PLASMA VON WILLEBRAND FACTOR LEVELS ARE AN INDEPENDENT RISK FACTOR ADVERSE EVENTS IN HIGH RISK ATRIAL FIBRILLATION PATIENTS TAKING ORAL ANTICOAGULATION THERAPY V. Roldán, F. Marín, B. Muiña, E. Jover, C. Muñoz-Esparza, M. Valdés, V. Vicente, GYH. Lip Hospital Morales Meseguer, and Hospital Universitario Virgen de la Arrixaca. University of Murcia. Spain City Hospital, University Department of Medicine, Haemostasis Thrombosis and Vascular Biology Unit, Birmingham. United Kingdom
INTRODUCTION Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice, with more than 4.5 million affected in Europe Lloyd-Jones, Circulation 2006
INTRODUCTION AF is associated with an increased risk of stroke and thromboembolism, although this risk is not homogeneous Arch Int Med 1994 Various clinical and echocardiographic features have been identified as contributing to risk of stroke and thromboembolism
INTRODUCTION C Congestive heart failure H Hypertension A Age 75 years D Diabetes S 2 Stroke or Transient ischaemic attack
ISCHEMIC STROKE MAJOR BLEEDING Van Walraven, JAMA 2002
INTRODUCTION In addition, AF clinical history is also complicated by other cardiovascular events including myocardial infarction and vascular death It is due to the presence of several risk factors for atherosclerosis, including hypertension, diabetes and dyslipidemia It is important to notice, that all the variables used to calculate CHADS score are key determinants of prognosis in vascular patients
Von Willebrand factor (vwf) is a well-established index of endothelial damage and dysfunction vwf has consistently been shown to be raised in patients with AF High levels of vwf are prognostically linked to stroke and vascular events D-dimer is a marker of fibrin turnover, and it has been reported to be increased in AF patients. It has also been shown to be predictor of thromboembolic events
An analysis from the Stroke Prevention in Atrial Fibrillation (SPAF) III study demonstrated that plasma vwf levels were predictive of subsequent stroke and vascular events in AF and had an additive role to clinical factors for risk stratification This analysis was performed in patients receiving aspirin and/or fixed inefficacious doses of warfarin Circulation 2003 Stroke 2006
AIMS There are limited data on the prognostic role of biomarkers in AF patients taking oral anticoagulants (OAC) We assessed the prognostic value of vwf and D-dimer in a large cohort of anticoagulated paroxysmal/permanent AF patients
PATIENTS We included consecutive patients with permanent/ paroxysmal AF who were stabilised (for at least 6 months) on OAC (INRs 2.0-3.0) from our outpatient anticoagulation clinic CHADS 2 risk score was recorded Follow-up was performed through visits at the outpatient anticoagulation clinic and adverse events were recorded: Thrombotic and cardiovascular events: stroke (ischaemic/embolic), acute coronary syndrome, acute heart failure Major haemorrhagic events (ISTH 2005 criteria) Global mortality and cardiovascular death Exclusion criteria: rheumatic AF, prosthetic heart valve, acute coronary syndrome, interventional procedures, stroke or haemodinamic instability in the last 6 months
METHODS Blood samples were drawn atraumatically and without stasis into syringes preloaded with trisodium citrate (0.011 mol/l). Platelet-poor plasma fractions were obtained by centrifugation at 4 C for 20 minutes at 2,200g Aliquots were stored at 80 C to allow batch analysis Both DD and vwf levels were assessed in an automated coagulometer (ACL top 3G, IL instruments)
STATISTICAL ANALYSIS We used Cox models to determine the association of DD/vWf levels with time to adverse events independent to clinical risk score, using the values that showed p 0.15 in the univariate analysis. The cut-off points used for each biomarker were assessed by ROC curves
Baseline characteristics N= 830 Male sex 416 (50%) Age, median (IQR) 76 (70-80) Hypertension 685 (82%) Diabetes mellitus 207 (25%) Heart failure 303 (36.5%) History of stroke or TIA 152 (18%) Coronary artery disease 157 (19%) Hipercholesterolemia 253 (30.5%) Current smoking 111 (13%) Previous bleeding episode 71 (9%) CHADS 2 score, median (IQR) 2 (2-3) Concomitant treatment Aspirin ACE inhibitors/angiotensin-renin blockers Calcium antagonist Beta-blockers Statins Digoxin Diuretics 133 (16%) 183 (22%) 183 (22%) 241 (29%) 174 (21%) 149 (18%) 332 (40%)
N= 830 D-dimer (ng/ml) 257 (177-389) Von Willebrand factor (UI/mL) 171 (131-230) Follow-up (days), median (IQR) 828 (680-994) Thrombosis, n (rate %/year) Stroke/embolism Acute Coronary Syndrome Acute heart failure Major haemorrhage Global death Cardiovascular death 94 (5.0%/year) 32 (1.7%/year) 35 (1.9%/year) 27 (1.5%/year) 68 (3.6%/year) 69 (3.7%/year) 25 (1.1%/year)
ROC CURVE VON WILLEBRAND FACTOR 1,0 0,8 220 UI/mL 0,6 0,4 0,2 0,0 0,0 0,2 0,4 0,6 0,8 1,0 Los segmentos AUC: 0.745 diagonales (0.634-0.856); son producidos por los p<0.001 empates. Cut-off: 220 UI/mL vwf Sensitivity: 0.73 Specify: 0.71
THROMBOTIC AND VASCULAR EVENTS Univariate analysis Multivariate analisys Age 75 years 2.46 (1.54-3.94); <0.001 2.00 (1.23-3.24); 0.005 Male sex 1.10 (0.73-1.63); 0.677 Hypertension 0.93 (0.56-1.56); 0.783 Diabetes 1.53 (1.00-2.34); 0.052 1.44 (0.93-2.22); 0.099 Previous stroke 2.02 (1.29-3.16); 0.002 1.81 (1.14-2.87); 0.012 Heart failure 2.03 (1.36-3.05); 0.001 1.79 (1.18-2.72); 0.006 Coronary artery disease 1.54 (0.97-2.46); 0.066 1.18 (0.73-1.92); 0.497 Renal impairment 1.53 (0.84-2.81); 0.167 Current smoking 1.62 (0.97-2.71); 0.066 1.67 (0.98-2.86);0.060 Hypercholesterolemia 1.10 (0.71-1.69); 0.672 Previous bleeding 1.56 (0.85-2.85); 0.156 vwf 220 UI/mL 3.33 (2.20-5.04); <0.001 2.71 (1.78-4.13); <0.001 D-dimer 1.00 (1.00-1.00); 0.989
HAEMORRHAGIC EVENTS Univariate analysis Multivariate analisys Age 75 years 1.82 (1.08-3.07); 0.025 1.51 (0.87-2.60); 0.139 Male sex 0.55 (0.34-0.91); 0.020 0.57 (0.35-0.95); 0.031 Hypertension 1.45 (0.72-2.94); 0.296 Diabetes 0.99 (0.57-1.72); 0.984 Previous stroke 1.14 (0.62-2.09); 0.665 Heart failure 1.22 (0.75-2.00); 0.415 Coronary artery disease 1.40 (0.80-2.46); 0.238 Renal impairment 2.71 (1.48-4.97); 0.001 1.99 (1.08-3.67); 0.028 Previous bleeding 5.72 (3.45-9.47); <0.001 4.69 (2.79-7.87); <0.001 vwf 220 UI/mL 3.44 (2.27-5.23); <0.001 4.47 (1.86-10.75); 0.001 D-dimer 1.00 (0.99-1.00); 0.875
GLOBAL DEATH Univariate analysis Multivariate analisys Age 75 years 3.68 (1.98-6.86); <0.001 3.26 (1.71-6.19); <0.001 Male sex 0.74 (0.45-1.20); 0.220 Hypertension 1.63 (0.78-3.40); 0.196 Diabetes 1.92 (1.17-3.15); 0.009 1.92 (1.17-3.15); 0.010 Previous stroke 1.58 (0.91-2.75); 0.100 1.44 (0.81-2.57); 0.207 Heart failure 1.80 (1.11-2.91); 0.016 1.56 (0.95-2.57); 0.080 Coronary artery disease 1.14 (0.63-2.06); 0.653 Renal impairment 2.04 (1.07-3.90); 0.032 1.28 (0.65-2.53); 0.480 Current smoking 2.15 (1.24-3.71);0.006 2.76 (1.56-4.89); <0.001 Hypercholesterolemia 0.50 (0.27-0.90); 0.026 0.46 (0.25-0.85); 0.014 Previous bleeding 1.06 (0.46-2.45); 8.893 vwf 220 UI/mL 2.88 (1.77-4.69); <0.001 2.03 (1.24-3.32); 0.005 D-dimer 1.00 (1.00-1.00); 0.465
CARDIOVASCULAR DEATH Multivariate analisys Age 75 years 4.64 (1.35-15.98); 0.015 Heart failure 2.40 (1.05-5.49); 0.038 Current smoking 4.88 (2.11-11.30); <0.001 Hypercholesterolemia 0.24 (0.07-0.82); 0.023 vwf 220 UI/mL 2.94 (1.25-6.96); 0.014
THROMBOSIS HAEMORRHAGE p<0.001 p<0.001 DEATH vwf<220 vwf>220 CARDIOVASCULAR DEATH p<0.001 p<0.001
CONCLUSIONS We reported in a large cohort of anticoagulated AF patients that vwf levels were independent predictors for thrombotic and bleeding events and death during more than 2 years follow-up This biomarker may potentially be used to refine stroke and bleeding risk stratification in AF