The Effect of ABCB1 and CES1 Polymorphisms on Plasma Levels of Dabigatran and Risk of Hemorrhagic Complications in Ischemic Stroke Patients.

BACKGROUND: Dabigatran directly inhibits thrombin and is used in primary and secondary stroke prevention in individuals with nonvalvular atrial fibrillation. The prodrug dabigatran etexilate is absorbed by enteral P-glycoprotein (ABCB1) and then activated by hepatic and intestinal carboxylesterases (CES1) to produce active metabolites. Variations in dabigatran metabolism because of genetics may affect concentration levels and clinical outcomes. STUDY QUESTION: We conducted a study to assess how polymorphisms in the CES1 (rs2244613) and ABCB1 (rs4148738) genes affect the through plasma level (c min ) of dabigatran and its correlation to clinical outcomes. STUDY DESIGN: Retrospective multicentric study of consecutive patients on dabigatran therapy. Examination of CES1 rs2244613 and ABCB1 rs4148738 polymorphisms, c min 12 hours after administration, clinical follow-up (ischemic stroke, major or clinically relevant hemorrhage, myocardial infarction, other thromboembolism, and death). MEASURES AND OUTCOMES: A total of 432 patients received treatment for an average of 19.78 months (SD of 20.165). The sex distribution of the patients was 56.5% male, and the average age was 67.56 years (SD of 14.7). The ABCB1 variant genotype was present in 67.8% of patients, whereas 37.5% carried the CES1 polymorphism. RESULTS: Compared with wild-type patients, patients with the CES1 variant had significantly lower dabigatran plasma levels (with a mean difference of 16.986; 95% confidence interval, 5.794-28.178 ng/mL, P = 0.003). We also found a significant risk of major bleeding in patients carrying the ABCB1 rs4148738 allele (hazard ratio = 1.99, confidence interval 95% 1.10 to 3.59, P = 0.024). CONCLUSIONS: The CES1 variant genotype rs2244613 is closely linked with reduced c min of dabigatran. Carriers of the ABCB1 rs4148738 polymorphism exhibit a tendency toward higher plasma levels of dabigatran, which leads to a significantly increased risk of bleeding.

Peripheral Vascular Resistance in Cerebral Arteries in Patients With Carotid Atherosclerosis - Substudy Results of the Atherosclerotic Plaque Characteristics Associated With a Progression Rate of the Plaque and a Risk of Stroke in Patients With the Carotid Bifurcation Plaque Study (ANTIQUE).

OBJECTIVES: Transcranial color-coded duplex sonography (TCCS) enables to measure blood flow characteristics in cerebral vessels, including vascular resistance and pulsatility. The study aims to identify factors influencing pulsatility (PI) and resistance (RI) indices measured using TCCS in patients with carotid atherosclerosis. METHODS: Self-sufficient patients with atherosclerotic plaque causing 20-70% carotid stenosis were consecutively enrolled to the study. All patients underwent duplex sonography of cervical arteries and TCCS with measurement of PI and RI in the middle cerebral artery, neurological, and physical examinations. Following data were recorded: age, gender, height, weight, body mass index, systolic and diastolic blood pressure, occurrence of current and previous diseases, surgery, medication, smoking, and daily dose of alcohol. Univariant and multivariant logistic regression analysis were used for identification of the factors influencing RI and PI. RESULTS: Totally 1863 subjects were enrolled to the study: 139 healthy controls (54 males, age 55.52 ± 7.05 years) in derivation cohort and 1724 patients (777 males, age 68.73 ± 9.39 years) in validation cohort. The cut off value for RI was 0.63 and for PI 1.21. Independent factors for increased RI/PI were age (odds ratio [OR] = 1.108/1.105 per 1 year), occurrence of diabetes mellitus (OR = 1.767/2.170), arterial hypertension (OR = 1.700 for RI only), width of the carotid plaque (OR = 1.260 per 10% stenosis for RI only), and male gender (OR = 1.530 for PI only; P ˂.01 in all cases). CONCLUSIONS: The independent predictors of increased cerebral arterial resistance and/or pulsatility in patients with carotid atherosclerosis were age, arterial hypertension, diabetes mellitus, carotid plaque width, and male gender.

Risk factors for carotid plaque progression after optimising the risk factor treatment: substudy results of the Atherosclerotic Plaque Characteristics Associated with a Progression Rate of the Plaque and a Risk of Stroke in Patients with the carotid Bifurcation Plaque Study (ANTIQUE).

BACKGROUND AND AIM: Carotid plaque progression contributes to increasing stroke risk. The study aims to identify factors influencing carotid plaque thickness progression after changing the preventive treatment to the 'treating arteries instead of risk factors' strategy, that is, change in treatment depending on the progression of atherosclerosis. METHODS: The study participants who completed sonographic controls over the course of 3 years were enrolled to the analysis. Duplex sonography of cervical arteries was performed in 6-month intervals with measurement of carotid plaque thickness. Plaque thickness measurement error (σ) was set as 3 SD. Only evidently stable and progressive plaques (defined as plaque thickness difference between initial and final measurements of ˂σ and >2σ, respectively) were included to analysis. Univariate and multivariate logistic regression analysis was performed to identify factors influencing plaque progression. RESULTS: A total of 1391 patients (466 males, age 67.2±9.2 years) were enrolled in the study. Progressive plaque in at least one carotid artery was detected in 255 (18.3%) patients. Older age, male sex, greater plaque thickness, coronary heart disease, vascular surgery/stenting history and smoking were more frequently present in patients with progressive plaque (p˂0.05 in all cases). Multivariate logistic regression analysis identified only the plaque thickness (OR 1.850 for left side, 95% CI 1.398 to 2.449; and OR 1.376 for right side, 95% CI 1.070 to 1.770) as an independent factor influencing plaque progression. CONCLUSION: Carotid plaque thickness corresponding to stenosis severity is the only independent risk factor for plaque thickness progression after optimising the prevention treatment. TRIAL REGISTRATION NUMBER: NCT02360137.

Histological Analysis of Carotid Plaques: The Predictors of Stroke Risk.

OBJECTIVES: The morphology and histological structure of the atherosclerotic plaque seem critical to its stability. Our study aimed to identify the epidemiological, morphological and histological parameters associated with stable and unstable plaques. MATERIALS AND METHODS: The study included 280 plaques harvested from 269 consecutive patients. Epidemiological and demographic data were recorded as well as the histological features of plaque, i.e. calcifications, myxoid changes, bleeding into plaque, presence of thrombus, inflammation, macrophages, giant cell reaction, siderophages, neovascularization and plaque ossification. All specimens were classified according to the American Heart Association (AHA). RESULTS: Monofactorial analysis identified three significant histological predictors for the symptomatic plaque: a plaque with a large necrotic core (odds ratio, OR=2.0, p = 0.03), thrombosis (OR=3.7, p = 0.01) and the formation of foamy macrophages (OR=2.0, p = 0.01). Multifactorial logistic regression revealed that the presence of foamy macrophages (OR=1.9, p = 0.03) and thrombosis (OR=3.5, p = 0.02) were significant predictors of symptomatic stenosis. Symptomatic plaques were significantly more frequently classified as AHA type VI than AHA type IV-V compared to asymptomatic ones (OR=1.8, p = 0.03). CONCLUSIONS: Our study shows that no single histological feature, except for the presence of foamy macrophages and thrombosis on the plaque, is predictive of plaque instability. Rather, a complex plaque structure (AHA type VI) is predictive of plaque instability. Our findings should be kept in mind during the assessment of non-invasive imaging and stroke risk estimation.

Shear-Wave Elastography Enables Identification of Unstable Carotid Plaque.

Shear-wave elastography (SWE) is a novel ultrasound technique for quantifying tissue elasticity. The aim of this study was to identify differences in atherosclerotic plaque elasticity measured using SWE among individuals with symptomatic, asymptomatic progressive and asymptomatic stable carotid plaques. Consecutive patients from the Atherosclerotic Plaque Characteristics Associated with a Progression Rate of the Plaque and a Risk of Stroke in Patients with the Carotid Bifurcation Plaque Study were screened for this research. Neurosonography examination of carotid arteries was performed to identify plaque stenosis of ≥50% using B-mode ultrasound and SWE imaging to measure the mean, maximal and minimal elasticity. The set consisted of 97 participants-74 with asymptomatic stable stenosis, 12 with asymptomatic progressive stenosis and 11 with symptomatic stenosis. The mean elasticity in the asymptomatic stable plaque group was significantly higher than in the asymptomatic progressive (52.2 vs. 30.4 kPa; p < 0.001) and symptomatic (52.2 vs. 36.4 kPa; p = 0.033) plaque groups. No significant differences were found between asymptomatic progressive and symptomatic (p > 0.1) plaque groups. Asymptomatic stable, asymptomatic progressive and symptomatic plaques did not differ in echogenicity, calcifications, homogeneity, occurrence of ulcerated surface, or intra-plaque hemorrhage (p > 0.05 in all cases). SWE was a helpful modality for differentiating between stable and unstable atherosclerotic plaques in carotid arteries.

Blood Flow Volume Measurement in Cervical and Intracranial Arteries using Quantitative Magnetic Resonance Angiography and Duplex Sonography (Bocaccia) - A Prospective Observational Study.

PURPOSE: Cerebral blood flow volume is an important factor for the accurate diagnosis of neurovascular diseases and treatment indication. This study aims to assess correlations of blood flow volume measurements in cervical and intracranial arteries between duplex sonography and quantitative magnetic resonance angiography (qMRA). MATERIALS AND METHODS: Consecutive patients with suspicion of cerebral vascular pathology underwent qMRA and duplex sonography of cervical and intracranial arteries with measurement of blood flow volume in bilateral common (CCA), internal (ICA) and external carotid arteries, vertebral and basilar arteries, middle, anterior, posterior cerebral and posterior communicating arteries using 2 different ultrasound machines. Ten patients underwent all examinations twice. Correlations between blood flow volume measurements were evaluated using Spearman's correlation coefficient and inter-class correlation coefficient (ICC). RESULTS: In total, 21 subjects (15 males, mean age: 56.3 ± 6.2 years) were included in the study. Duplex sonography inter-investigator correlation was excellent (ICC = 0.972, p < 0.0001) as well as intra-investigator correlations of both qMRA and duplex sonography (ICC ˃ 0.990, p < 0.0001). Mostly high correlations were recorded between qMRA and duplex sonography in particular cervical arteries but only low to moderate correlations were obtained for intracranial arteries. The mean differences between blood flow volume measurements were 10.9 ±â€Š8.1 % in the CCA and its branches when using qMRA and 15.0 ±â€Š11.9 % when using duplex sonography, 13.5 ±â€Š11.8 %/35.4 ±â€Š34.2 % in the ICA siphon and its branches when using qMRA/duplex sonography, and 24.1 ±â€Š19.7 %/44.9 ± 44.0 % in both vertebral arteries and the basilar artery when using qMRA/duplex sonography. CONCLUSION: Duplex sonography as well as qMRA allow for highly reproducible measurement of blood flow volume in cervical and intracranial arteries in routine clinical practice.

SONOlysis in prevention of Brain InfaRctions During Internal carotid Endarterectomy (SONOBIRDIE) trial - study protocol for a randomized controlled trial.

BACKGROUND: Carotid endarterectomy (CEA) is a beneficial procedure for selected patients with an internal carotid artery (ICA) stenosis. Surgical risk of CEA varies from between 2 and 15%. The aim of the study is to demonstrate the safety and effectiveness of sonolysis (continual transcranial Doppler monitoring, TCD) using a 2-MHz diagnostic probe with maximal diagnostic energy on the reduction of the incidence of stroke, transient ischemic attack (TIA) and brain infarction detected using magnetic resonance imaging (MRI) by the activation of the endogenous fibrinolytic system during CEA. METHODS/DESIGN: Design: a multicenter, randomized, double-blind, sham-controlled trial. SCOPE: international, multicenter trial for patients with at least 70% symptomatic or asymptomatic ICA stenosis undergoing CEA. INCLUSION CRITERIA: patients with symptomatic or asymptomatic ICA stenosis of at least 70% are candidates for CEA; a sufficient temporal bone window for TCD; aged 40-85 years, functionally independent; provision of signed informed consent. Randomization: consecutive patients will be assigned to the sonolysis or control (sham procedure) group by computer-generated 1:1 randomization. Prestudy calculations showed that a minimum of 704 patients in each group is needed to reach a significant difference with an alpha value of 0.05 (two-tailed) and a beta value of 0.8 assuming that 10% would be lost to follow-up or refuse to participate in the study (estimated 39 endpoints). ENDPOINTS: the primary endpoint is the incidence of stroke or TIA during 30 days after CEA and the incidence of new ischemic lesions on brain MRI performed 24 h after CEA in the sonolysis and control groups. Secondary endpoints are occurrence of death, any stroke, or myocardial infarction within 30 days, changes in cognitive functions 1 year post procedure related to pretreatment scores, and number of new lesions and occurrence of new lesions ≥0.5 mL on post-procedural brain MRI. ANALYSIS: descriptive statistics and linear/logistic multiple regression models will be performed. Clinical relevance will be measured as relative risk reduction, absolute risk reduction and the number needed to treat. DISCUSSION: Reduction of the periprocedural complications of CEA using sonolysis as a widely available and cheap method may significantly increase the safety of CEA and extend the indication criteria for CEA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02398734 . Registered on 20 March 2015.