Risk factors for intracranial hemorrhage during vitamin K antagonist therapy in patients with nonvalvular atrial fibrillation: A case-control study.

BACKGROUND: Intracranial hemorrhage (ICH) is the most fearful side effect of oral anticoagulant therapy. It is still unclear which risk factor is involved in ICH during vitamin K antagonists (VKAs) treatment and if commonly used bleeding risk scores are able to predict ICH. PURPOSE: Search for individual risk factors and bleeding risk scores (HAS-BLED, ATRIA and ORBIT) associated with ICHs in patients with atrial fibrillation treated with VKAs. METHODS: This is a retrospective case-control study in a single Thrombosis Center. During a 7-year period, patients with nonvalvular atrial fibrillation (NVAF) who developed ICH during VKAs were identified as cases. Four control patients matched for gender, age and length of VKAs were assigned to each case. The association between considered risk factors and ICHs was evaluated using a linear logistic regression method and expressed as odds ratio. Receiver operator characteristic (ROC) curves to assess the predictive ability of bleeding risk scores HAS-BLED, ATRIA and ORBIT were also evaluated. RESULTS: Fifty-one cases of ICH, most of whom were 80 years of age or older (72.5%), were retrieved from the Thrombosis Center's database. Compared to 204 controls, no individual risk factors were associated with ICH. Poor ability to predict ICH was also found using ROC curves (C-statistic for HAS-BLED, ATRIA, and ORBIT were 0.55, 0.53 and 0.54, respectively). CONCLUSIONS: ICHs during VKA therapy preferentially occur in very elderly patients. The risk of ICH is not predicted by the commonly used risk scores.

Warfarin prescription in patients with nonvalvular atrial fibrillation and one non-gender-related risk factor (CHA2 DS2 VASc 1 or 2): A treatment dilemma.

INTRODUCTION: The issue of anticoagulation in individuals with nonvalvular atrial fibrillation (NVAF) and 1 non-gender-related (NGR) risk factor is subject to debate. The reported risk of stroke in untreated individuals is not uniform, and the rate of hemorrhage associated with anticoagulation in this group of individuals is not well defined. To this end, we assessed the rate of stroke and major hemorrhage in individuals treated with warfarin. MATERIALS AND METHODS: individuals were extracted from the START register, an observational, multicenter, dynamic inception cohort study that collects data on NVAF individuals starting anticoagulation therapy. Risk of stroke is stratified using the CHA2 DS2 VASc score upon entry into the registry. RESULTS: Overall, 431 individuals with 1 NGR risk factor were followed up for 604 person-years. One nonfatal ischemic stroke was recorded (0.17 per 100 person-years) during follow-up. On the other hand, there were 9 major bleeding events (1.49 per 100 person-years), with 4 being intracranial hemorrhage (0.66 per 100 person-years), 1 of which was fatal. No difference in patient characteristics, bleeding risk factors, and quality of treatment were found between individuals who bled versus those who did not. However, a trend toward more bleeding events was observed in individuals <65 years old. CONCLUSION: We found an elevated risk of major bleeding and intracranial hemorrhage in NVAF individuals treated with warfarin with 1 NGR risk factor for stroke. These data call for caution when treating with warfarin these individuals.

Effectiveness and safety of oral anticoagulation with non-vitamin K antagonists compared to well-managed vitamin K antagonists in naïve patients with non-valvular atrial fibrillation: Propensity score matched cohort study.

BACKGROUND: The global real-life impact of non-vitamin K antagonist oral anticoagulants (NOACs) introduction in the healthcare system in a setting of well-managed vitamin K antagonist (VKA) therapy has not been specifically addressed. METHODS: We did a population-based retrospective cohort study in naïve patients initiating oral anticoagulants for stroke prevention in atrial fibrillation in a region with a well-managed VKA therapy. NOAC and VKA cohorts were identified using Anatomical Therapeutic Chemical (ATC) codes, while excluding other indications for anticoagulation therapy using ICD-9CM codes. Propensity score was conducted using two different approaches: stratification and 1:1 matching. Event-rates were assessed using both an intention to treat (ITT) and as treated analyses. RESULTS: Of the 137,800 selected patients, 40,411 (6923 treated with NOACs and 33,488 with VKAs) were identified (June 2013-December 2015). Overall ischaemic stroke and major bleeding risk did not significantly differ between the groups both in the ITT and as treated analyses. Noteworthy, intracranial bleeding risk was lower with NOACs (stratified model HR=0.69; 95%CI 0.48-0.99; 1:1 matched model HR=0.73; 95%CI 0.47-1.13) reaching statistical significance in the as treated analysis in both stratified and 1:1 matched models (HR=0.51; 95%CI 0.32-0.80 and HR=0.52; 95%CI 0.30-0.90, respectively). CONCLUSION: Despite well-managed anticoagulation with VKAs, NOACs' introduction has a positive global impact in the public healthcare system in terms of effectiveness and safety especially by lowering intracranial bleeding.

A Randomized Trial of Pharmacogenetic Warfarin Dosing in Naïve Patients with Non-Valvular Atrial Fibrillation.

UNLABELLED: Genotype-guided warfarin dosing have been proposed to improve patient's management. This study is aimed to determine whether a CYP2C9- VKORC1- CYP4F2-based pharmacogenetic algorithm is superior to a standard, clinically adopted, pharmacodynamic method. Two-hundred naïve patients with non-valvular atrial fibrillation were randomized to trial arms and 180 completed the study. No significant differences were found in the number of out-of-range INRs (INR<2.0 or >3.0) (p = 0.79) and in the mean percentage of time spent in the therapeutic range (TTR) after 19 days in the pharmacogenetic (51.9%) and in the control arm (53.2%, p = 0.71). The percentage of time spent at INR>4.0 was significantly lower in the pharmacogenetic (0.7%) than in the control arm (1.8%) (p = 0.02). Genotype-guided warfarin dosing is not superior in overall anticoagulation control when compared to accurate clinical standard of care. TRIAL REGISTRATION: ClinicalTrials.gov NCT01178034.

Minimizing the risk of hemorrhagic stroke during anticoagulant therapy for atrial fibrillation.

INTRODUCTION: Oral anticoagulation (OAC) is given for ischemic stroke prevention in patients with nonvalvular atrial fibrillation. OAC's most serious complications are major bleeding and, in particular, hemorrhagic stroke. Together with vitamin K antagonists (VKAs), direct oral anticoagulants (DOAC) are now available which have a more rapid onset/offset of action and more predictable anticoagulant effect. The advent of DOAC has given to the clinician an opportunity to tailor OAC therapy in order to maximize advantages and minimize complications. AREAS COVERED: This review covers data published in literature regarding the risk of hemorrhagic stroke in patients taking OAC. Bleeding risk assessment is discussed and different bleeding risk factors are presented. The paper will also review clinical studies comparing DOAC against standard anticoagulation, in regard to the risk of hemorrhagic stroke. EXPERT OPINION: Bleeding assessment is mandatory in order to select patients at high hemorrhagic risk who will benefit the most from close monitoring. Blood pressure, alcohol intake, concomitant medication and comorbidities should be constantly evaluated and treated accordingly. During VKA therapy, adherence and intensity of anticoagulation must be strictly monitored. DOAC are associated with lower risk of hemorrhagic stroke than VKA. However, periodic hepatic and renal checks as well as careful evaluation of time adherence are necessary to reduce the risk of bleeding.

Normal left ventricular mechanics by two-dimensional speckle-tracking echocardiography. Reference values in healthy adults.

INTRODUCTION AND OBJECTIVES: Two-dimensional speckle-tracking echocardiography is a novel tool to assess myocardial function. The purpose of this study was to evaluate left ventricular myocardial strain and rotation parameters by two-dimensional speckle-tracking echocardiography in a large group of healthy adults across a wide age range to establish their reference values and to assess the influence of age, sex, and hemodynamic factors. METHODS: Transthoracic echocardiograms were acquired in 247 healthy volunteers (139 women, 44 years [standard deviation, 16 years old] (range, 18-80 years). We measured longitudinal, circumferential, and radial peak systolic strain values, and left ventricular rotation and twist. RESULTS: Average values of global longitudinal, radial, and circumferential strain were -21.5% (standard deviation, 2.0%), 40.1% (standard deviation, 11.8%) and -22.2% (standard deviation, 3.4%), respectively. Longitudinal strain was significantly more negative in women, whereas radial and circumferential strain and rotational parameters were similar in both sexes. Accordingly, lower limits of normality for the strain components were -16.9% in men and -18.5% in women for longitudinal strain, and -15.4% for circumferential and 24.6% for radial strain, irrespective of sex. Longitudinal strain values were more negative at the base than at apical segments. Mean rotational values were -6.9° (standard deviation, 3.5°) for the base, 13.0° (standard deviation, 6.5°) for apical rotation, and 20.0° (standard deviation, 7.3°) for net twist. CONCLUSIONS: We report the comprehensive assessment of normal myocardial deformation and rotational mechanics in a large cohort of healthy volunteers. We found that women have more negative longitudinal strain, accounting for their higher left ventricular ejection fraction. Availability of reference values for these parameters may foster their implementation in the clinical routine.

Left ventricular myocardial strain by three-dimensional speckle-tracking echocardiography in healthy subjects: reference values and analysis of their physiologic and technical determinants.

BACKGROUND: Despite growing interest in applying three-dimensional (3D) speckle-tracking echocardiography (STE) to measure left ventricular (LV) myocardial deformation in various diseases, normative values for 3D speckle-tracking echocardiographic parameters and the effects of demographic, hemodynamic, and technical factors on these values are unknown. METHODS: In 265 healthy volunteers (age range, 18-76; 57% women), longitudinal strain (3DLε), circumferential strain (3DCε), radial strain (3DRε), and area strain (3DAε) were measured by using vendor-specific (Vsp) 3D speckle-tracking echocardiographic equipment. LV strain was also measured by using Vsp two-dimensional (2D) and vendor-independent 3D speckle-tracking echocardiographic software packages, for comparison. RESULTS: Reference values (lower limit of normality) for Vsp 3D STE were -17% to -21% (-15%) for 3DLε, -17% to -20% (-14%) for 3DCε, -31% to -36% (-26%) for 3DAε, and 47% to 59% (38%) for 3DRε. Three-dimensional longitudinal strain decreased, whereas 3DCε increased, with aging (P < .003), with different trends in men and women. Men had lower 3DLε, 3DRε, 3DAε, and 2D longitudinal strain than women (P < .02). LV 3D strain parameters were also influenced by LV volumes and mass, image quality, and temporal resolution (P < .02). Reference values obtained by Vsp 2D STE were -20% to -23% (-18%) for 2D longitudinal strain, -20% to -24% (-17%) for 2D circumferential strain, and 39% to 54% (28%) for 2D radial strain (P < .001 vs Vsp 3D STE). Significantly different 3DCε and 3DRε values were obtained with vendor-independent versus Vsp 3D STE (P < .001). CONCLUSIONS: In healthy subjects, reference values of LV 3D strain parameters were significantly influenced by demographic, cardiac, and technical factors. Limits of normality of LV strain by Vsp 3D STE should not be used interchangeably with Vsp 2D STE or with Vin 3D STE software.

Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study.

Persistent antiphospholipid (aPL) antibodies are occasionally found in subjects without prior history of thromboembolic events (TEs), raising the dilemma of whether to initiate or not a primary thromboprophylaxis. A first TE is considered rare in aPL carriers, but previous studies did not consider the aPL profile nor was the test positivity confirmed in a reference laboratory. In this study, 104 subjects with high-risk aPL profile (positive lupus anticoagulant, anticardiolipin, and anti-ß(2)-glycoprotein I antibodies, triple positivity) confirmed in a reference laboratory, were followed up for a mean of 4.5 years. There were 25 first TEs (5.3% per year): the cumulative incidence after 10 years was 37.1% (95% confidence interval [CI], 19.9%-54.3%). On multivariate analysis, male sex (hazard ratio = 4.4; 95% CI, 1.5-13.1, P = .007) and risk factors for venous thromboembolism (hazard ratio = 3.3; 95% CI, 1.3-8.5, P = .01) were independent predictors for TEs. Aspirin did not significantly affect the incidence of TE. In conclusion, the occurrence of a first TE in carriers of high-risk aPL profile is considerable; it is more frequent among male subjects and in the presence of additional risk factors for venous TE. These data can help in the decision to initiate primary thromboprophylaxis in these subjects.