Anticoagulant and non-anticoagulant therapy in thrombotic antiphospholipid syndrome: old drugs and new treatment targets.

In this review, we discuss the current evidence on classic and newer oral anticoagulant therapy, older drugs such as HCQ and statins, and new potential treatment targets in APS. Vitamin K antagonists (VKAs) remain the cornerstone treatment for thrombotic events in APS. In patients fulfilling criteria for definite APS presenting with a first venous thrombosis, treatment with VKAs with a target international normalized ratio (INR) 2.0-3.0 is recommended. In patients with arterial thrombosis, treatment with VKA with target INR 2.0-3.0 or 3.0-4.0 is recommended by recent guidelines, considering the individual's bleeding and thrombosis recurrence risk. A combination of VKAs and low-dose aspirin (75-100 mg/daily) may also be considered. According to available evidence direct oral anticoagulants should be avoided in patients with arterial thrombosis and/or those with triple aPL positivity. Adjunctive treatment with HCQ and/or statins can be considered, especially in anticoagulation treatment-refractory APS. Potential targeted treatments in APS include B-cell targeting, complement inhibition, mammalian target of rapamycin inhibition, IFN targeting, adenosine receptors agonists, CD38 targeting or chimeric antigen receptor T-cell therapy. The safety and efficacy of these treatment targets needs to be examined in well-designed randomized controlled trials.

Effectiveness and safety of direct oral anticoagulants versus vitamin K antagonists in patients on chronic dialysis: a nationwide registry study.

BACKGROUND AND HYPOTHESIS: Clinical trials of direct oral anticoagulants (DOAC) are scarce and inconclusive in patients who are receiving dialysis, for whom DOAC are not labelled in Europe. In a French nationwide registry study of patients on chronic dialysis, we compared the effectiveness and safety of off-label DOAC use vs. approved vitamin K antagonist (VKA). METHODS: Data on patients on dialysis were extracted from the French Renal Epidemiology and Information Network (REIN) registry and merged with data from the French national healthcare system database (Système National des Données de Santé, SNDS). Patients on dialysis who had initiated treatment with an oral anticoagulant between January 1st, 2012, and December 31st, 2020, were eligible for inclusion. The primary safety outcome was the occurrence of major bleeding events and the primary effectiveness outcome was the occurrence of thrombotic events. Using propensity-score-weighted cause-specific Cox regression, we compared the safety and effectiveness outcomes for DOAC and VKA. RESULTS: 8,954 patients received an oral anticoagulant (483 DOAC and 8,471 VKA) for the first time after the initiation of dialysis. Over a median [interquartile range] follow-up period of 1.7 [0.8-3.2] years, 2,567 patients presented a first thromboembolic event and 1,254 patients had a bleeding event. After propensity score adjustment, the risk of a thromboembolic event was significantly lower in patients treated with a DOAC than in patients treated with a VKA (weighted hazard ratio (wHR) [95% confidence interval (CI)]: 0.66 [0.46; 0.94]. A non-significant trend toward a lower risk of major bleeding events was found in DOAC-treated patients, relative to VKA-treated patients (wHR [95%CI]: 0.68 [0.41; 1.12]). The results were consistent across subgroups and in sensitivity analyses. CONCLUSIONS: In a large group of dialysis patients initiating an oral anticoagulant, the off-label use of DOACs was associated with a significantly lower risk of thromboembolic events and a non-significantly lower risk of bleeding, relative to VKA use. This provides reassurance regarding the off-label use of DOACs in people on dialysis.

Anticoagulation and Antiplatelet Regimen in Cardiac Transplant. Clinical Characteristics, Outcomes, and Blood Product Transfusion.

BACKGROUND: We aimed to evaluate the characteristics, clinical outcomes, and blood product transfusion (BPT) rates of patients undergoing cardiac transplant (CT) while receiving uninterrupted anticoagulation and antiplatelet therapy. METHODS: A retrospective, single-center, and observational study of adult patients who underwent CT was performed. Patients were classified into four groups: (1) patients without anticoagulation or antiplatelet therapy (control), (2) patients on antiplatelet therapy (AP), (3) patients on vitamin K antagonists (AVKs), and (4) patients on dabigatran (dabigatran). The primary endpoints were reoperation due to bleeding and perioperative BPT rates (packed red blood cells (PRBC), fresh frozen plasma, platelets). Secondary outcomes assessed included morbidity and mortality-related events. RESULTS: Of the 55 patients included, 6 (11%) received no therapy (control), 8 (15%) received antiplatelet therapy, 15 (27%) were on AVKs, and 26 (47%) were on dabigatran. There were no significant differences in the need for reoperation or other secondary morbidity-associated events. During surgery patients on dabigatran showed lower transfusion rates of PRBC (control 100%, AP 100%, AVKs 73%, dabigatran 50%, p = 0.011) and platelets (control 100%, AP 100%, AVKs 100%, dabigatran 69%, p = 0.019). The total intraoperative number of BPT was also the lowest in the dabigatran group (control 5.5 units, AP 5 units, AVKs 6 units, dabigatran 3 units; p = 0.038); receiving significantly less PRBC (control 2.5 units, AP 3 units, AVKs 2 units, dabigatran 0.5 units; p = 0.011). A Poisson multivariate analysis showed that only treatment on dabigatran reduces PRBC requirements during surgery, with an expected reduction of 64.5% (95% CI: 32.4%-81.4%). CONCLUSIONS: In patients listed for CT requiring anticoagulation due to nonvalvular atrial fibrillation, the use of dabigatran and its reversal with idarucizumab significantly reduces intraoperative BPT demand.

SAMe-TT2R2 to Predict Clinical Outcomes and Time in Therapeutic Range in Patients on Vitamin K Antagonists: A Systematic Review and Meta-Analysis.

BACKGROUND: The SAMe-TT2R2 score identifies patients on vitamin K antagonists (VKAs) who are more likely to have poor time in therapeutic range (TTR); however, the association between SAMe-TT2R2 and clinical outcomes remains controversial. OBJECTIVES: The objective is to assess the association of SAMe-TT2R2 score with clinical outcomes and poor TTR in patients on VKAs. METHODS: We searched using the term "SAMe-TT2R2." Original articles reporting clinical outcomes and SAMe-TT2R2 scores before October 2021 were included. Odds ratios (ORs) of clinical outcomes, diagnostic accuracy parameters of poor TTR (<60%-70%), and mean TTR were extracted. Meta-analysis was performed using random-effects models. RESULTS: Ten studies were included (N = 22 894); 4 showed pooled changes in TTR of -3.61% (95% CI:-4.88% to -2.35%) and -3.98% (95% CI: -6.08% to -1.87%) at SAMe-TT2R2 scores ≥2 and ≥3, respectively, compared with lower scores. The diagnostic accuracy parameters for poor TTR were too heterogeneous to conclude. SAMe-TT2R2 ≥3 significantly correlated with all adverse events (OR = 1.43 [95% CI: 1.29-1.54; P < 0.001]), composite thromboembolism (OR = 1.53 [95% CI: 1.19-1.97; P = 0.001]), and composite bleeding (OR = 1.33 [95% CI: 1.12-1.59; P = 0.001] regardless of the indication, while an SAMe-TT2R2 ≥2 significantly correlated with mortality (OR = 1.32 [95% CI: 1.02-1.70; P = 0.033]). We found no relationship between an SAMe-TT2R2 ≥3 and mortality or between a score ≥2 and clinical outcomes. CONCLUSIONS AND RELEVANCE: Patients on VKAs with SAMe-TT2R2 ≥3 experienced more adverse events, bleeding, and thromboembolism compared with patients who had an SAMe-TT2R2 <3. However, the score had limited and inconclusive predictability for poor TTR in the study.

The efficacy and safety of direct oral anticoagulants compared with vitamin K antagonist in patients with hypertrophic cardiomyopathy and atrial fibrillation.

BACKGROUND: The benefit-risk profile of direct oral anticoagulants (DOAC) therapy in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF) has not been well established yet. This study aimed to evaluate the efficacy and safety of DOAC compared with vitamin K antagonists (VKA) in patients with HCM and AF. METHODS: PubMed, EMBASE, the Cochrane Library, and clinicaltrials.gov were searched to identify studies comparing DOAC with VKA in patients with HCM and AF. The primary endpoint was thromboembolic events. The relative risks and standard errors were pooled by random-effect models using the generic inverse variance method. RESULTS: Seven observational studies involving 9395 patients were included in this meta-analysis. Compared to the VKA group, the DOAC group displayed a similar risk of thromboembolic events [RR (95%CI): 0.93 (0.73-1.20), p = 0.59] and ischemic stroke [RR (95%CI): 0.65 (0.33-1.28), p = 0.22]. The incidence of major bleeding was comparable between the two groups [RR (95%CI): 0.75 (0.49-1.15), p = 0.19]. Meanwhile, DOAC therapy was superior to VKA therapy in reducing the incidences of all-cause death [RR (95%CI): 0.44 (0.35-0.55), p < 0.001], cardiovascular death [RR (95%CI): 0.41 (0.22-0.75), p = 0.004], and intracranial hemorrhage [RR (95%CI): 0.42 (0.24-0.74), p = 0.003]. CONCLUSION: In patients with HCM and AF, DOAC therapy was similar to VKA therapy in reducing the risk of thromboembolic events, without increasing bleeding risk. In addition, the DOAC group displayed significant advantages in reducing mortality and intracranial hemorrhage compared with the VKA group. Further randomized controlled trials are needed to provide more evidence for DOAC therapy in this population.

Anticoagulation control among patients on vitamin K antagonists in nine countries in Sub-Saharan Africa.

Vitamin K antagonists (VKA) is the primary anticoagulant in most settings of Sub-Saharan Africa. Understanding the quality of anticoagulation services in the continent is vital in optimising the intended benefits. This study assessed the quality of anticoagulation and associated factors among VKA-treated patients in nine SSA countries. We conducted a retrospective cohort study of randomly selected patients on anticoagulation from 20 clinics in Botswana, the Democratic Republic of Congo, Ethiopia, Gambia, Ghana, Mozambique, Nigeria, Tanzania, and South Africa. Eligible participants were those on VKAs for at least three months and with at least four international normalised ratios (INR) results in 2019-2021. We report the proportion of INR values in the therapeutic range, time-in-therapeutic range (TTR) using the Rosendaal method, and the proportion of patients with TTR ≥ 65% (optimal anticoagulation). The mean age was 51.1(16.1) years, and 64.2% were women. The most common indications for VKA included venous thromboembolism (29.6%), prosthetic valves (26.7%) and atrial fibrillation/flutter (30.1%). We analysed 6743 INR tests from 1011 participants, and of these, 48.5% were sub-therapeutic, 34.1% therapeutic, and 17.4% were supratherapeutic relative to disease-specific reference ranges. TTR was calculated for 660 patients using 4927 INR measurements. The median (interquartile range [IQR]) TTR was 35.8(15.9,57.2) %. Optimal anticoagulation control was evident in 19.2% of participants, varying from 2.7% in Tanzania to 23.1% in Ethiopia. The proportion of patients with TTR ≥ 65% was 15,4% for prosthetic heart valves, 21.1% for venous thromboembolism and 23.7% for atrial fibrillation or flutter. Countries with universal health coverage had higher odds of optimal anticoagulation control (adjusted odds ratio (aOR) 1.79, 95% confidence interval [CI], 1.15- 2.81, p = 0.01). Patients on VKAs for different therapeutic indications in SSA had suboptimal TTR. Universal health coverage increased the odds of achieving TTR by 79%. The evidence calls for more intensive warfarin management strategies in SSA, including providing VKA services without out-of-pocket payments.

Cerebral venous sinus thrombosis associated with cancer: analysis of the ACTION-CVT study.

Nearly one fifth of patients with venous thromboembolism (VTE) have cancer. When both of these conditions occur, especially in cases of cerebral vein thrombosis (CVT), patient management is often challenging. The aim of this study was to compare the characteristics and event courses in patients affected by CVT with and without cancer. Consecutive patients with CVT from the ACTION-CVT cohort study were included if cancer status was reported. Risk factors as well as the clinical and radiological characteristics of patients were compared. Univariable and multivariable analyses were performed to assess variables associated with cancer. Kaplan-Meier method and log-rank test, logistic regression analysis, and propensity score matching were used to investigate any association between cancer-related CVT and study outcomes (primary outcome at 3-months: recurrent VTE or major hemorrhage; recurrent VTE; major hemorrhage; recanalization status; all-cause-death). Overall, 1,023 patients with CVT were included, of which 6.5% had cancer. Older age (adjusted odds ratio [aOR] 1.28 per decade increase; 95% confidence interval [CI] 1.08-1.52) and absence of headache (aOR 0.47; 95% CI 0.27-0.84) were independently associated with cancer. Patients with cancer had a higher risk of recurrent VTE or major hemorrhage (aOR 3.87; 95% CI 2.09-7.16), all-cause-death (aOR 7.56 95% CI 3.24-17.64), and major hemorrhage (aOR 3.70 95% CI 1.76-7.80). Recanalization rates, partial or complete, was not significantly different. CVT patients with cancer were more likely to be older, have no referred headache, and have worse outcomes compared to CVT patients without cancer.

Direct oral anticoagulants versus vitamin K antagonists in patients with atrial fibrillation and stage 5 chronic kidney disease under dialysis: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: In patients with atrial fibrillation (AF) and normal or slightly impaired renal function, the use of direct oral anticoagulants (DOACs) is preferable to vitamin K antagonists (VKAs). However, in patients undergoing hemodialysis, the efficacy, and safety of DOACs compared with VKAs are still unknown. PURPOSE: To review current evidence about the safety and efficacy of DOACs compared to VKAs, in patients with AF and chronic kidney disease under hemodialysis. METHODS: We systematically searched PubMed, Scopus, and Cochrane databases for RCTs comparing DOACs with VKAs for anticoagulation in patients with AF on dialysis therapy. Outcomes of interest were: (1) stroke; (2) major bleeding; (3) cardiovascular mortality; and (4) all-cause mortality. Statistical analysis was performed using RevMan 5.1.7 and heterogeneity was assessed by I2 statistics. RESULTS: Three randomized controlled trials were included, comprising a total of 383 patients. Of these, 218 received DOACs (130 received apixaban; 88 received rivaroxaban), and 165 were treated with VKAs (116 received warfarin; 49 received phenprocoumon). The incidence of stroke was significantly lower in patients treated with DOACs (4.7%) compared with those using VKAs (9.5%) (RR 0.42; 95% CI 0.18-0.97; p = 0.04; I2 = 0%). However, the difference was not statistically significant in the case of ischemic stroke specifically (RR 0.42; 95% CI 0.17-1.04; p = 0.06; I2 = 0%). As for the major bleeding outcome, the DOAC group (11%) had fewer events than the VKA group (13.9%) but without statistical significance (RR 0.75; 95% CI 0.45-1.28; p = 0.29; I2 = 0%). There was no significant difference between groups regarding cardiovascular mortality (RR 1.23; 95% CI 0.66-2.29; p = 0.52; I2 = 13%) and all-cause mortality (RR 0.98; 95% CI 0.77-1.24; p = 0.84; I2 = 16%). CONCLUSION: This meta-analysis suggests that in patients with AF on dialysis, the use of DOACs was associated with a significant reduction in stroke, and a numerical trend of less incidence of major bleeding compared with VKAs, but in this case with no statistical significance. Results may be limited by a small sample size or insufficient statistical power.

The use of non-vitamin K antagonist oral anticoagulants in chronic thromboembolic pulmonary hypertension: an updated meta-analysis.

Studies have demonstrated the beneficial effects of non-vitamin K antagonist oral anticoagulants (NOACs) for the treatment of atrial fibrillation and venous thromboembolism (VTE). The impact of NOACs on chronic thromboembolic pulmonary hypertension (CTEPH) remains controversial. This meta-analysis was conducted to investigate the effectiveness and safety of NOACs compared with vitamin K antagonists (VKAs) in patients with CTEPH. A comprehensive search of PubMed, Embase, and Cochrane Library was conducted for relevant studies, encompassing data from inception until November 2023. The data were pooled using a fixed-effects model if the I2 value was less than 50%; otherwise, a random-effects model was employed. Overall, two randomized controlled trials (RCTs) and eight observational studies involving 4556 patients with CTEPH were included. Patients receiving NOACs exhibited a significantly lower incidence of all-cause mortality (odds ratio [OR] = 0.52, 95% confidence interval [CI]: 0.36-0.76) and major bleeding (OR = 0.58, 95% CI: 0.36-0.92) compared to those with VKAs. There were no significant differences in the rate of VTE recurrence (OR = 1.07, 95% CI: 0.72-1.59), total bleeding (OR = 0.78, 95% CI: 0.60-1.01), and minor bleeding (OR = 1.11, 95% CI: 0.73-1.69) between the two studied groups. Similar results were found in the subgroup analysis and sensitivity analysis.This meta-analysis provided evidence that NOACs could be superior to VKAs for the treatment of CTEPH. NOACs might be safe and a convenient alternative to VKAs for thromboprophylaxis in patients with CTEPH.

Safety and efficacy of fixed versus variable-dose prothrombin complex concentrate for emergent reversal of vitamin K antagonists: A systematic review and meta-analysis.

STUDY OBJECTIVE: Four-factor prothrombin complex concentrate (4F-PCC) is standard of care for emergent vitamin K antagonist (VKA) reversal but optimal dosing is uncertain. This meta-analysis estimated the proportion of patients treated with fixed dose (FD) 4F-PCC who achieved adequate reversal and compared safety and efficacy of FD versus weight-based dose (WB) strategies. METHODS: This review was conducted according to PRISMA guidelines. Medline and Scopus were searched and included studies evaluating FD regimens and comparing FD and WB for emergent VKA reversal. Data was pooled using random effects. Subgroup analyses examined heterogeneity. Risk of bias was assessed with Newcastle-Ottawa Scale and RoB2 score. RESULTS: Twenty-three studies (n = 2055) were included with twelve (n = 1143) comparing FD versus WB. The proportion of patients achieving goal INR with FD varied depending on the INR target, being significantly higher for INR <2 (90.9%, 95% Confidence Interval (CI) 87.2, 94.06) compared to INR <1.6 (70.97%, 95%CI 65.33, 76.31). Compared to WB, FD was less likely to achieve a goal INR <1.6 (Risk Difference (RD) -13%, 95% CI -21, -4) but achieved similar reversal for a goal INR <2.0, (RD -1%, 95%CI -7, 4). There was no difference in hospital mortality (RD 4%, 95%CI -2, 9) or thrombosis (RD 0.0%, 95%CI -3, 3). CONCLUSION: FD VKA reversal was associated with significantly lower attainment of goal INR compared to WB with lower INR targets. This did not translate to differences in hospital mortality, but these results should be interpreted cautiously in light of the observational nature of the included studies.

Cardiorenal Outcomes Among Patients With Atrial Fibrillation Treated With Oral Anticoagulants.

RATIONALE & OBJECTIVE: Direct oral anticoagulants (DOACs) have progressively replaced vitamin K antagonists (VKAs) for stroke prevention in patients with nonvalvular atrial fibrillation (AF). DOACs cause fewer bleeding complications, but their other advantages, particularly related to kidney outcomes, remain inconclusive. We studied the risks of chronic kidney disease (CKD) progression and acute kidney injury (AKI) after DOAC and VKA administration for nonvalvular AF. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Cohort study of Swedish patients enrolled in the Stockholm Creatinine Measurements (SCREAM) project with a diagnosis of nonvalvular AF during 2011-2018. EXPOSURE: Initiation of DOAC or VKA treatment. OUTCOME: Primary outcomes were CKD progression (composite of >30% estimated glomerular filtration rate [eGFR] decline and kidney failure) and AKI (by diagnosis or KDIGO-defined transient creatinine elevations). Secondary outcomes were death, major bleeding, and the composite of stroke and systemic embolism. ANALYTICAL APPROACH: Propensity score weighted Cox regression was used to balance 50 baseline confounders. Sensitivity analyses included falsification end points, subgroups, and estimation of per-protocol effects. RESULTS: We included 32,699 patients (56% initiated DOAC) who were observed for a median of 3.8 years. Their median age was 75 years, 45% were women, and 27% had an eGFR <60mL/min/1.73m2. The adjusted HRs for DOAC versus VKA were 0.87 (95% CI, 0.78-0.98) for the risk of CKD progression and 0.88 (95% CI, 0.80-0.97) for AKI. HRs were 0.77 (95% CI, 0.67-0.89) for major bleeding, 0.93 (95% CI, 0.78-1.11) for the composite of stroke and systemic embolism, and 1.04 (95% CI, 0.95-1.14) for death. The results were similar across subgroups of age, sex, and baseline eGFR when restricting to patients at high risk for thromboembolic events and when censoring follow up at treatment discontinuation or change in type of anticoagulation. LIMITATIONS: Missing information on time in therapeutic range and treatment dosages. CONCLUSIONS: Among patients with nonvalvular AF treated in routine clinical practice compared with VKA use, DOAC use was associated with a lower risk of CKD progression, AKI, and major bleeding but a similar risk of the composite of stroke, systemic embolism, or death.

Time Trends of Etiology, Treatment, and Long-Term Outcomes Among Patients with Left Ventricular Thrombus.

Background: Recommendations for drug treatment of left ventricular thrombus (LVT) are based on the ST-segment elevation myocardial infarction (STEMI) guidelines; however, the etiology of LVT has changed. Due to the lack of evidence regarding LVT treatment in the heart failure population, current heart failure guidelines do not cover LVT treatment. We sought to review the etiology of LVT and changes in antithrombotic therapy over the previous 12 years and explore the impact of anticoagulation treatment from a single center's experience. Methods: From January 2009 to June 2021, we studied 1675 patients with a discharge diagnosis of LVT at a single center to investigate the clinical characteristics, incidence of all-cause death, cardiovascular death, ischemic stroke, major adverse cardiac and cerebrovascular events (MACCE), systemic embolism (SE), and major bleeding events. Patients were divided into an anticoagulant group and a non-anticoagulant group according to whether they received oral anticoagulant therapy at discharge. Results: The study included 909 patients (anticoagulation, 510; no anticoagulation, 399). While overall antiplatelet therapy dramatically decreased, more patients with LVT received oral anticoagulation in 2021 (74.0%) than in 2009 (29.6%). In addition, more than half of the patients had heart failure with reduced ejection fraction (HFrEF) each year. The all-cause mortality was 17.3% during 3.8 years of follow-up. The incidences of cardiovascular death, stroke, MACCE, SE, and major bleeding were 16.0%, 3.3%, 19.8%, 5.1%, and 1.7%, respectively. The anticoagulation group had a significantly higher proportion of dilated cardiomyopathy than the non-anticoagulation group (24.7% vs. 5.5%, p < 0.001), and a lower LVEF (34.0 vs. 41.0, p < 0.001). The anticoagulation group also had a higher probability of adverse events on long-term follow-up (p > 0.05). A multivariable competing risk regression model found no significant difference in all six endpoints between the groups (all p > 0.05). Similar results were found by matched and weighted data analysis. Diabetes mellitus (hazard ratio (HR), 1.42; 95% confidence interval (CI), 1.04-1.93; p = 0.027), renal insufficiency (HR, 2.36; 95% CI, 1.60-3.50; p < 0.001), history of previous stroke (HR, 1.60; 95% CI, 1.13-2.29; p = 0.009), and HFrEF (HR, 2.54; 95% CI, 1.78-3.64; p < 0.001) were predictors of increased risk of MACCE. Conclusions: Heart failure, rather than acute myocardial infarction, is currently the primary cause of LVT. A trend towards better prognosis in the no anticoagulation group was noted. Multivariable, matching and weighting analysis showed no improvement in prognosis with anticoagulant therapy. Our study does not negate the efficacy of anticoagulation but suggests the need to strengthen the management of anticoagulation in order to achieve better efficacy.

Differences in the location of bleeding with direct oral anticoagulants vs. vitamin K antagonists: A study in the World Health Organization's pharmacovigilance database.

AIMS: Clinical trials have found differences in bleeding locations between direct oral anticoagulants (DOAC) and vitamin K antagonists (VKA). The present study was performed to investigate these differences in real life using reports of adverse drug reactions registered in the World Health Organization's pharmacovigilance database, VigiBase®. METHODS: All bleeding registered between 1 January 2008 and 31 December 2021 in adults were included. The main objective was to compare bleeding locations reported with DOAC with those with VKA. As a secondary objective, we performed the same comparison with Xa vs. thrombin inhibitors. Results were presented as reporting odds ratios (RORs) adjusted on age, gender, origin of reports and co-medications with their 95% confidence interval. RESULTS: During this 14-year period, 142 228 instances of bleeding were registered with oral anticoagulants, including 39 570 with VKA and 102 658 with DOAC. Mean time to event was lower with DOAC (7.6 months) than with VKA (29.9 months) (P < .001). Significant differences in bleeding locations were found in the reports with less cerebral, urologic and nasal bleeding, more gynaecologic bleeding with DOAC than with VKA, without any significant differences in digestive and cutaneous locations. A higher risk of bleeding reports was found with Xa inhibitors vs. dabigatran whatever the locations (except digestive bleeding). CONCLUSION: This real-life study shows that the differences in bleeding locations between DOAC and VKA are not limited to the brain or gastrointestinal tracts. Significant differences were also found between Xa and thrombin inhibitors.

Design of a structure-activity relationship model of vitamin K epoxide reductase (VKORC1) inhibitors combining chemical synthesis of new compounds, enzymatic assays and molecular modelling.

Vitamin K antagonists (VKAs) anticoagulants have been used since the 1950s as medicines and rodenticides. These molecules are mainly 4-hydroxycoumarin derivatives and act by inhibiting the vitamin K epoxide reductase (VKORC1), an endoplasmic reticulum membrane resident enzyme. However, many VKORC1 mutations have been reported over the last decade, inducing VKAs resistances and thus treatments failures. Although studies have reported experimental and computational investigations of VKAs based on VKORC1 structural homology models, the development of new effective anticoagulants has been quite complex due to the lack of structural data and reliable structure-activity relationships. However, the recent publication of VKORC1 crystal structure provides new information for further studies. Based on these findings, we combined chemical synthesis, enzymatic assays and molecular modelling methods to design a structure-activity relationship (SAR) model. Our results proved that the lipophilicity, the membrane permeability of inhibitors and their affinity towards human VKORC1 enzyme are the main characteristics for potent anticoagulants. Our SAR model managed to rank compounds according to their ability to inhibit the human VKORC1. Such a tool might constitute an alternative to evaluate new molecules potency before their chemical synthesis and biological assessment and might assist the development of new VKAs.

The efficacy and safety of direct oral anticoagulants versus vitamin K antagonists in patients with left-sided bioprosthetic heart valves and atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND: The efficacy and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) for the treatment of patients with left-sided bioprosthetic heart valves (BHV) and atrial fibrillation (AF) remain controversial. This study aims to perform a meta-analysis to evaluate the efficacy and safety of DOACs versus VKAs in this region. METHODS: We retrieved all relevant randomized controlled studies and observational cohort studies, which critically assessed the efficacy and safety of DOACs versus VKAs among patients with left-sided BHV and AF in databases of PubMed, Cochrane, ISI Web of Sciences, and Embase. The efficacy outcomes of this meta-analysis were stroke events and all-cause death when the safety outcomes included major and any bleeding. RESULTS: The analysis integrated 13 studies while enrolling 27,793 patients with AF and left-sided BHV. DOACs reduced the rate of stroke by 33% compared with VKAs (risk ratio [RR] 0.67; 95% CI 0.50-0.91), with no increased incidence of all-cause death (RR 0.96; 95% CI 0.82-1.12). For safety outcomes, major bleeding was reduced by 28% using DOACs rather than VKAs (RR 0.72; 95% CI 0.52-0.99), while there was no difference in the events of any bleeding (RR 0.84; 95% CI 0.68-1.03). In addition, in patients younger than 75 years old, the stroke rate was reduced by 45% in the population using DOACs (RR 0.55; 95% CI 0.37-0.84). CONCLUSION: Our meta-analysis demonstrated that in patients with AF and BHV, compared with VKAs, using DOACs was associated with reduced stroke and major bleeding events without an increase of all-cause mortality and any bleeding. In the population younger than 75 years old, DOAC might be more effective in preventing cardiogenic stroke.

Comparing the risk of dementia in subjects with atrial fibrillation using non-vitamin K antagonist oral anticoagulants versus vitamin K antagonists: a Belgian nationwide cohort study.

BACKGROUND: Atrial fibrillation (AF) is associated with cognitive decline, with anticoagulated subjects potentially having a reduced risk compared with non-anticoagulated subjects. However, whether non-vitamin K antagonist oral anticoagulants (NOACs) may reduce the risk of dementia compared with vitamin K antagonists (VKAs) is unclear yet. Therefore, the risk of dementia was compared between AF subjects on NOACs versus VKAs. METHODS: AF subjects initiating anticoagulation between 2013 and 2019 were identified in Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate cognitive outcomes. RESULTS: Among 237,012 AF subjects (310,850 person-years (PYs)), NOAC use was associated with a significantly lower risk of dementia (adjusted hazard ratio (aHR) 0.91, 95% confidence interval (CI) (0.85-0.98)) compared with VKAs. A trend towards a lower risk of vascular dementia (aHR 0.89, 95% CI (0.76-1.04)) and significantly lower risk of other/unspecified dementia (aHR 0.91, 95% CI (0.84-0.99)) were observed with NOACs compared with VKAs, whereas the risk of Alzheimer's disease was similar (aHR 0.99, 95% CI (0.88-1.11)). Apixaban (aHR 0.91, 95% CI (0.83-0.99)) and edoxaban (aHR 0.79, 95% CI (0.63-0.99)) were associated with significantly lower risks of dementia compared with VKAs, while risks were not significantly different with dabigatran (aHR 1.02, 95% CI (0.93-1.12)) and rivaroxaban (aHR 0.97, 95% CI (0.90-1.05)). Comparable risks of dementia were observed between individual NOACs, except for significantly lower risks of dementia (aHR 0.93, 95% CI (0.87-0.98)) and other/unspecified dementia (aHR 0.90 (0.84-0.97)) with apixaban compared with rivaroxaban. CONCLUSION: NOACs were associated with a significantly lower risk of dementia compared with VKAs, likely driven by apixaban and edoxaban use.

Oral anticoagulants in patients with atrial fibrillation at low stroke risk: a multicentre observational study.

AIMS: There is currently no consensus on whether atrial fibrillation (AF) patients at low risk for stroke (one non-sex-related CHA2DS2-VASc point) should be treated with an oral anticoagulant. METHODS AND RESULTS: We conducted a multi-country cohort study in Sweden, Denmark, Norway, and Scotland. In total, 59 076 patients diagnosed with AF at low stroke risk were included. We assessed the rates of stroke or major bleeding during treatment with a non-vitamin K antagonist oral anticoagulant (NOAC), a vitamin K antagonist (VKA), or no treatment, using inverse probability of treatment weighted (IPTW) Cox regression. In untreated patients, the rate for ischaemic stroke was 0.70 per 100 person-years and the rate for a bleed was also 0.70 per 100 person-years. Comparing NOAC with no treatment, the stroke rate was lower [hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.56-0.94], and the rate for intracranial haemorrhage (ICH) was not increased (HR 0.84; 95% CI 0.54-1.30). Comparing VKA with no treatment, the rate for stroke tended to be lower (HR 0.81; 95% CI 0.59-1.09), and the rate for ICH tended to be higher during VKA treatment (HR 1.37; 95% CI 0.88-2.14). Comparing NOAC with VKA treatment, the rate for stroke was similar (HR 0.92; 95% CI 0.70-1.22), but the rate for ICH was lower during NOAC treatment (HR 0.63; 95% CI 0.42-0.94). CONCLUSION: These observational data suggest that NOAC treatment may be associated with a positive net clinical benefit compared with no treatment or VKA treatment in patients at low stroke risk, a question that can be tested through a randomized controlled trial.

Challenges of Anticoagulant Therapy in Atrial Fibrillation-Focus on Gastrointestinal Bleeding.

The rising prevalence and the complexity of atrial fibrillation (AF) pose major clinical challenges. Stroke prevention is accompanied by non-negligible risks, making anticoagulant treatment an ongoing challenge for the clinician. Current guidelines recommend direct oral anticoagulants (DOACs) over warfarin for stroke prevention in most AF patients, mainly due to the ease of their use. However, assessing the bleeding risk in patients receiving oral anticoagulants remains-particularly in the case of DOACs-highly challenging. Using dose-adjusted warfarin increases threefold the risk of gastrointestinal bleeding (GIB). Although the overall bleeding risk appears to be lower, the use of DOACs has been associated with an increased risk of GIB compared to warfarin. Accurate bleeding (including GIB-specific) risk scores specific for DOACs remain to be developed. Until then, the assessment of bleeding risk factors remains the only available tool, although the extent to which each of these factors contributes to the risk of bleeding is unknown. In this paper, we aim to provide a comprehensive review of the bleeding risk associated with oral anticoagulant therapy in AF patients, with a highlight on the latest insights into GIB associated with oral anticoagulation; we emphasize questions that remain to be answered; and we identify hotspots for future research.

Factors influencing real-life use of direct oral anticoagulants in patients with cerebral sinus and venous thrombosis.

BACKGROUND: Direct oral anticoagulants (DOAC) are advocated as equally effective to vitamin K antagonists (VKA) for the treatment of patients with cerebral sinus and venous thrombosis (CSVT). However, data concerning the real-life management practices in CSVT patients are is lacking. METHODS: Prospective CSVT databases from four large academic medical centers were retrospectively studied. Demographics, clinical presentations, risk factors, radiological and outcome parameters were compared between CSVT patients treated with DOAC and VKA. RESULTS: Out of 504 CSVT patients, 43 (8.5%) were treated with DOAC, and the remaining 461 (91.5%) were treated with VKA. All patients with antiphospholipid syndrome (APLA) were treated with VKA (61 vs. 0, p=0.013). Patients with a history or presence of malignancy were also more often treated with VKA (16% vs. 5%, p=0.046). Other risk factors for thrombosis did not differ between the groups. There were no differences in clot extent or location and no differences in the percentage of favorable outcomes or mortality were observed. CONCLUSION: Our data suggests that only malignancy and antiphospholipid antibodies significantly influenced physician's decisions towards choosing VKA rather than DOAC. DOAC appear to be as effective and safe as VKA in patients with CSVT.

Risk of bleeding after ground-level falls in elderly patients with atrial fibrillation and warfarin therapy.

OBJECTIVES: The aim of this study was to investigate bleeding risk in patients treated with VKAs after ground-level falls, considering the type and severity of bleeding. METHODS: The study was designed as a retrospective cohort study and included a total of 204 elderly patients aged > 65 years treated for AF continuously with warfarin for more than 3 years. Data were obtained from hospital registries in Bratislava, Slovakia. A 5-year assessment of death/survival was performed to determine mortality. RESULTS: There was no statistically significant difference in severe bleeding (2.13 % with falls vs 2.55 % without, p = 1) and 5-year mortality (45 % and 38 % respectively, p = 0.3987) based on the presence of falls. Multivariate analysis, after adjustment for age, CHA2DS2VASc, HASBLED, stroke history, labile INR and number of falls showed that only HASBLED score was a statistically significant contributor (CI: 1.0245 - 1.0919, p = 0.0007) to severe bleeding. There was statistically significant difference in severe bleeding (18 % vs 0 %, p = 0.0132) between patients suffering from spontaneous and bleeding after falls and also when comparing individual bleeding episodes (12 % vs 1 %, p < 0.0001). There was no statistically significant difference in 5-year mortality between the two groups (43 % vs 42 % respectively, p = 0.3931). CONCLUSIONS: Our results show that occurrence of falls in AF patients treated with VKAs have no significant impact on the incidence of severe bleeding and 5-year mortality and that spontaneous bleeding was associated with a significantly higher risk of severe bleeding compared to bleeding after falling (Tab. 4, Ref. 30).