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.

Ticagrelor or prasugrel versus clopidogrel in elderly patients with an acute coronary syndrome: Optimization of antiplatelet treatment in patients 70 years and older--rationale and design of the POPular AGE study.

RATIONALE: Dual antiplatelet therapy with acetylsalicylic acid in combination with a more potent P2Y12- inhibitor (ticagrelor or prasugrel) is recommended in patients with acute coronary syndrome without ST-segment elevation (NSTE-ACS) to prevent atherothrombotic complications. The evidence on which this recommendation is based shows that ticagrelor and prasugrel reduce atherothrombotic events at the expense of an increase in bleeding events when compared with clopidogrel. However, it remains unclear whether ticagrelor or prasugrel has a better net clinical benefit in elderly patients with NSTE-ACS when compared with clopidogrel. The POPular AGE trial is designed to address the optimal antiplatelet strategy in elderly NSTE-ACS patients. STUDY DESIGN: POPular AGE is a multicenter, open-label, randomized controlled trial that aims to include 1000 patients ≥70years of age with NSTE-ACS. Patients are randomly assigned to receive either clopidogrel or a more potent P2Y12 inhibitor (ticagrelor or prasugrel). The first primary end point is any bleeding event requiring medical intervention. The second primary end point is the net clinical benefit, a composite of all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, "PLATelet inhibition and patient Outcomes" major bleeding, or "PLATelet inhibition and patient Outcomes" minor bleeding. Patients will be followed for 1 year after randomization, and analyses will be performed on the basis of intention to treat. CONCLUSION: The POPular AGE is the first randomized controlled trial that will assess whether the treatment strategy with clopidogrel will result in fewer bleeding events without compromising the net clinical benefit in patients ≥70years of age with NSTE-ACS when compared with a treatment strategy with ticagrelor or prasugrel.

Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial.

BACKGROUND: If percutaneous coronary intervention (PCI) is required in patients taking oral anticoagulants, antiplatelet therapy with aspirin and clopidogrel is indicated, but such triple therapy increases the risk of serious bleeding. We investigated the safety and efficacy of clopidogrel alone compared with clopidogrel plus aspirin. METHODS: We did an open-label, multicentre, randomised, controlled trial in 15 centres in Belgium and the Netherlands. From November, 2008, to November, 2011, adults receiving oral anticoagulants and undergoing PCI were assigned clopidogrel alone (double therapy) or clopidogrel plus aspirin (triple therapy). The primary outcome was any bleeding episode within 1 year of PCI, assessed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00769938. FINDINGS: 573 patients were enrolled and 1-year data were available for 279 (98·2%) patients assigned double therapy and 284 (98·3%) assigned triple therapy. Mean ages were 70·3 (SD 7·0) years and 69·5 (8·0) years, respectively. Bleeding episodes were seen in 54 (19·4%) patients receiving double therapy and in 126 (44·4%) receiving triple therapy (hazard ratio [HR] 0·36, 95% CI 0·26-0·50, p<0·0001). In the double-therapy group, six (2·2%) patients had multiple bleeding events, compared with 34 (12·0%) in the triple-therapy group. 11 (3·9%) patients receiving double therapy required at least one blood transfusion, compared with 27 (9·5%) patients in the triple-therapy group (odds ratio from Kaplan-Meier curve 0·39, 95% CI 0·17-0·84, p=0·011). INTERPRETATION: Use of clopiogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events. FUNDING: Antonius Ziekenhuis Foundation, Strect Foundation.

Conservative versus Invasive Strategy in Elderly Patients with Non-ST-Elevation Myocardial Infarction: Insights from the International POPular Age Registry.

This registry assessed the impact of conservative and invasive strategies on major adverse clinical events (MACE) in elderly patients with non-ST-elevation myocardial infarction (NSTEMI). Patients aged ≥75 years with NSTEMI were prospectively registered from European centers and followed up for one year. Outcomes were compared between conservative and invasive groups in the overall population and a propensity score-matched (PSM) cohort. MACE included cardiovascular death, acute coronary syndrome, and stroke. The study included 1190 patients (median age 80 years, 43% female). CAG was performed in 67% (N = 798), with two-thirds undergoing revascularization. Conservatively treated patients had higher baseline risk. After propensity score matching, 319 patient pairs were successfully matched. MACE occurred more frequently in the conservative group (total population 20% vs. 12%, adjHR 0.53, 95% CI 0.37-0.77, p = 0.001), remaining significant in the PSM cohort (18% vs. 12%, adjHR 0.50, 95% CI 0.31-0.81, p = 0.004). In conclusion, an early invasive strategy was associated with benefits over conservative management in elderly patients with NSTEMI. Risk factors associated with ischemia and bleeding should guide strategy selection rather than solely relying on age.

Long-term clinical outcome after a first angiographically confirmed coronary stent thrombosis: an analysis of 431 cases.

BACKGROUND: There are limited data on the long-term clinical outcome after an angiographically confirmed (definite) stent thrombosis (ST). METHODS AND RESULTS: Four hundred thirty-one consecutive patients with a definite ST were enrolled in this multicenter registry. The primary end point was the composite of cardiac death and definite recurrent ST. Secondary end points were all-cause death, cardiac death, definite recurrent ST, definite and probable recurrent ST, any myocardial infarction, and any target-vessel revascularization. The primary end point occurred in 111 patients after a median follow-up of 27.1 months. The estimated cumulative event rates at 30 days and 1, 2, and 3 years were 18.0%, 23.6%, 25.2%, and 27.9%, respectively. The cumulative incidence rates of definite recurrent ST, definite or probable recurrent ST, any myocardial infarction, and any target-vessel revascularization were 18.8%, 20.1%, 21.3%, and 32.0%, respectively, at the longest available follow-up. Independent predictors for the primary end point were diabetes mellitus, total stent length, severe calcification, American College of Cardiology/American Heart Association B2-C lesions, TIMI (Thrombolysis In Myocardial Infarction) flow grade <3 after percutaneous coronary intervention, and left ventricular ejection fraction <45%. The implantation of an additional coronary stent during the first ST was also associated with unfavorable outcome. Clinical outcome was not affected by the type of previously implanted stent (drug-eluting or bare-metal stent) or the category of ST (early versus late). CONCLUSIONS: The long-term clinical outcome after a first definite ST is unfavorable, with a high mortality and recurrence rate. Diabetes mellitus, left ventricular ejection fraction <45%, long total stent length, complex coronary lesions, TIMI flow grade <3 after percutaneous coronary intervention, and implantation of an additional coronary stent during the emergent percutaneous coronary intervention for the ST were associated with this unfavorable outcome.

Coronary stent thrombosis in the current era: challenges and opportunities for treatment.

OPINION STATEMENT: The introduction of the drug-eluting stent has raised concerns regarding the occurrence of stent thrombosis (ST), particularly late (and very late) thrombosis. This renewed attention shows that ST remains a major concern after implantation of both bare metal and drug-eluting stents. Cardiologists should be aware of this dreadful complication, because it is associated with substantial morbidity and mortality. Numerous clinical, procedural, and angiographic risk factors have been identified. Moreover, the influence of novel determinants, such as high on-treatment reactivity, genetic predisposition, and the stent's direct effects on the (healing of the) vessel wall, now are recognized. Consequently, the pathophysiology of ST has evolved into a complex multifactorial model. This broader understanding of the pathophysiology of ST enables cardiologists to perform extensive risk stratification to identify patients at higher risk and provides clues to important treatment options. The core of primary prevention after stent implantation, as well as secondary prevention after ST, should consist of a) the prevention of modifiable risk factors and b) optimal individualized treatment for each patient. Future developments, such as genetic bedside testing, point-of-care platelet testing, and sophisticated imaging modalities, might aid in this approach.

Coronary artery pseudoaneurysm: closure with pericardium-covered stents, guided by cardiac computed tomography angiography.

Coronary aneurysms are found in approximately 5% of patients undergoing coronary angiography. We describe a case of a coronary artery pseudoaneurysm. The use of cardiac computed tomography angiography is demonstrated in the planning and follow-up of a percutaneous closure of the pseudoaneurysm with pericardium-covered stents.

Triggering mechanisms of stent thrombosis.

AIMS: The aim of this study was to determine the role of potential triggers of stent thrombosis. METHODS AND RESULTS: Patients (n = 437) with "definite" ST were recruited consecutively in the setting of a large multicentre observational cohort study. Patients were interviewed with validated questionnaires to identify one of the following triggers: i) timing of onset of ST, ii) performance of vigorous ( ≥ 6 MET) physical activity in the two hours preceding ST, iii) presence of emotional stress (experiencing a serious life event in the 14 days preceding the ST or feelings of anger in the 12 hours of ST) and iv) presence of a documented active infection at the time of ST. A total of 363 patients (83.1%) were able to supply adequate information. A significant trigger was identified in 83 patients (22.9%). Analysis of the different categories according to timing of ST revealed a higher prevalence of triggers with an increasing time-interval between index PCI and ST. Analysis of circadian variation showed a steep peak incidence from 7 am-12 pm. CONCLUSIONS: Triggering mechanisms such as time of the day, physical exertion, emotional stress and infection may play an important role in a considerable number of patients presenting with ST, in particular in patients with (very) late ST.