A systematic review and meta-analysis of supplemental education in patients treated with oral anticoagulation.

Oral anticoagulants (OACs) are indicated for treatment and prevention of thromboembolic diseases. Supplemental patient education (education) has been proposed to improve outcomes, and this systematic review assesses the effect of education on mortality, thromboembolic events (TEEs) including venous thromboembolism (VTE), and bleeding in patients taking OACs. Randomized controlled trials were included, and 2 authors independently screened articles and assessed risk of bias. In 9 trials (controls, n = 720; intervention group patients, n = 646), 4 assessed critical outcomes of mortality, TEEs (VTE, stroke, and systemic embolism), and bleeding to estimate absolute risk ratios. When comparing education with usual care, in 1000 patients, there may be 12 fewer deaths (95% confidence interval [CI], 19 fewer to 154 more) and 16 fewer bleeding events (95% CI, 34 fewer to 135 more), but this evidence is uncertain; the evidence also suggests 6 fewer VTEs (95% CI, 10 fewer to 16 more) and 8 fewer TEEs (95% CI, 16 fewer to 18 more). The mean difference in time in therapeutic range may be 2.4% higher in the education group compared with usual care (95% CI, 2.79% lower to 7.58% higher). We also found very low certainty of evidence for a large increase in knowledge scores (standardized mean difference, 0.84 standard deviation units higher; 95% CI, 0.51-1.16). Overall, the certainty of evidence was low to very low because of serious risk of bias and serious imprecision. Additional sufficiently powered trials or different approaches to education are required to better assess supplemental education effects on outcomes in patients taking OACs.

American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy.

BACKGROUND: Clinicians confront numerous practical issues in optimizing the use of anticoagulants to treat venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and other health care professionals in their decisions about the use of anticoagulants in the management of VTE. These guidelines assume the choice of anticoagulant has already been made. METHODS: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 25 recommendations and 2 good practice statements to optimize management of patients receiving anticoagulants. CONCLUSIONS: Strong recommendations included using patient self-management of international normalized ratio (INR) with home point-of-care INR monitoring for vitamin K antagonist therapy and against using periprocedural low-molecular-weight heparin (LMWH) bridging therapy. Conditional recommendations included basing treatment dosing of LMWH on actual body weight, not using anti-factor Xa monitoring to guide LMWH dosing, using specialized anticoagulation management services, and resuming anticoagulation after episodes of life-threatening bleeding.

Endurance exercise per se reduces the cardiovascular risk marker t-PA antigen in healthy, younger, overweight men.

INTRODUCTION: The cardiovascular risk marker tissue plasminogen activator antigen (t-PA:Ag) can be reduced by long-term exercise interventions, but it is unknown, whether this is due to the weight loss induced by physical activity or due to the physical activity per se. MATERIALS AND METHODS: This was tested in 60 healthy, younger (20-40years), overweight (BMI: 25-30kg/m2) men randomly assigned to 12weeks of intervention in one of four groups: training (T); energy-reduced diet (D); training and increased diet (T-iD); sedentary lifestyle and unchanged diet (controls, C). Fasting blood samples were obtained before and after 12weeks of intervention and analyzed for plasma t-PA:Ag. RESULTS: Body weight was reduced in groups T and D. We observed a decrease in t-PA:Ag from baseline to 12weeks in all three exercise and diet intervention groups, and no change in the control group. A between-group difference in t-PA:Ag was observed at 12weeks (p=0.001), and this was due to lower values in T (p=0.0005), D (p=0.005) and T-iD (p=0.009) compared with the control group. Total body fat mass was reduced in all three exercise groups, and we observed a positive correlation between changes in t-PA:Ag and changes in intra-abdominal and subcutaneous adipose tissue volume. CONCLUSIONS: Our results demonstrate that t-PA:Ag was reduced in all three intervention groups. This suggests that 12weeks of endurance training per se, irrespective of concomitant weight loss, beneficially affects cardiovascular risk in healthy, younger, overweight men.

Gender Differences in Fibrin Polymerization and Lysability of Fibrin in Patients with Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia for both men and women. The embolic cardiovascular events represent serious complications of AF, and apparently women are affected more seriously than men. Little is known about prothrombotic factors and possible gender differences. The present study aimed to characterize fibrin polymerization, fibrinolysis, and fibrin fiber properties in men and in women with AF. MATERIALS AND METHODS: Forty-six female and 101 male patients with AF and without previous stroke were included. Polymerization kinetics, lysis of preformed clot, and fibrin fiber properties were determined by turbidimetric methods. RESULTS: Women were slightly older than men (P < .01), and the male group had a higher systolic blood pressure (P < .01) and a higher incidence of peripheral arterial disease (P < .01) than the female group. Compared with men, women had a higher Vmax during fibrin polymerization (P < .04) and a lower lysability of fibrin, when recombinant tissue plasminogen activator (rt-PA) was added during clot formation (P < .01), while external lysis (rt-PA added after clot formation), plasma fibrinolytic activity, d-dimer, and fibrin fiber properties did not differ between men and women. A significantly higher number of men received acetylsalicylic acid (ASA) compared with women (P < .004). Subgroup analyses on subjects not receiving ASA demonstrated that women still had higher Vmax (P < .04) and a lower rt-PA-induced fibrinolysis (P < .03). CONCLUSION: Women with AF have a higher velocity of lateral aggregation of fibrin fiber protofibrils and a lower lysis of fibrin clots than men.

Prevention of Bleeding in Orthognathic Surgery--A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

PURPOSE: The objective of the present study was to evaluate the efficacy of hemostatic adjuncts on intraoperative blood loss (IOB) in orthognathic surgery (OS) detected by randomized controlled trials (RCTs) of the highest quality. MATERIALS AND METHODS: A search of the Medline, Cochrane, Embase, and Web of Science databases was performed in January 2015, and the risk of bias was assessed using the Jadad and Delphi scales. The predictor variable was the hemostatic measures, and the main outcome variable was the total IOB volume. The secondary outcome variables were the hemoglobin and hematocrit and operating time. This review is registered at PROSPERO (CRD42014014840). RESULTS: Eleven trials were included for review. The individual trials demonstrated the effects on IOB from hypotensive anesthetic regimens, the use of aprotinin, and the herbal medicine Yunnan Baiyao. Six studies of tranexamic acid (TXA), with 288 patients, were suitable for a meta-analysis of continuous data. TXA reduced IOB by an average of 171 mL (95% confidence interval [CI] -230 to -112; P < .00001). Its topical use yielded similarly significant results (mean difference -197, 95% CI -319 to -76; P < .001). A subgroup analysis showed a decreased operating time in the TXA groups by an average of 15 minutes (mean difference -14.78, 95% CI -22.21 to -7.35; P < .0001). CONCLUSIONS: Efficient hemostatic adjuncts exist for OS. Our meta-analysis showed that TXA significantly reduces IOB by an average of one third, regardless of whether it was given intravenously (IV) or applied topically. Additional RCTs are needed to confirm the effect of topical TXA in OS, and larger studies of intravenous administration are needed before any routine recommendations. No hemostatic effect of hypotensive anesthesia was found, mainly owing to imprecise descriptions of the blinding procedures. Transparent and uniform trial reporting is thus encouraged in future studies.

Stroke Risk Perception in Atrial Fibrillation Patients is not Associated with Clinical Stroke Risk.

BACKGROUND: Clinical risk stratification models, such as the CHA2DS2-VASc, are used to assess stroke risk in atrial fibrillation (AF) patients. No study has yet investigated whether and to which extent these patients have a realistic perception of their personal stroke risk. The purpose of this study was to investigate and describe the association between AF patients' stroke risk perception and clinical stroke risk. METHODS: In an observational cross-sectional study design, we surveyed 178 AF patients with a mean age of 70.6 years (SD 8.3) in stable anticoagulant treatment (65% treatment duration >12 months). Clinical stroke risk was scored through the CHA2DS2-VASc, and patients rated their perceived personal stroke risk on a 7-point Likert scale. RESULTS: There was no significant association between clinical stroke risk assessment and patients' stroke risk perception (rho = .025; P = .741). Approximately 60% of the high-risk patients had an unrealistic perception of their own stroke risk, and there was no significant increase in risk perception from those with a lower compared with a higher risk factor load (χ(2) = .010; P = .522). CONCLUSIONS: Considering possible negative implications in terms of lack of motivation for lifestyle behavior change and adequate adherence to the treatment and monitoring of vitamin K antagonist, the apparent underestimation of risk by large subgroups warrants attention and needs further investigation with regard to possible behavioral consequences.

Three months of strictly controlled daily endurance exercise reduces thrombin generation and fibrinolytic risk markers in younger moderately overweight men.

PURPOSE: Physical activity is associated with a decreased risk of cardiovascular disease, but dose dependency of long-term physical exercise on biomarkers within coagulation and fibrinolysis is unknown. We aimed to investigate effects of two doses of daily endurance exercise on biomarkers of the haemostatic balance in overweight men. METHODS: Haemostatic variables were investigated in 53 healthy, younger (20-40 years), moderately overweight (BMI 25-30 kg/m(2)) men randomly assigned to 3 months of strictly controlled endurance exercise at two different doses corresponding to an energy expenditure of 600 kcal/day (HIGH), 300 kcal/day (MOD), or to maintain their habitual lifestyle (CON). Fasting blood samples were collected before and after the intervention and analysed for thrombin generation (endogenous thrombin potential, ETP) and concentrations of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1), and von Willebrand factor (vWF). RESULTS: We observed significant within-group decreases in ETP (MOD 7 %; HIGH 6 %) and in t-PA (MOD 22 %; HIGH 21 %) and PAI-1 (MOD 16 %; HIGH 32 %) in both training groups, and no changes in the CON group. At 3 months, between-group differences were observed for ETP (p = 0.016) and t-PA (p = 0.012) due to significantly lower values in MOD and HIGH compared with CON. Borderline significant between-group differences were observed for PAI-1 (p = 0.082). A significant increase was observed in vWF in HIGH, but with no between-group differences. CONCLUSIONS: Our results demonstrate an effect of 3 months of daily endurance exercise on biomarkers of the haemostatic balance in the direction of reduced cardiovascular risk, independent of exercise dose.

Lysability of fibrin clots is a potential new determinant of stroke risk in atrial fibrillation.

INTRODUCTION: Atrial fibrillation increases the risk of ischemic stroke, but the risk depends on other factors as well. Present risk stratification schemes use age and co-morbidities, but not biochemical markers. We investigated the hypothesis that the formation, structure and lysability of fibrin clots are potential determinants of stroke risk in patients with atrial fibrillation. MATERIALS AND METHODS: A total of 179 patients with atrial fibrillation in stable anticoagulant treatment were included. Thirty-two had a previous ischemic stroke. We measured thrombin generation, plasma concentrations of fibrinogen and C-reactive protein and analysed fibrin structure and lysability by turbidity. Fibrinolytic capacity was measured using the euglobulin fraction of plasma expressed in terms of t-PA equivalents (IU/ml). RESULTS: The patients with previous stroke had a slightly higher burden of co-morbidities compared with the remaining patients as indicated by the CHA2DS2-VASc score, but no significant differences were found regarding age, fibrinogen concentration, C-reactive protein, thrombin generation or fibrinolytic capacity. Furthermore, the patients with previous stroke had a higher mass/length ratio of fibrin fibers (5.5 vs. 5.1 x10(12) Da/cm, p=0.044) and an increased lysability (79.3 vs. 55.3%, p<0.01). CONCLUSION: The higher lysability of fibrin clots in atrial fibrillation patients with previous stroke is most likely a result of a difference in fibrin fiber properties. An increased lysability may increase the risk of embolization of clots formed in the atria, and therefore fibrin clot structure seems to be a determinant of stroke risk in atrial fibrillation.

Biomarkers of coagulation, fibrinolysis, endothelial function, and inflammation in arterialized venous blood.

Effects of venous blood arterialization on cardiovascular risk markers are still unknown. We evaluated biomarkers of inflammation, coagulation, fibrinolysis, and endothelial function in arterialized compared with regular venous blood. Cubital venipunctures were obtained from 10 healthy volunteers. Arterialization was generated by 10 min heating of the contralateral hand. Concentrations of albumin, C-reactive protein (CRP), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1), and von Willebrand factor (vWF) were measured by validated assays. Concentrations of albumin, CRP, and vWF were significantly lower in arterialized than in venous blood (albumin: 43.8 g/l and 44.8 g/l, P = 0.02). Differences in CRP and vWF became insignificant after adjusting for albumin. The endogenous thrombin potential (ETP) was significantly higher in arterialized than in venous blood (1929 nmol/l*min vs. 1872 nmol/l*min, P = 0.02). Addition of the FXIIa inhibitor Corn Trypsin Inhibitor (CTI) prior to the thrombin generation test eliminated the ETP difference suggesting that hand heating activates the FXII-dependent coagulation pathway.

Difference in fibrinolytic capacity in young patients with venous thrombosis or ischaemic stroke.

Many recent studies focus on the common pathophysiological mechanisms and risk factors for arterial and venous thrombosis. We investigated the hypothesis that fibrinolytic capacity is similar in patients with ischaemic stroke and venous thromboembolism. Retrospective study of 604 consecutive patients (age <50 years) referred to systematic thrombophilia testing at a single regional centre. The thrombophilia test included clinical variables, genetic polymorphisms, biomarkers of coagulation and a global assay of fibrinolysis that tested the patient's blood fibrinolytic capacity by application of the euglobulin fraction of plasma to a preformed clot of plasminogen-rich bovine fibrin. The patients with venous thromboembolism (n = 284) were slightly younger (32.3 vs. 33.9 years; <0.01) than those with ischaemic stroke (n = 320), had a significantly higher prevalence of obesity (28 vs. 18%; P < 0.01), higher plasminogen activator inhibitor 1 (PAI-1) activity (12.3 vs. 11.1 IU/ml; P = 0.049) and a significantly lower fibrinolytic capacity (3.4 vs. 3.9 IU/ml; P < 0.01). The lower fibrinolytic capacity in patients with venous thromboembolism was also observed in the subgroup of patients with PAI-1 activity within the normal range (n = 430, 3.7 vs. 4.1IU/ml; P < 0.01). After adjustment for age, BMI, fibrinogen concentration, PAI-1 activity and tissue plasminogen activator activity, fibrinolytic capacity still differed significantly between the two groups. Our results indicate that the capacity for fibrinolysis is lower in young patients with venous thromboembolism than ischaemic stroke, suggesting a different mechanistic role of fibrinolysis in arterial and venous thromboembolism.

The influence of VKORC1 and CYP2C9 gene sequence variants on the stability of maintenance phase warfarin treatment.

INTRODUCTION: A substantial part of the inter-individual variation in vitamin K-antagonist dose can be explained by certain sequence variants in the genes CYP2C9 (NG_008385.1:g.8633C>T or *1/*2, NG_008385.1:g.47639A>C or *1/*3) and VKORC1 (NG_011564.1:g.6399C>T). Patients possessing these variant alleles require lower doses and have increased risk of overanticoagulation. METHODS: We investigated the influence of the above sequence variants on stability of maintenance phase warfarin therapy in a prospective study of 300 consecutive patients followed for one year at an anticoagulant clinic. RESULTS: Patients having one VKORC1 variant allele (n=144) had a time in therapeutic range of INR (TTR) of 71.4%, significantly lower (p=0.02) than the 76.7% TTR of patients with none (n=96) or two (n=46) variant alleles. Patients carrying the CYP2C9 *3 allele (n=40) trended towards lower TTR than patients without this variant allele (69.8% vs. 74.7%, p=0.09). Six patients possessed two variant alleles of CYP2C9 (*2/*3 or *3/*3) and had significantly lower TTR (60.5% vs. 74.3%, p=0.012) and higher risk of an INR>4.5 (67% vs. 23%, p=0.03) compared with the remaining patients. CONCLUSIONS: We observed modest effects of common gene sequence variants in CYP2C9 and VKORC1 on stability of maintenance phase warfarin therapy. Patients attending an anticoagulant clinic using computer-assisted dosage were safely monitored regardless of these sequence variants, but for the small subgroup of patients with the CYP2C9 genotype *2/*3 or *3/*3, treatment stability was reduced.

Multivariate analysis of the relation between diet and warfarin dose.

PURPOSE: The vitamin K antagonist (VKA) warfarin is effective for the prevention of thromboembolisms. Maintenance doses differ greatly among patients and are known to be primarily determined by genetic polymorphisms. The relative impact of dietary vitamin K intake is still a matter of debate. We hypothesize that a multivariate model is more suitable for exploring the relation between dietary intake of vitamin K and warfarin dose than conventional uni- or bivariate analyses. METHODS: In a cross-sectional study, we interviewed 244 patients in the maintenance phase of warfarin therapy and detected polymorphisms in the VKORC1 and CYP2C9 genes. Dietary vitamin K intake was estimated from food frequency questionnaires. RESULTS: A univariate correlation analysis and the regression coefficient from the multivariate model showed a small but significant negative relation between vitamin K intake and warfarin dose. A loading plot of the partial least squares regression model illustrated this counter-intuitive observation, which might be explained by the latent structure between variables. The variation in warfarin dose could be divided into two significant latent variables, the so-called components. In component one, pharmacogenetics explained 52% of dose variation. Component two described health-related behavior (diet, physical activity and body weight) and explained 8% of dose variation. Here, vitamin K intake positively correlated with warfarin dose. DISCUSSION: This study highlights the importance of choosing a statistical method that reflects the complexity of data for interpretation of results from observational studies. The multivariate model appears to be well suited to describe the complex relationship between vitamin K intake and VKA dose.

Genetic, clinical and behavioural determinants of vitamin K-antagonist dose--explored through multivariable modelling and visualization.

Vitamin K antagonists (VKA) are highly effective anticoagulants but their use is hampered by multiple interactions with food and medicine and a narrow therapeutic range. The large variation in dose requirements has led to the development of several dosing algorithms based on pharmacogenetic and clinical variables. In contrast, evidence about the influence of behavioural (i.e. diet and exercise) and socio-psychological factors is sparse. To investigate the impact of pharmacogenetic, clinical, behavioural and socio-psychological factors on maintenance dose of VKA. In a cross-sectional study, we interviewed 250 consecutive patients from an anticoagulant clinic and subsequently measured pharmacogenetic and anthropometric variables. Statistical analyses were carried out using linear regression and multivariable models with visualization features. In both types of analyses, the strongest determinants of VKA dose were polymorphisms in the VKORC1 and CYP2C9 genes and age. Half of the variation in VKA dose could be explained by a linear regression model including four variables, while a multivariable model with 20 pharmacogenetic and clinical variables explained 60%. A multivariable model including 94 predictor variables was not notably better regarding predictive performance, but visualization of this model offered information about the correlation structure between predictor variables. The strongest determinants of VKA dose are well-known pharmacogenetic variables and age. The variables describing health-related behaviour and socio-psychological factors are strongly inter-correlated and not useful in dosing algorithms.

Plenty of pills: polypharmacy prevails in patients of a Danish anticoagulant clinic.

PURPOSE: Vitamin K antagonist (VKA) treatment can successfully prevent thromboembolic complications, but the modality has a narrow therapeutic window and numerous interactions with other pharmaceuticals. The aim of the study reported here was to describe the use of co-medications and the prevalence of polypharmacy among patients treated with VKA. METHODS: In a cross-sectional study, 250 consecutive patients (65% male, median age 68 years, most common indication for VKA treatment: atrial fibrillation) in the maintenance phase of VKA treatment were interviewed about their use of prescription medications, over-the-counter drugs and alternative medicines during the last 7 days. RESULTS: The interviewed patients used a median of five medications (range 1-13), including VKA. Approximately 50% of the patients also took alternative medicines. A wide range of conventional and alternative medicines were used, several of which harbour possible interactions with VKA. Polypharmacy was defined as the use of five or more medications, excluding alternative medicines. The group of polypharmacy patients included 53% of the study population. The use of amiodarone, age >50 years, the indication for VKA treatment being atrial fibrillation or mechanical heart valves and diabetes were independent predictors of polypharmacy. CONCLUSIONS: The results of this study highlight that polypharmacy is a common phenomenon among patients on anticoagulant medication, particularly among elderly patients or those suffering from cardiovascular disease or diabetes.

Baclofen and adenosine inhibition of synaptic transmission at CA3-CA1 synapses display differential sensitivity to K+ channel blockade.

The metabotropic GABA(B) and adenosine A(1) receptors mediate presynaptic inhibition through regulation of voltage-dependent Ca(2+) channels, whereas K(+) channel regulation is believed to have no role at the CA3-CA1 synapse. We show here that the inhibitory effect of baclofen (20 µM) and adenosine (300 µM) on field EPSPs are differentially sensitive to Cs(+) (3.5 mM) and Ba(2+) (200 µM), but not 4-aminopyridine (100 µM). Barium had no effect on paired-pulse facilitation (PPF) in itself, but gave significant reduction (14 ± 5%) when applied in the presence of baclofen, but not adenosine, suggesting that the effect is presynaptic and selective on the GABA(B) receptor-mediated response. The effect of Ba(2+) on PPF was not mimicked by tertiapin (30 nM), indicating that the underlying mechanism does not involve GIRK channels. Barium did not affect PPF in slices from young rats (P7-P8), suggesting developmental regulation. The above effects of Ba(2+) on adult tissue were reproduced when measuring evoked whole-cell EPSCs from CA1 pyramidal neurons: PPF was reduced by 22 ± 3% in the presence of baclofen and unaltered in adenosine. In contrast, Ba(2+) caused no significant change in frequency or amplitude of miniature EPSCs. The Ba(2+)-induced reduction of PPF was antagonized by LY341495, suggesting metabotropic glutamate receptor involvement. We propose that these novel effects of Ba(2+) and Cs(+) are exerted through blockade of inwardly rectifying K(+) channels in glial cells, which are functionally interacting with the GABA(B) receptor-dependent glutamate release that generates heterosynaptic depression.

The slow Ca2+ -dependent K+ -current facilitates synchronization of hyperexcitable pyramidal neurons.

Studies on in vivo and in vitro epilepsy models have shown that progression and maintenance of epileptiform activity can be affected by the slow Ca(2+)-dependent K(+) current (I(sAHP)). This study aimed to investigate the influence of the I(sAHP) on population activity and single cell activity during the transition from the interictal- to the ictal-like phase of an epileptiform field potential induced by Cs(+). Extracellular and intracellular recordings were performed in area CA1 on 400 microm thick hippocampal slices from adult male Wistar rats. During maintained exposure to Cs(+), the transition between the two phases underwent a slow, time-dependent change, where synchronized population activity gradually disappeared and a plateau-like prolongation of the interictal-like phase emerged. In parallel, the size of the ictal-like phase increased. These effects could be ascribed to a gradual block of the I(sAHP) and were mimicked by the I(sAHP) antagonists carbacholine (2 microM), isoproterenol (4 microM) and Ba(2+) (0.2 mM). Cessation of population activity generally occurred without a concomitant decrease in firing rate of single CA1 pyramidal neurons, but was accompanied by the disappearance of hyperpolarizing prepotentials, indicating a shift in the mechanism of action potential initiation. These findings suggest that the presence of the I(sAHP) increases the tendency of hyperexcitable neurons to fire in synchrony, but at the same time serves to dampen the ictal-like activity that follows the hyperexcitable state. Our data indicate that both effects can be attributed to the influence of this current on the steady-state membrane potential in the period of the transition from interictal- to ictal-like activity.