Von Willebrand factor antigen levels predict major adverse cardiovascular events in patients with carotid stenosis of the ICARAS study.

BACKGROUND AND AIMS: Von Willebrand factor (VWF) plays an important role in thrombogenesis and mediates platelet adhesion particularly under high shear stress. Such conditions are generally found in stenotic arteries and can eventually cause myocardial infarction or stroke. We aimed to study whether levels of VWF antigen (VWF:Ag) predict future major adverse cardiovascular events (MACE) in patients suffering from carotid artery stenosis. METHODS: Patients with atherosclerotic carotid artery disease defined by the presence of nonstenotic plaques or any degree of carotid stenosis were prospectively enrolled. Concentrations of VWF were measured by enzyme immunoassay. RESULTS: VWF:Ag levels were more stable after 4 freeze-thaw cycles, when compared to VWF activity, and we showed similar concentrations of VWF in citrated plasma and serum (±4%). Levels of VWF:Ag predicted future cardiovascular events in 811 patients with carotid stenosis independent of known cardiovascular risk factors. Patients with VWF:Ag concentrations in the 4th quartile had a 44% event rate after an average 3-year follow up and a hazard ratio of 2.15 (95% confidence interval 1.46-3.16; p < 0.001). CONCLUSIONS: High concentrations of VWF:Ag predict major cardiovascular events in patients with carotid stenosis, and given their high event rate may be useful for risk stratification of such patients.

Relationship between renal function and circulating microparticles, soluble P-selectin and E-selectin levels in atrial fibrillation.

Atrial fibrillation (AF) and chronic kidney disease are closely related, and any associated risk of stroke and thromboembolism due to AF is increased by concurrent renal dysfunction. The mechanism(s) for this include abnormalities in platelets and endothelial cells. We hypothesized relationships between levels of circulating platelet microparticles (PMPs, defined by CD42b), soluble P selectin (both reflecting platelet activation), soluble E-selectin (reflecting endothelial activation) and endothelial/platelet microparticles (EPMPs, defined by CD31) with progressive renal dysfunction. Blood samples were obtained from 160 anticoagulated AF patients. Microparticles were measured by flow cytometry, soluble E and P selectin levels by ELISA. Renal function was determined by estimated glomerular filtration rate (eGFR). EPMP levels demonstrated a linear increased trend across quartiles of eGFR (p = 0.034) and CKD stage (p < 0.001), and correlated with eGFR and serum creatinine (p < 0.01). PMPs, P-selectin and E-selectin levels were not significantly different across groupings of renal dysfunction, and no significant correlations with eGFR were evident (p = 0.186, p = 0.561, p = 0.746 respectively). Stepwise multivariable regression analysis demonstrated that worsening renal function was an independent predictor of EPMP levels (p < 0.001). In well-anticoagulated AF patients, there is potential relationship between endothelial function (as judged by elevated EPMP levels, with no change in PMPs) and renal function. Other markers of prothombotic state or cellular activation (PMP, P-selectin and E-selectin levels) were not significantly different across the various degree of renal dysfunction. Renal function must be addressed when measuring EPMP levels.

Modelling projections for the uptake of edoxaban in an European population to 2050: effects on stroke, thromboembolism, and health economics perspectives.

AIMS: In the coming decades, the number of Europeans with atrial fibrillation (AF) is set to rise as the population ages, and so with it will the number of strokes. The risk of thromboembolism (principally stroke and systemic embolism) and death can be reduced by the use of the vitamin K antagonists (VKA, e.g. warfarin) and more so by non-VKA oral anticoagulants (NOACs) such as edoxaban. METHODS AND RESULTS: We modelled the effect of the increasing use of edoxaban in preference to warfarin in a European AF population from both clinical and economic perspectives. We estimate that the introduction of NOACs in 2010 eliminated over 88 000 thromboembolisms and deaths annually, of which over 17 000 were ischaemic strokes. At a 1-year cost of €30k per ischaemic stroke, this strategy saved €510 million annually. Should the use of edoxaban increase from 11% in 2013 to 75% by 2030, we expect that rate of thromboembolism and death will fall from 5.67 to 5.42 total events per million patients per year, which will further eliminate over 12 000 of these events annually. At an inflation-adjusted 1-year cost of approximately €35k per ischaemic stroke, this will save €44.5 million each year. At a conservative rate of increase in the AF population of 2.2-fold from 2005, in 2050 there will be around 180 000 AF-related ischaemic strokes that, at an inflation-adjusted cost of around €62k per stroke, sums to €11 116 million. Should the rate of AF rise 2.6-fold from 2005, then in 2050 there will be 214 500 ischaemic strokes that will cost around €13 300 million. CONCLUSION: Our data point to a substantial increase in the human and economic cost burden of AF and so emphasize the need to reduce this burden. This may be achieved by the increased use of oral anticoagulants, particularly with the NOACs such as edoxaban.

Atrial Fibrillation and Thromboembolism in Patients With Chronic Kidney Disease.

A bidirectional relationship exists between atrial fibrillation (AF) and chronic renal disease. Patients with AF have a higher incidence of renal dysfunction, and the latter predisposes to incident AF. The coexistence of both conditions results in a higher risk for thromboembolic-related adverse events but a paradoxical increased hemorrhagic risk. Oral anticoagulants (both vitamin K antagonists [VKAs] and non-VKA oral anticoagulants [NOACs]) have been demonstrated to be effective in mild to moderate renal dysfunction. Patients with severe renal impairment were excluded from the non-VKA oral anticoagulant trials, so limited data are available. In end-stage renal failure, the net clinical benefit of VKAs in dialysis-dependent patients remains uncertain, although some evidence suggests that such patients may do well with high-quality anticoagulation control. Risk stratification and careful follow-up of such patients are necessary to ensure a net clinical benefit from thromboprophylaxis.

Effects of non-vitamin K antagonist oral anticoagulants on fibrin clot and whole blood clot formation, integrity and thrombolysis in patients with atrial fibrillation.

Non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin and heparins in several clinical situations. With varying modes of action, the effects of NOACs on thrombus formation, integrity, and lysis is unknown. To determine whether two techniques of thrombelastography (TEG) and a micro-plate assay (MPA) provide novel data on thrombus formation, integrity and lysis in those taking a NOACs compared to warfarin and a control group taking aspirin. We assessed thrombogenesis, clot integrity and fibrinolysis in blood (TEG) and plasma (MPA) from 182 atrial fibrillation patients-50 on aspirin, 50 on warfarin, and 82 on a NOAC (17 apixaban, 19 dabigatran and 46 rivaroxaban). Eleven of 16 TEG indices and 4 of 5 MPA indices differed (p ≤ 0.01) between those on aspirin, warfarin or a NOAC. Three TEG indices and 4 MPA indices differed (p < 0.01) between the NOACs. Time to initiation of clot formation was most rapid on apixaban, then rivaroxaban and slowest on dabigatran. The rate of clot formation was most rapid on dabigatran, then apixaban, and slowest on rivaroxaban. Clot density was greatest on rivaroxaban, then apixaban, but weakest on dabigatran. The rate of clot dissolution was most rapid in apixaban, then dabigatran, and slowest on rivaroxaban. The TEG and MPA identify major differences in thrombogenesis and fibrinolysis in different NOACs. These techniques may have value in investigating the effects of these drugs on haemostasis in a clinical setting, and in identifying those in need of targeted therapy.

Effect of renal function on whole blood and fibrin clot formation in atrial fibrillation patients on warfarin.

OBJECTIVE: Atrial fibrillation (AF) brings a risk of thrombosis, requiring oral coagulation, and is associated with renal impairment. The two processes may be linked, as altered fibrin clot structure is present in end-stage renal failure. We hypothesised that progressively deteriorating renal function is linked to altered whole blood and fibrin clot properties and fibrinolysis. METHODS: Thrombogenesis and fibrinolysis in 200 warfarinised AF patients was assessed by thromboelastography (TEG), a micro-plate assay (MPA) and the international normalized ratio (INR). Renal function was determined by creatinine clearance and two versions of the estimated glomerular filtration rate (eGFR). RESULTS: Two TEG indices independently reflecting thrombogenesis were linked to creatinine clearance (p < 0.01), whilst a third, reflecting clot strength, was linked to the eGFR (p < 0.001). MPA indices of thrombogenesis and clot density (p < 0.001), and an index of fibrinolysis (p < 0.001) were linked to the eGFR. The time for 50% of the fibrin clot to lyse was linked to creatinine clearance (p = 0.001). The INR was unrelated to any renal function index, and the CHA2DS2VASc score was unrelated to any index. CONCLUSION: In warfarinised AF patients, renal function is linked to whole blood clot and fibrin clot formation, structure and dissolution, but has no effect on the INR. Key messages Despite oral anticoagulation, patients with atrial fibrillation (AF) still suffer from stroke and venous thromboembolism. The effect of renal function in warfarinised patients with AF is unknown and may account for excess thrombosis and/or haemorrhage. Using two different laboratory methods, our data point to an effect of renal function on clot structure and function that is independent of an effect of warfarin.

Net Clinical Benefit of Edoxaban for Stroke, Mortality, and Bleeding Risk: Modeling Projections for a European Population.

OBJECTIVES: The purpose of this study was to determine, in a model based on Europeans at risk of stroke by virtue of atrial fibrillation (AF), the net clinical benefit of edoxaban in the reduction of the risk of stroke, mortality, and of hemorrhage. BACKGROUND: Vitamin K antagonists (e.g., warfarin) are commonly underused because of such factors as fear of hemorrhage in patients with high-risk AF. The non-vitamin K antagonist oral anticoagulants are similarly or more effective than warfarin and have lower rates of serious hemorrhage. Although outcomes of the ENGAGE AF-TIMI 48 trial that compared the non-vitamin K antagonist oral anticoagulant edoxaban with warfarin and indicated similar efficacy and better safety compared with warfarin for stroke prevention in AF, the application of trial data to the general population is unknown. METHODS: This study modelled a treatment effect of edoxaban on the risks of thromboembolism, major bleeding, and death in a real-world population of patients with AF drawn from the Euro Heart Survey, and extrapolated this to the general European population. RESULTS: In those at high risk of stroke (CHA2DS2VASc ≥2), edoxaban would need to be taken by 319 patients to prevent 1 thromboembolism, major bleeding event, or death compared with warfarin, and by 41 patients to prevent 1 thromboembolism or death compared with no treatment. These translate to demonstrating a net clinical benefit of 8.9 events saved per 1,000 patients with edoxaban 60 mg. Modeling these data to the population of Europe of 508 million, use of edoxaban 30 mg and 60 mg instead of warfarin would, respectively, prevent approximately 19,400 and 30,300 thromboembolic events, major bleeds, and deaths annually. CONCLUSIONS: Our modeling exercise suggests that the use of edoxaban for thromboprophylaxis in AF based on current guidelines could provide a profound benefit on rates of stroke, major bleeds, and deaths in European patients with AF.

Net clinical benefit of edoxaban versus no treatment in a 'real world' atrial fibrillation population: A modelling analysis based on a nationwide cohort study.

BACKGROUND: In non-valvular atrial fibrillation (AF), oral anticoagulation reduces the risk of thromboembolism such as stroke and systemic embolism (SSE), but increases the risk of major bleeding such as intracranial haemorrhage (ICH). The risk-benefit balance between SSE versus ICH can be expressed as the net clinical benefit (NCB); however, the risk of SSE and ICH varies according to clinical factors that can be assessed using CHADS2, CHA2DS2-VASc (both quantifying risk of stroke) and HAS-BLED (quantifying risk of major bleeding) scores, respectively. METHODS: Using established modelling based on event rates for thromboembolism and haemorrhage in the Danish nationwide cohort study, we tested the hypothesis that edoxaban has a superior NCB compared with warfarin. RESULTS: In our overall model, compared to no treatment, warfarin had a NCB of 0.26 (95% CI 0.24,0.28) events prevented per 100 patient years, edoxaban 60 mg daily a NCB of 0.71 [0.69,0.76], and edoxaban 30 mg daily a NCB of 0.71 [0.0.68,0.73]. When compared to no treatment, both doses of edoxaban have superior NCB values than those of warfarin at all CHADS2 and CHA2DS2-VASc scores. At CHADS2 ≥2 and CHA2DS2-VASc ≥2, edoxaban 60 mg dose had a better NCB than the 30 mg dose or warfarin, when compared to no treatment. With HAS-BLED score ≥3, both doses of edoxaban had a positive NCB compared to warfarin, at CHADS2 or CHA2DS2-VASc ≥2. CONCLUSION: Our modelling study suggests that both 30 mg and 60 mg doses of edoxaban have a favourable NCB compared to warfarin, and the degree of benefit differs according to CHADS2, CHA2DS2-VASc and HAS-BLED scores. At CHA2DS2-VASc score ≥2, both edoxaban doses were superior to warfarin, but compared to no treatment, the 60 mg dose had a better NCB than the 30 mg dose or warfarin.

Circulating Endothelial Cells and Platelet Microparticles in Mitral Valve Disease With and Without Atrial Fibrillation.

Hypercoagulability in mitral valve disease (MVD), a cause of atrial fibrillation (AF) and stroke, is potentially due to endothelial damage/dysfunction (marked by circulating endothelial cells [CECs]), platelet activation (soluble P-selectin [sPsel], platelet microparticles [PMPs], and soluble CD40 [sCD40]), and oxidized low-density lipoprotein (oxLDL) cholesterol. We measured these variables in 24 patients with MVD as well as in 21 with MVD + AF and compared them with 20 healthy controls (HCs). The CECs and PMPs were measured by flow cytometry; sPsel, oxLDL, and CD40 by enzyme-linked immunosorbent assay. Compared with HCs, sPsel and PMPs were equally higher in MVD and MVD + AF; sCD40 and oxLDL were higher in MVD + AF than in HCs and MVD; and CECs were higher in MVD than in the HCs, with further increases in MVD + AF (all P < .001). We conclude that excess platelet activation is present in MVD regardless of AF, and that increased endothelial damage in MVD is greater when compounded by AF.

Effects of radiofrequency catheter ablation of atrial fibrillation on soluble P-selectin, von Willebrand factor and IL-6 in the peripheral and cardiac circulation.

BACKGROUND: Catheter ablation (CA) of atrial fibrillation (AF) is associated with inflammatory response, endothelial damage and with increased risk of thrombosis. However, whether these processes differ in peripheral and cardiac circulation is unknown. METHODS: Plasma markers (von Willebrand factor (vWf), soluble P-selectin (sPsel) and interleukin-6 (IL-6)) were measured by ELISA at three time points in 80 patients (62±10 years, 63% males, 41% paroxysmal AF) undergoing CA. These were at baseline--from femoral vein (FV) and left atrium (LA) before ablation; directly after ablation--from the pulmonary vein (PV), LA and FV; and 24 hours after procedure--from a cubital vein (CV). RESULTS: The levels of vWF and IL6--but not sP-sel--increased significantly 24 h after procedure (p<0.001). Baseline vWF was significantly associated with persistent AF (Beta = .303, p = 0.006 and Beta = .300, p = 0.006 for peripheral and cardiac levels, respectively), while persistent AF (Beta = .250, p = 0.031) and LAA flow pattern (Beta = .386, p<0.001) remained associated with vWF in cardiac blood after ablation. Advanced age was significantly associated with IL6 levels at baseline and after ablation in peripheral and cardiac blood. There were no clinical, procedural or anti-coagulation characteristics associated with sP-sel levels in cardiac blood, while peripheral sP-sel levels were associated with hypertension before (Beta = -.307, p = 0.007) and with persistent AF after ablation (Beta = -.262, p = 0.020). CONCLUSIONS: vWF levels are higher in persistent AF and are associated with LAA rheological pattern after AF ablation. Increase of peripheral vWF and IL6 levels after procedure supports current AF ablation management with careful control of post-procedural anticoagulation to avoid ablation-related thromboembolism.

Plasma CX3CL1 levels and long term outcomes of patients with atrial fibrillation: the West Birmingham Atrial Fibrillation Project.

BACKGROUND: There is growing evidence that chemokines are potentially important mediators of the pathogenesis of atherosclerotic disease. Major atherothrombotic complications, such as stroke and myocardial infarction, are common among atrial fibrillation (AF) patients. This increase in risk of adverse events may be predicted by a score based on the presence of certain clinical features of chronic heart failure, hypertension, age 75 years or greater, diabetes and stroke (the CHADS2 score). Our objective was to assess the prognostic value of plasma chemokines CCL2, CXCL4 and CX3CL1, and their relationship with the CHADS2 score, in AF patients. METHODS: Plasma CCL2, CXCL4 and CX3CL1 were measured in 441 patients (59% male, mean age 75 years, 12% paroxysmal, 99% on warfarin) with AF. Baseline clinical and demographic factors were used to define each subject's CHADS2 score. Patients were followed up for a mean 2.1 years, and major adverse cardiovascular and cerebrovascular events (MACCE) were sought, being the combination of cardiovascular death, acute coronary events, stroke and systemic embolism. RESULTS: Fifty-five of the AF patients suffered a MACCE (6% per year). Those in the lowest CX3CL1 quartile (≤ 0.24 ng/ml) had fewest MACCE (p = 0.02). In the Cox regression analysis, CX3CL1 levels >0.24 ng/ml (Hazard ratio 2.8, 95% CI 1.02-8.2, p = 0.045) and age (p = 0.042) were independently linked with adverse outcomes. The CX3CL1 levels rose directly with the CHADS2 risk score (p = 0.009). The addition of CX3CL1 did not significantly increased the discriminatory ability of the CHADS2 clinical factor-based risk stratification (c-index 0.60 for CHADS2 alone versus 0.67 for CHADS2 plus CX3CL1 >0.24 ng/ml, p = 0.1). Aspirin use was associated with lower levels of CX3CL1 (p = 0.0002) and diabetes with higher levels (p = 0.031). There was no association between CXCL4 and CCL2 plasma levels and outcomes. CONCLUSION: There is an independent association between low plasma CX3CL1 levels and low risk of major cardiovascular events in AF patients, as well as a linear association between CX3CL1 plasma levels and CHADS2-defined cardiovascular risk. The potential for CX3CL1 in refining risk stratification in AF patients merits consideration.

Angiogenin outperforms VEGF, EPCs and CECs in predicting Dukes' and AJCC stage in colorectal cancer.

BACKGROUND: Circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), Willebrand factor (vWf), soluble E-selectin, vascular endothelial growth factor (VEGF) and angiogenin are of interest in cancer vascular biology. However, few studies have looked at more than one in combination. We set out to determine which would be best in predicting the Dukes' and American Joint Committee on Cancer (AJCC) scores in colorectal cancer patients. METHODS: We recruited 154 patients with colorectal cancer, 29 healthy controls and 26 patients with benign bowel disease. CD34(+) /CD45(-) /CD146(+) CECs and CD34(+) /CD45(-) /CD309[KDR](+) EPCs were measured by flow cytometry, plasma markers by ELISA. RESULTS: All research indices were raised in colorectal cancer (P < 0·05) compared to control groups. Although CECs (P < 0·05), EPCs (P < 0·01) and angiogenin (P < 0·01) increased stepwise across the four Dukes' stages and four AJCC stages, only angiogenin remained significant in multiple regression analysis (P = 0·003 for Dukes, P = 0·01 for AJCC). Angiogenin levels were higher in Dukes' stages C and D compared to stage A, and AJCC stages 4-6 and 7-10 compared to stage 1 (all P < 0·05). Adding a second research marker to angiogenin did not markedly improve this relationship. CONCLUSION: Although we found disturbances in endotheliod cells and plasma markers of the endothelium and growth factors, only angiogenin levels were independently associated with progression of the Dukes' stage and AJCC stage, with the association with Duke's stage being stronger. We suggest that angiogenin is a potential biomarker in risk stratification for colorectal cancer, and may aid clinical decision making.

Left ventricular fibrosis in atrial fibrillation.

Excessive atrial fibrosis is involved in the pathogenesis of atrial fibrillation (AF), but little is known of left ventricular (LV) fibrotic status in patients with AF. In the present study, we investigated the presence of abnormal LV fibrosis in AF, its effect on cardiac function, a possible association with arterial stiffness (i.e., systemic cardiovascular fibrosis), and the parameters of endothelial activation, dysfunction, and damage. We also studied whether LV fibrosis could be linked to the future risk of AF onset. In a cross-sectional study, the severity of LV fibrosis was assessed by echocardiographic acoustic densitometry in patients with permanent AF (n = 49), patients with paroxysmal AF (n = 44), AF-free "disease controls" (n = 42) and "healthy controls" (n = 48). Arterial stiffness (pulse wave velocity), plasma markers of endothelial activation (E-selectin), endothelial damage/dysfunction (von Willebrand factors), and microvascular endothelial function (laser Doppler flowmetry) were quantified. In a longitudinal study, 93 patients with pacemakers (22 with AF) were followed up for ≥1 year to assess the predictive value of LV fibrosis for the development of new-onset AF. More severe LV fibrosis was present in both paroxysmal and permanent AF than in the AF-free controls (p <0.001), with more LV fibrosis in permanent than in paroxysmal AF (p = 0.002). The severity of LV fibrosis in AF wais independently associated with diastolic dysfunction (p = 0.03), but not with LV contractility, arterial stiffness, or endothelial damage/dysfunction. In conclusion, LV fibrosis might contribute to LV diastolic dysfunction and the high prevalence of heart failure with preserved ejection fraction in subjects with AF.