a function of time. RESULTS: Optical coherence tomography was performed in 134 patients presenting with VLST. A total of 58 lesions in 58 patients with neoatherosclerosis were compared with 76 lesions in 76 patients without neoatherosclerosis. Baseline characteristics were similar between groups. In-stent plaque rupture was the most frequent cause (31%) in all patients presenting with VLST. In patients with neoatherosclerosis, in-stent plaque rupture was identified as the cause of VLST in 40 cases (69%), whereas uncovered stent struts (n = 22 [29%]) was the most frequent cause in patients without neoatherosclerosis. Macrophage infiltration was significantly more frequent in optical coherence tomographic frames with plaque rupture compared with those without (50.2% vs. 22.2%; p < 0.0001), whereas calcification was more often observed in frames without plaque rupture (17.2% vs. 4%; p < 0.0001). Implantation of a drug-eluting stent was significantly associated with the formation of neoatherosclerosis (p = 0.02), whereas previous myocardial infarction on index percutaneous coronary intervention was identified as a significant risk factor for plaque rupture in patients with neoatherosclerosis (p = 0.003). No significant difference was observed in thrombus composition between patients with or without neoatherosclerosis. CONCLUSIONS: Neoatherosclerosis was frequently observed in patients with VLST. Implantation of a drug-eluting stent was significantly associated with neoatherosclerosis formation. In-stent plaque rupture was the prevailing pathological mechanism and often occurred in patients with neoatherosclerosis and previous myocardial infarction at index percutaneous coronary intervention. Increased macrophage infiltration heralded plaque vulnerability in our study and might serve as an important indicator.

A clinical risk score to identify patients at high risk of very late stent thrombosis.

OBJECTIVES: The aim of this study was to determine predictors of very late stent thrombosis (VLST; >1 year after stenting), and to evaluate whether addition of these predictors to the dual antiplatelet therapy (DAPT) score would improve the ability to identify patients at high risk of VLST who might benefit from DAPT. BACKGROUND: VLST is a severe complication of percutaneous coronary intervention (PCI). Extended knowledge about the predictors of VLST is needed to prevent this life-threatening complication. Recent data showed a reduction in VLST after treatment with prolonged DAPT. The DAPT study developed a prediction score to identify patients after PCI who might benefit from prolonged DAPT duration. METHODS: The Dutch stent thrombosis study is a multi-center case-control study. Consecutive patients with definite VLST were included between 2007 and 2014. Baseline characteristics from the index PCI were collected. Independent predictors of VLST were identified and added to the DAPT score to develop the VLST score. RESULTS: In total, 155 VLST cases and 155 matched controls were included. Suboptimal result of stenting, right coronary artery as target vessel, and diffuse coronary artery ectasia were independent predictors of VLST, and added to the DAPT score. The power of the VLST score to identify patients who experienced VLST was increased (AUC, 95%CI; DAPT score: 0.64, 0.57-0.70; VLST score: 0.70, 0.63-0.76, P = 0.010). CONCLUSIONS: Addition of newly identified independent predictors of VLST resulted in a prediction model with a higher ability to identify patients at high risk of VLST who might benefit from prolonged DAPT.

Safety of Ticagrelor Compared to Clopidogrel after Prehospital Initiation of Treatment.

Objectives The objective of this registry was to study the safety of prehospital initiation of ticagrelor compared with clopidogrel. Background Ticagrelor has replaced clopidogrel in many hospitals as the routinely used antiplatelet drug in patients with ST-segment elevation myocardial infarction (STEMI). Nevertheless, in the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor was associated with an increase in non-CABG (non-coronary artery bypass grafting)-related major bleeding. Data comparing the safety of ticagrelor and clopidogrel after prehospital initiation of treatment are not available. Methods A retrospective, multicenter registry was performed. Selection criteria were the administration of a prehospital loading dose of ticagrelor or clopidogrel according to the ambulance STEMI treatment protocol and the presentation to a percutaneous coronary intervention-capable hospital in our region between January 2011 and December 2012. Follow-up was performed using the electronic patient files for the time period between the antiplatelet loading dose and hospital discharge. The data were analyzed using a primary bleeding end point (any bleeding) and a secondary thrombotic end point (all-cause mortality, spontaneous myocardial infarction, definite stent thrombosis, stroke, or transient ischemic attack). Results Data of 304 clopidogrel-treated and 309 ticagrelor-treated patients were available for analysis. No significant difference in bleeding rate was observed between both groups, using univariate (17.8 vs. 20.1%; p = 0.47; odds ratio, 1.16 [95% confidence interval, 0.78-1.74]) and multivariate ( p = 0.42) analysis. Also for the secondary thrombotic end point (6.3 vs. 4.9%, p = 0.45), no significant differences were observed. Conclusion In this real-world registry, no significant differences in bleeding or thrombotic event rate were found between ticagrelor and clopidogrel after prehospital initiation of treatment.

Observational Study of Platelet Reactivity in Patients Presenting With ST-Segment Elevation Myocardial Infarction Due to Coronary Stent Thrombosis Undergoing Primary Percutaneous Coronary Intervention: Results From the European PREvention of Stent Thrombosis by an Interdisciplinary Global European Effort Registry.

OBJECTIVES: High platelet reactivity (HPR) was studied in patients presenting with ST-segment elevation myocardial infarction (STEMI) due to stent thrombosis (ST) undergoing immediate percutaneous coronary intervention (PCI). BACKGROUND: HPR on P2Y12 inhibitors (HPR-ADP) is frequently observed in stable patients who have experienced ST. The HPR rates in patients presenting with ST for immediate PCI are unknown. METHODS: Consecutive patients presenting with definite ST were included in a multicenter ST registry. Platelet reactivity was measured before immediate PCI with the VerifyNow P2Y12 or Aspirin assay. RESULTS: Platelet reactivity was measured in 129 ST patients presenting with STEMI undergoing immediate PCI. HPR-ADP was observed in 76% of the patients, and HPR on aspirin (HPR-AA) was observed in 13% of the patients. HPR rates were similar in patients who were on maintenance P2Y12 inhibitor or aspirin since stent placement versus those without these medications. In addition, HPR-ADP was similar in patients loaded with a P2Y12 inhibitor shortly before immediate PCI versus those who were not. In contrast, HPR-AA trended to be lower in patients loaded with aspirin as compared with those not loaded. CONCLUSIONS: Approximately 3 out of 4 ST patients with STEMI undergoing immediate PCI had HPR-ADP, and 13% had HPR-AA. Whether patients were on maintenance antiplatelet therapy while developing ST or loaded with P2Y12 inhibitors shortly before undergoing immediate PCI had no influence on the HPR rates. This raises concerns that the majority of patients with ST have suboptimal platelet inhibition undergoing immediate PCI.

High risk of stent thrombosis in the first 6 months after coronary stenting: Do not discontinue clopidogrel early after ACS.

OBJECTIVES: To estimate the incidence of stent thrombosis (ST) after early discontinuation of clopidogrel. BACKGROUND: Premature discontinuation of clopidogrel is the strongest risk factor for ST. In contrast, recent studies suggest that shorter dual antiplatelet therapy (DAPT) can be discontinued as soon as 3 months after stenting. However, these studies included very few ACS patients and were not powered for ST. Hence, little is known about the occurrence of ST in high-risk populations when DAPT is discontinued early. METHODS: This is a subanalysis of The Dutch ST Registry 437 ST cases (mainly first-generation DES and BMS). Acute coronary syndrome was the indication for index-PCI in 74% of the patients. Clopidogrel discontinuation rates in ST patients and matched controls were used to calculate the absolute incidence of ST after early clopidogrel discontinuation. RESULTS: The overall rate of ST after cessation of clopidogrel was 4.6% (95%CI: 3.9-5.4%), as compared to 1.7% (95%CI: 1.5-1.9%) in patients who did not discontinue clopidogrel. The incidence of ST was 35.4% when clopidogrel was discontinued in the first 30 days after index-PCI declining to 11.7% when clopidogrel was discontinued in the first 180 days. CONCLUSIONS: This dedicated ST registry shows that ST rates were very high when clopidogrel was discontinued before 6 months after index-PCI and therefore suggests that clopidogrel discontinuation in the first 6 months after ACS should be avoided.

Incidence and Causes for Early Ticagrelor Discontinuation: A "Real-World" Dutch Registry Experience.

OBJECTIVES: The PLATO trial revealed superiority of ticagrelor over clopidogrel for the prevention of atherothrombotic events in patients with acute coronary syndrome. However, adverse events such as bleeding, dyspnea, and bradycardia were frequently reported, potentially leading to excess early ticagrelor discontinuation (ETD), later confirmed in the PEGASUS trial. We here evaluated the incidence and causes for ETD in a real-world patient cohort in a high-volume nonacademic percutaneous coronary intervention center in the Netherlands. METHODS: In a retrospective single-center registry, all patients discharged from the hospital with a new ticagrelor prescription were screened for ETD. Follow-up data were obtained using the hospital electronic patient file records and confirmed by telephone contact with the patient and/or general practitioner, if necessary, to complement the data. RESULTS: Ticagrelor was prescribed in 354 patients between December 2011 and December 2012. The follow-up data were available in 301 patients with a mean follow-up duration of 330 days. ETD or switching to another antiplatelet agent occurred in 73 patients (24.3%), mostly due to dyspnea (11.6%), bleeding (3.7%), or planned major surgery (2.7%). CONCLUSIONS: Almost one quarter of ticagrelor patients were discontinued prematurely or switched to another antiplatelet agent within 1 year, mostly due to dyspnea or bleeding.

Optical Coherence Tomography Findings in Patients With Coronary Stent Thrombosis: A Report of the PRESTIGE Consortium (Prevention of Late Stent Thrombosis by an Interdisciplinary Global European Effort).

BACKGROUND: Stent thrombosis (ST) is a serious complication following coronary stenting. Intravascular optical coherence tomography (OCT) may provide insights into mechanistic processes leading to ST. We performed a prospective, multicenter study to evaluate OCT findings in patients with ST. METHODS: Consecutive patients presenting with ST were prospectively enrolled in a registry by using a centralized telephone registration system. After angiographic confirmation of ST, OCT imaging of the culprit vessel was performed with frequency domain OCT. Clinical data were collected according to a standardized protocol. OCT acquisitions were analyzed at a core laboratory. Dominant and contributing findings were adjudicated by an imaging adjudication committee. RESULTS: Two hundred thirty-one patients presenting with ST underwent OCT imaging; 14 (6.1%) had image quality precluding further analysis. Of the remaining patients, 62 (28.6%) and 155 (71.4%) presented with early and late/very late ST, respectively. The underlying stent type was a new-generation drug-eluting stent in 50.3%. Mean reference vessel diameter was 2.9±0.6 mm and mean reference vessel area was 6.8±2.6 mm2. Stent underexpansion (stent expansion index <0.8) was observed in 44.4% of patients. The predicted average probability (95% confidence interval) that any frame had uncovered (or thrombus-covered) struts was 99.3% (96.1-99.9), 96.6% (92.4-98.5), 34.3% (15.0-60.7), and 9.6% (6.2-14.5) and malapposed struts was 21.8% (8.4-45.6), 8.5% (4.6-15.3), 6.7% (2.5-16.3), and 2.0% (1.2-3.3) for acute, subacute, late, and very late ST, respectively. The most common dominant finding adjudicated for acute ST was uncovered struts (66.7% of cases); for subacute ST, the most common dominant finding was uncovered struts (61.7%) and underexpansion (25.5%); for late ST, the most common dominant finding was uncovered struts (33.3%) and severe restenosis (19.1%); and for very late ST, the most common dominant finding was neoatherosclerosis (31.3%) and uncovered struts (20.2%). In patients presenting very late ST, uncovered stent struts were a common dominant finding in drug-eluting stents, and neoatherosclerosis was a common dominant finding in bare metal stents. CONCLUSIONS: In patients with ST, uncovered and malapposed struts were frequently observed with the incidence of both decreasing with longer time intervals between stent implantation and presentation. The most frequent dominant observation varied according to time intervals from index stenting: uncovered struts and underexpansion in acute/subacute ST and neoatherosclerosis and uncovered struts in late/very late ST.

How Long Does It Take for Clopidogrel and Ticagrelor to Inhibit Platelets in Patients Undergoing Primary Percutaneous Coronary Intervention? A Detailed Pharmacodynamic Analysis: Time Course of Platelet Reactivity in STEMI (TOPS).

Antiplatelet therapy plays a pivotal role in patients with an ST-segment elevation myocardial infarction (STEMI) to prevent further atherothrombotic events, such as stent thrombosis. Although the risk of stent thrombosis is highest in the first hours after primary percutaneous coronary intervention (pPCI), little is known about when an adequate level of platelet inhibition is achieved following a clopidogrel or ticagrelor loading dose in STEMI patients. Patients presenting with STEMI in whom pPCI was performed and who were loaded with 600 mg clopidogrel or 180 mg ticagrelor were eligible for enrolment in this nonrandomized, open label, single-center study. Platelet reactivity was measured before PCI, 6 and 24 hours after loading dose and after 2, 7, and 14 days, using the VerifyNow P2Y12 assay as well as 20 µmol/L adenosine diphosphate stimulated light transmittance aggregometry (LTA). We analyzed the time until a VerifyNow result of < 236 P2Y12 reaction units or LTA maximum platelet aggregation of < 64.5% was reached. A total of 28 patients were participated in this study. Platelet reactivity dropped below the high platelet reactivity cutoff level after 11.4 (VerifyNow) and 5.7 (LTA) hours in patients who were loaded with clopidogrel, and after 2.4 (VerifyNow) and 3.9 (LTA) hours in patients who were loaded with ticagrelor. Despite the administration of a clopidogrel or ticagrelor loading dose, it still takes multiple hours (2-11) to reach adequate platelet inhibition in STEMI patients. This might indicate the need for additional antiplatelet therapy in the first hours after loading in patients undergoing pPCI with stenting.

Effect of Tailored Antiplatelet Therapy to Reduce Recurrent Stent Thrombosis and Cardiac Death After a First Episode of Stent Thrombosis.

The recurrence rate of coronary stent thrombosis (ST) is high. Patients with ST often demonstrate high on-treatment platelet reactivity (HPR). It is suggested that patients at high risk of atherothrombotic events, that is patients with ST, could benefit from tailored antiplatelet therapy (APT). This study evaluated whether tailored APT, based on platelet function testing, reduced the rate of cardiac death and/or recurrent ST at 1 year after ST, compared with a historical cohort of patients with ST without tailored APT. Patients with definite ST visited our ST outpatient clinic for platelet function testing and tailored APT. These patients were evenly matched to a historical cohort of patients with ST treated with aspirin and clopidogrel, which was the standard of care at that time. The primary end point was a composite of cardiac death and/or recurrent definite ST after 1 year. In total, 113 patients who visited the outpatient clinic were included. HPR was observed in 46%, 6.7%, and 0% of the patients on clopidogrel, prasugrel, and ticagrelor, respectively. After tailored APT, 93% of the patients with HPR demonstrated normal platelet reactivity. The primary end point was observed in 4 patients who had visited the outpatient clinic and in 23 patients of the historical cohort. The odds ratio of tailored APT on the primary end point was 0.26 (95% confidence interval 0.11 to 0.64, p = 0.003), independent from the possible confounders prior myocardial infarction and stent type. In conclusion, the outpatient ST clinic was associated with lower HPR rates in patients with ST after tailored APT. Patients who visited the ST outpatient clinic had a lower risk for cardiac death and/or recurrent ST compared with a historical cohort of patients with ST without tailored APT. Regarding the high HPR rate in patients with ST on clopidogrel, these patients might benefit in particular from the strategy of tailored APT.

Fibrin clot formation and fibrinolysis in patients with a history of coronary stent thrombosis.

INTRODUCTION: Coronary stent thrombosis is a devastating complication of percutaneous coronary intervention (PCI). Multiple factors underlie the pathophysiological mechanisms of stent thrombosis. Previous studies demonstrated that patients with stent thrombosis, compared to control PCI patients, formed denser fibrin clots in vitro which were more resistant to fibrinolysis, suggesting that altered fibrin clot properties may contribute to the pathophysiology of stent thrombosis. We assessed the plasma fibrin clot formation and fibrinolysis of patients with and without stent thrombosis. METHODS: Cases (patients with stent thrombosis) and matched controls (patients without stent thrombosis) were included for a matched case-control study. Matching was performed on indication and time of the index PCI (initial stent implantation) from the cases. Fibrin clot formation and fibrinolysis were assessed in vitro by turbidimetric assays, with human thrombin to initiate fibrin polymerization and tissue type plasminogen activator to initiate fibrinolysis. Lag time, maximal absorbance and clot lysis time were determined by these assays. RESULTS: In total, 27 cases and 27 controls were included. No significant differences were observed between cases and controls in lag time (173 vs. 162s, p=0.18), maximal absorbance (0.78 vs. 0.83, p=0.36), and clot lysis time (69 vs. 71min, p=0.78). Fibrin clot formation and fibrinolysis were not associated with stent thrombosis. CONCLUSIONS: Plasma fibrin clot formation and fibrinolysis were not significantly different between patients with stent thrombosis and matched control patients, suggesting that fibrin clot formation and fibrinolysis play no significant role in the pathophysiology of stent thrombosis.

Histopathological evaluation of thrombus in patients presenting with stent thrombosis. A multicenter European study: a report of the prevention of late stent thrombosis by an interdisciplinary global European effort consortium.

BACKGROUND: Stent thrombosis (ST) is a rare but serious complication following percutaneous coronary intervention. Analysis of thrombus composition from patients undergoing catheter thrombectomy may provide important insights into the pathological processes leading to thrombus formation. We performed a large-scale multicentre study to evaluate thrombus specimens in patients with ST across Europe. METHODS: Patients presenting with ST and undergoing thrombus aspiration were eligible for inclusion. Thrombus collection was performed according to a standardized protocol and specimens were analysed histologically at a core laboratory. Serial tissue cross sections were stained with haematoxylin-eosin (H&E), Carstairs and Luna. Immunohistochemistry was performed to identify leukocyte subsets, prothrombotic neutrophil extracellular traps (NETs), erythrocytes, platelets, and fibrinogen. RESULTS: Overall 253 thrombus specimens were analysed; 79 (31.2%) from patients presenting with early ST, 174 (68.8%) from late ST; 79 (31.2%) were from bare metal stents, 166 (65.6%) from drug-eluting stents, 8 (3.2%) were from stents of unknown type. Thrombus specimens displayed heterogeneous morphology with platelet-rich thrombus and fibrin/fibrinogen fragments most abundant; mean platelet coverage was 57% of thrombus area. Leukocyte infiltrations were hallmarks of both early and late ST (early: 2260 ± 1550 per mm(2) vs. late: 2485 ± 1778 per mm(2); P = 0.44); neutrophils represented the most prominent subset (early: 1364 ± 923 per mm(2) vs. late: 1428 ± 1023 per mm(2); P = 0.81). Leukocyte counts were significantly higher compared with a control group of patients with thrombus aspiration in spontaneous myocardial infarction. Neutrophil extracellular traps were observed in 23% of samples. Eosinophils were present in all stent types, with higher numbers in patients with late ST in sirolimus-and everolimus-eluting stents. CONCLUSION: In a large-scale study of histological thrombus analysis from patients presenting with ST, thrombus specimens displayed heterogeneous morphology. Recruitment of leukocytes, particularly neutrophils, appears to be a hallmark of ST. The presence of NETs supports their pathophysiological relevance. Eosinophil recruitment suggests an allergic component to the process of ST.