Nikesh Malik

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

Abstract 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 mm2 vs. late: 2485 ± 1778 per mm2; P = 0.44); neutrophils represented the most prominent subset (early: 1364 ± 923 per mm2 vs. late: 1428 ± 1023 per mm2; 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.

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.

69 Development and Validation of a Stent Thrombosis Risk Scoring System

Introduction Coronary stent thrombosis (ST) is a rare but potentially lethal complication of percutaneous coronary intervention (PCI). Previous studies have identified various patient, lesion and procedure-related risk factors, but there are currently no risk scoring tools in clinical use. In this study, we aimed to develop a scoring system to predict the risk of ST at different time points following PCI, to help guide the potency and duration of antiplatelet treatment. Methods Two research methods were used to identify risk factors for acute (within 24 h), early (within 30 days), late (30 days to 1 year) and very late (more than 1 year after PCI) ST and their associated odds ratios (ORs). This included a systematic literature review and meta-analysis of studies that met certain pre-defined criteria, and a modified Delphi RAND panel to gain expert opinion from eight experienced interventional cardiologists (Figure 1). Abstract 69 Figure 1 A Bayesian model was used to combine the results of both methods to produce a list of risk factors for each time point with associated ORs and confidence intervals (CIs) (Figure 2). Abstract 69 Figure 2 The risk scores were validated by applying them to patient level data from the TRITON-TIMI 38 study and the discriminatory power was tested by developing receiver operator characteristic (ROC) curves for each time point. The ability of the risk scores to predict ST was tested using the Hosmer-Lemeshow goodness-of-fit test. Results In total, 20 risk factors (9 patient-, 3 lesion- and 8 PCI procedure-related) were found to significantly influence the risk of developing ST. The combined ORs with CIs for some of the risk factors common to all time points are shown in Table 1 below. Abstract 69 Table 1 Risk factor Acute STOR (95% CI) Early STOR (95% CI) Late STOR (95% CI) VLSTOR (95% CI) Discontinued dual antiplatelet therapy N/A 3.49 (2.17-5.30) 3.44 (2.09-5.36) 1.75 (0.97-2.92) Bifurcation lesion PCI 1.62 (1.17-2.19) 1.66 (1.18-2.26) 1.57 (1.00-2.34) 1.39 (0.92-2.01) Incomplete stent expansion 1.63 (1.08-2.38) 1.73 (1.14-2.55) 1.91 (1.19-2.94) 1.54 (0.98-2.31) Undersized stent relative to vessel 1.95 (1.18-3.03) 2.00 (1.24-3.07) 1.91 (1.17-2.96) N/A Diabetes mellitus 1.62 (1.24-2.07) 1.69 (1.29-2.18) 1.53 (1.08-2.10) 1.61 (1.04-2.36) The final weighted risk scores, divided into patient-, treated lesion- and PCI procedure-related factors ranged from 0 to 22, 0 to 22 and 0 to 20 for acute, early and late ST respectively. When applied to the patient cohort within the TRITON-TIMI 38 study, the related risk of ST was 0–1.53%, 0–3.85% and 0–0.96% for acute, early and late ST respectively. Model discrimination, measured by area under the ROC curve, was 0.60 (95% CI 0.54–0.67, p = 0.0028) for acute ST, 0.67 (0.61–0.73, p < 0.0001) for early ST and 0.66 (0.58–0.73, p < 0.0001) for late ST, indicating good discriminatory power for all 3 risk scores. Conclusions In conclusion, published data were combined with expert opinion to produce a weighted scoring system to predict the risk of acute, early, late and very late ST following PCI. This will be assessed prospectively in clinical practice. Use of such a tool will be invaluable in combination with established bleeding risk scores to tailor the potency and duration of antiplatelet therapy in patients undergoing PCI.

38 Development of a rabbit iliac model for testing the bio-neutrality of novel coronary stents and scaffolds

Introduction We developed a rabbit iliac model to investigate the in vivo interaction of coronary stents with the vessel wall and circulating blood. A recovery model was used to assess the biocompatibility of RGD coated stents. Methods The stent thrombosis model consisted of male NZW rabbits medicated with Aspirin and Clopidogrel 1mg/kg, following platelet function studies to test appropriate antiplatelet response. Platelets were fluorescently labelled ex-vivo and re-injected pre-operatively. Superficial femoral (SFA) and iliac arteries were exposed bilaterally. An angioplasty balloon catheter introduced via a femoral arteriotomy was used to injure the proximal common iliac artery. A stent was deployed at the site of injury and the SFA ligated to reduce flow. Contralateral procedures allowed testing of study and control stents. Iliac blood flow was measured bilaterally for 2 h post stenting and following euthanasia, stented vessels removed and fixed. Platelet deposition on both stents was compared using immunofluorescence and explanted vessels were imaged with OCT. The recovery model involved limited dissection. After 28 days, the stented vessels were perfusion fixed, explanted and sent to CVPath for processing. Results We performed 15 acute, including 6 BVS vs durable polymer stents and 13 recovery procedures, including 10 RGD coated vs BMS. Differences in flow, platelet deposition and OCT will be presented. Conclusions The rabbit iliac model has proven to be a reproducible method to assess the acute thrombogenicity and chronic biocompatibility of coronary stents and scaffolds.

12 Understanding factors in the development of stent thrombosis: results from a large UK cohort study

Introduction Despite advances in stent technology, stent thrombosis (ST) remains a significant complication of PCI. Mechanisms are multi-factorial and poorly understood. Methods As part of the European multi-centre PRESTIGE project, we established a ST study, collecting data from patients with definite ST at 12 UK sites from April 2012 to October 2014. Demographic and clinical data were collected and angiographic images analysed. Intracoronary thrombus was examined histopathologically and OCT done when possible. We performed platelet function testing (PFT) at 3 time points and took blood for thrombin generation and DNA analysis. All non-invasive studies were also done in a mean of 2.6 matched controls per ST case. Results 138 patients with definite ST and 353 controls were recruited in the UK. Of the ST cases, 23% were early, 8.7% late and 68.1% very late after the initial PCI. A summary of the OCT findings is shown in Figure 1. Demographics, clinical data, PFT and thrombin generation results will be presented. Abstract 12 Figure 1 Preliminary OCT findings from the Prestige study Conclusions Using a multi-centre approach, we collected multi-source data from patients with coronary ST and matched controls. PFT data, thrombin generation and OCT pullbacks have been analysed to identify important risk factors and to validate strategies to reduce the risk of ST. We are able to establish a profile of potential ST cases, potentially identifying those at high risk.

116 Clinical Profile of UK Stent Thrombosis Patients in the Prestige Study

Introduction Despite major advances in coronary stent technology, stent thrombosis (ST) remains a significant complication of percutaneous coronary intervention (PCI) with a high rate of MI and death. The underlying mechanisms are multi-factorial and poorly understood. Previous studies have involved small sample sizes, with incomplete patient characterisation, a lack of intracoronary imaging or platelet function data. Methods As part of the European multi-centre PRESTIGE project, we established and coordinated a ST study, collecting multi-source data from patients presenting with definite ST between April 2012 and October 2014 at 12 UK cardiac centres. Demographic and clinical data were collected and all angiographic images reviewed. Intracoronary thrombus was examined histopathologically and intravascular ultrasound (IVUS) and/or optical coherence tomography (OCT) performed whenever possible. We undertook platelet function testing (PFT) acutely, at 24 h and at 30–60 days, and collected blood for thrombin generation assays and DNA analysis. All non-invasive studies including PFT were also undertaken in an average of 2.6 matched controls per ST case. Results A total of 138 patients with definite ST were recruited in the UK, with 353 controls. Of the ST cases, 4.3% were acute (within 24 h), 18.8% sub-acute (24 h to 1 month), 8.7% late (1–12 months) and 68.1% very late (> 1 year) after the initial PCI. PFT was carried out in 74.6% and 86.4% of the ST patients and controls respectively, and 89.1% of the ST cases and 98.0% of the control patients had a blood sample stored for DNA analysis. Of the ST cases, 63.8% had thrombus retained, 38.4% had IVUS and 21.7% had OCT imaging. The ST cases and control groups were well matched for gender, hypertension, heart failure, renal impairment and indication for PCI. The ST group were younger (mean age 59.2 ± 11.6 vs 63.2 ± 10.5 years; p < 0.01), had more smokers (39.1% vs 20.7%; P < 0.01), previous MI (32.6% vs 21.4%; p < 0.01), diabetes mellitus (22.5% vs 14.2%; p = 0.03) and active malignancy (3.6% vs 0.6%; p = 0.01). The angiographic features were well matched between the two groups, apart from less circumflex artery involvement in the ST group (13.0% vs 24.9%; p < 0.01). Factors that differed between the ST cases and controls were use of aspirin on presentation in the ST group (84.1% vs 92.1%; p = 0.01) non-cardiac surgery in the 90 days prior to randomisation (6.5% vs 2.8%; p = 0.04), number of stents inserted (2.2 vs 1.7; p < 0;01), a higher proportion of first generation drug eluting stents (31.9% vs 19.0%; p < 0.01) and of two-stent bifurcation procedures (6.5% vs 2.8%; p = 0.05). Conclusions Using a multi-centre approach, we collected multi-source data from patients presenting with coronary ST, along with matched controls. PFT, thrombin generation and OCT data have been analysed to identify important risk factors for ST and these will be presented.

78 Oct Findings from the European Multi-centre Prestige Stent Thrombosis Study

Background Coronary stent thrombosis (ST) remains the ‘Achilles Heel’ of percutaneous coronary intervention (PCI). Although relatively rare, it is associated with a high rate of acute myocardial infarction and death.A specific point of concern is the ongoing risk of very late ST, occurring more than one year after stent implantation, and the fact that this seems to occur steadily at an annual rate of 0.5% with a high risk of recurrence. The exact mechanisms are multi-factorial and poorly understood and previous studies have been hampered by small sample sizes, incomplete patient characterisation, and a lack of intracoronary imaging and platelet function data. Methods The PRESTIGE study (PREvention of Stent Thrombosis by an Interdisciplinary Global European effort) is a European Union FP7-funded multi-centre European study that commenced in December 2010. Along with a number of preclinical work packages involving a large multidisciplinary consortium, the clinical arm is an observational study aiming to collect multi-source data from at least 500 ST patients recruited at multiple sites across Europe along with appropriately matched controls. Enrolment of ST cases is expected to be complete by April 2014. We have so far recruited just over 450 ST cases in Europe, with a large contribution (96 ST cases and 120 controls) from the 12 UK centres. Data collection involves a full clinical history, including details of antithrombotic therapy, a careful assessment of the original PCI procedure, intracoronary thrombus histopathology, a DNA bank and platelet function testing, using both the VerifyNow and Multiplate systems, carried out acutely, at 24 h and 30 days post event. In addition, we are performing optical coherence tomography (OCT) in ST cases pre and post intervention. To date 130 OCT pullbacks have been received from participating centres in Europe and these are being analysed at a core lab in Munich, Germany. Results The first 80 OCT pullbacks have been assessed systematically using both qualitative and quantitative criteria. Each frame is divided into 4 quadrants and analysed at 1mm intervals. A summary of the predominant underlying factors, along with an example frame of each, is shown below. Conclusions Stent thrombosis continues to be a serious complication of PCI. The PRESTIGE study aims to identify and validate more selective strategies that reduce the risk of ST whilst minimising bleeding complications associated with current antithrombotic regimes. From the initial OCT studies analysed in the PRESTIGE study, the underlying mechanisms for early ST (within 30 days) have mostly been mechanical issues, predominantly uncovered struts and for late and very late ST (after 1 year), neoatherosclerosis appears to play a significant role. Full details and findings of the PRESTIGE study, including results from the thrombus histopathology and platelet function sub-studies will be presented later next year. Abstract 78 Figure 1

The clinical and economic impact of bivalirudin for percutaneous coronary intervention.

Bivalirudin (BVR) is a direct thrombin inhibitor used as an adjunctive antithrombotic agent in combination with aspirin and an ADP-receptor blocker in patients with acute coronary syndrome undergoing percutaneous coronary intervention. When compared to a strategy of heparin plus a glycoprotein IIb/IIIa inhibitor, BVR has been shown in a number of randomized clinical trials to be at least as effective at reducing ischemic endpoints and to have a consistently lower rate of bleeding complications. In addition, various economic analyses have shown it to be cost-effective compared to heparin plus a glycoprotein IIb/IIIa inhibitor and this, coupled with its proven clinical efficacy, has led to the incorporation of BVR into both EU and US clinical guidelines. Previous studies with BVR have mostly assessed its use in patients treated with aspirin and clopidogrel and further studies are ongoing to determine its role in combination with newer, more potent oral antiplatelet agents.