Effectiveness Of Direct Oral Anticoagulants Research Articles

Lower dose direct oral anticoagulants and improved survival: A combined analysis in patients with established atherosclerosis

BackgroundAntithrombotic/anticoagulation effects of direct oral anticoagulants (DOACs) are dose-dependent. However, recent observations suggest that administering lower dose DOACs may better protect against all-cause mortality. We investigated whether, in patients with established atherosclerosis, DOAC dose selection would affect the risk of all-cause mortality. MethodsWe performed a structured literature research for controlled trials allowing random assignment to a lower dose DOAC, a higher dose DOAC, or control therapy in patients with established atherosclerosis. Pooled risk ratios (RRs) of all-cause mortality in lower and higher dose DOACs versus control therapy were estimated using a random-effect model. ResultsAtherosclerosis manifested as acute coronary syndrome (n=17,220), stable coronary (CAD) and/or peripheral artery disease (PAD) (n=27,395) or CAD associated with atrial fibrillation (n=4,510). Antithrombotic doses of rivaroxaban (2.5 mg or 5.0 mg BID) or dabigatran (50 mg, 75 mg, 110 mg, or 150 mg, BID) were tested in three trials versus single or dual antiplatelet control therapy, whereas anticoagulation doses of edoxaban (30 mg or 60 OD) were tested versus warfarin in one trial. Compared to control, patients receiving lower dose (RR 0.80, 95% CI 0.73-0.89, p<0.0001, I²=0%), but not those receiving higher dose DOACs (RR 0.95, 95% CI 0.87-1.05, p=0.3074, I²=0%), had a significant reduction of all-cause mortality. Benefit from lower dose DOACs remained after sensitivity analysis or direct comparison with higher dose DOACs (RR 0.84, 95% CI 0.76-0.93, p=0.0009, I²=0%). ConclusionsWithin antithrombotic/anticoagulation regimens of DOAC administration, selection of lower dose appears to protect from all-cause mortality in patients with established atherosclerosis.

Upper extremities deep vein thrombosis and DOAC treatment: a prospective cohort study

Abstract Background Data on the use of direct oral anticoagulants (DOACs) in patients with upper extremities deep vein thrombosis (UEDVT) are limited. Purpose To assess the effectiveness and safety of DOACs in the treatment of UEDVT. Methods Data on patients with an objective diagnosis of acute UEDVT treated with DOACs were merged from prospective cohorts of patients with venous thromboembolism (VTE). Study outcomes were recurrent VTE and major bleeding (MB) occurring during DOAC treatment. Results Overall, 132 patients were included: mean age was 47.7±18.0 years (range 18 to 97), males were 42.4%. Twenty-seven percent of patients had 2 or more risk factors for VTE, 29.5% had UEDVT complicating a central venous line or after pacemaker implantation (Table). Ninety-two patients (70%) were managed as outpatients. Increased age (OR 1.03, 95% CI 1.0–1.05) and anemia (OR 1.35, 95% CI 1.07–1.70) were associated with in-patient management. Among patients treated with apixaban (40) or rivaroxaban (85) loading dose was used in 72%; in patients treated with dabigatran (5) or edoxaban (2) mean heparin pre-treatment was 8 days. DOACs were started after 1 month from UEDVT diagnosis in 12.9% of patients; active cancer was a main predictor for delayed initiation (OR 22.2, 95% CI 5.8–84.4). Mean treatment duration in patients with a scheduled stop was 4.9 months, while mean followup in those who continued DOACs was 9.3 months. No recurrence of VTE nor MBs occurred during DOAC treatment; one patient had acute limb ischemia (1.38% patient-year), 7 clinically relevant non-MBs (3 genital, 2 epistaxis, 1 gingival, 1 genital bleeding plus epistaxis; 10.51% patient-year), 5 deaths (4 cancer, 1 advanced age; 9.69% patient-year). Conclusions Our data support the effectiveness and safety of DOACs for the treatment of acute UEDVT. Further studies are required to confirm these findings. Funding Acknowledgement Type of funding source: None

The use of mathematical model approach to select direct oral anticoagulants in patients with atrial fibrillation

Abstract Purpose To evaluate the clinical and economic effectiveness of direct oral anticoagulants (DOAC) - dabigatran/D, rivaroxaban/R, apixaban/A compared with warfarin/W in the treatment of atrial fibrillation (AF). Methods The mathematical model (MM) was used (decision-tree building- DTB) to assess the clinical and economic effectiveness of the DOAC use in comparison with W in the AF treatment. MM was based on the results of basic clinical trials on the use of D (RE-LY); R (ROCKET) and A (ARISTOTLE). MM was carried out on a time horizon of 5 years from the perspective of the healthcare system (HS). The method of cost-effectiveness analysis CER. CER = DC/Ef, CER is the cost-effectiveness balance of the alternative, DC is direct costs, Ef is the number of adjusted life years (ALY) and adjusted life years without complications (ALYC). Budget Impact Analysis. BIA = S (1) − S (2), BIA is the result of the analysis of “impact on the budget”, in monetary terms; S (l) – the total economic effect of the use of one drug, in monetary terms; S (2) – the total economic effect of the use of another drug, in monetary terms. Analysis of “lose opportunities”. MOA = ΔS/Costmin, MOA is the result of the analysis of “lose opportunities”, ΔS is the difference in the total economic effects of the two compared drugs, Costmin is the cost of using the lowest cost drugs. Results The MM showed that as a result of pair-wise comparison the DOAC and W, the greatest DC were in group of treatment with the W. The total costs when using D were 10.3% less and amounted to 4129711 against 4605164 rub. per 100 patients. The cost of using R is 5.2% less (4887744 against 5156589); using A by 10.9% (3946528 against 4433820). The greatest difference was due to the different costs of adverse drug reaction treatment (30–38% in the cost structure). In the D group, this cost component was less than the W -by 22.0%, in the R – by 10.9%, in the A – by 36.8%. Costs associated with ischemic stroke treatment were less then 28.1% in the D group. The strategy of using DOAK compared with W allows to provide a greater number of ALY and ALYC – 4, 34 and 4.3 when comparing D and W, 4.3 and 4.25 when R and W; and 4.25 and 4.2 – A and W. ALYC respectively – 3.92 and 3.79; 3.51 and 3.6; 3.9 and 3.74. The cost of ALY is 9516.65 against 10706.45 rub; 11,374.34/12123.81; 9,295.19/10547.31. The cost of ALYC respectively: 10,534.98 against 12150.83 rub.; 13,925.20/14733.11 and 10119.3/11855.13. The use of DOAK allows to save significant public funds, and the savings saved allow to treat the patients in addition by modern drugs. Savings up to 12% in 5 years, while up to 33 patients out of 1000 can be treated additionally. Conclusion DC resulting from the prevention of thromboembolic complications when using DOAC in comparison with W can be reduced by 28.1%, hemorrhagic complications by 36.8%. DOAC can save a greater number of ALY and ALYC at a lower cost. Funding Acknowledgement Type of funding source: None

Vitamin K antagonists versus direct oral anticoagulants after cardiac surgery: a 31-country cohort study

Abstract Background About 10% of patients undergoing cardiac surgery have a history of atrial fibrillation (AF). Among these patients, uncertainty exists regarding the safest and most effective oral anticoagulant (OAC) during the postoperative period. Purpose To evaluate practice patterns regarding OAC early after cardiac surgery in patients with a preoperative history of AF and to compare the safety and effectiveness of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs). Methods We conducted a nested cohort study within the Left Atrial Appendage Occlusion Study (LAAOS) III (NCT01561651). LAAOS III included patients with AF undergoing cardiac surgery with a CHA2DS2-VASC ≥2. In this substudy, we examined patients without end-stage renal dysfunction (eGFR &amp;gt;30 mL/min/1.73m2) who were discharged on OAC. We evaluated bleeding and thromboembolism within 90 days postoperatively using logistic regression adjusting for CHA2DS2-VASC score. Results Recruitment started in 2012 and completed in 2018 in 113 centres in 31 countries. Of the 4811 patients enrolled in LAAOS III, 3725 (77%) were included in this substudy. Preoperatively, 58% of patients received OAC: 56% DOACs and 44% VKAs. At hospital discharge 23% received DOACs and 77% VKAs; 55% of patients on a DOAC at baseline were switched to a VKA while 5% of patients on a VKA were switched to a DOAC. Patients discharged on a DOAC were older, had a higher CHA2DS2-VASC, and were more likely to be male. Patients having undergone an isolated coronary bypass procedure were more likely prescribed DOACs than VKAs (41% vs 23%, p&amp;lt;0.001) whereas isolated non-mechanical valve patients were more likely to be prescribed VKAs (43% vs 28%, p&amp;lt;0.001). Switching from a DOAC to a VKA postoperatively occurred in 42% of patients In Australia/New Zealand, 49% in Europe, and 63% in North America. Major bleeding between 48 hours postoperatively and 30 days occurred in 1.5% in the DOAC group and 1.3% in the VKA group (aOR 1.14, 95% CI 0.60–2.15, p=0.69) while between 48 hours and 90 days, it occurred in 1.8% of patients in both groups (aOR 0.97, 95% CI, 0.54–1.17, p=0.91). Cardiac tamponade, the composite of stroke and systemic arterial embolism, and the composite of stroke, systemic arterial embolism and death did not differ significantly at 30 and 90 days between the DOAC and VKA groups. Conclusions VKAs was the dominant OAC used early after cardiac surgery, but postoperative OAC practices varied by region. After adjustment for CHA2DS2-VASC score, the early postoperative incidence of major bleeding and of the composite of stroke and systemic arterial embolism did not differ significantly when DOACs were compared with VKAs. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): CIHR, Heart and Stroke Foundation

The Number of Concomitant Drugs and the Safety of Direct Oral Anticoagulants in Routine Care Patients with Atrial Fibrillation.

Background The benefit of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) on major bleeding was less prominent among atrial fibrillation (AF) patients with polypharmacy in post-hoc randomized controlled trials analyses. Whether this phenomenon also exists in routine care is unknown. The aim of the study is to investigate whether the number of concomitant drugs prescribed modifies safety and effectiveness of DOACs compared with VKAs in AF patients treated in general practice. Study Design Adult, nonvalvular AF patients with a first DOAC or VKA prescription between January 2010 and July 2018 were included, using data from the United Kingdom Clinical Practice Research Datalink. Primary outcome was major bleeding, secondary outcomes included types of major bleeding, nonmajor bleeding, ischemic stroke, and all-cause mortality. Effect modification was assessed using Cox proportional hazard regression, stratified for the number of concomitant drugs into three strata (0–5, 6–8, ≥9 drugs), and by including the continuous variable in an interaction term with the exposure (DOAC vs. VKA). Results A total of 63,600 patients with 146,059 person-years of follow-up were analyzed (39,840 person-years of DOAC follow-up). The median age was 76 years in both groups, the median number of concomitant drugs prescribed was 7. Overall, the hazard of major bleeding was similar between VKA-users and DOAC-users (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.87–1.11), though for apixaban a reduction in major bleeding was observed (HR 0.81; 95% CI 0.68–0.98). Risk of stroke was comparable, while risk of nonmajor bleeding was lower in DOAC users compared with VKA users (HR 0.92; 95% CI 0.88–0.97). We did not observe any evidence for an impact of polypharmacy on the relative risk of major bleeding between VKA and DOAC across our predefined three strata of concomitant drug use ( p -value for interaction = 0.65). For mortality, however, risk of mortality was highest among DOAC users, increasing with polypharmacy and independent of the type of DOAC prescribed ( p -value for interaction <0.01). Conclusion In this large observational, population-wide study of AF patients, risk of bleeding, and ischemic stroke were comparable between DOACs and VKAs, irrespective of the number of concomitant drugs prescribed. In AF patients with increasing polypharmacy, our data appeared to suggest an unexplained yet increased risk of mortality in DOAC-treated patients, compared with VKA recipients.

Proximal femur fractures in patients taking anticoagulants.

Thirty per cent of patients presenting with proximal femoral fractures are receiving anticoagulant treatment for various other medical reasons. This pharmacological effect may necessitate reversal prior to surgical intervention to avoid interference with anaesthesia or excessive peri/post-operative bleeding. Consequently, delay to surgery usually occurs.Platelet inhibitors (aspirin, clopidogrel) either alone or combined do not need to be discontinued to allow acute hip surgery. Platelet transfusions can be useful but are rarely needed.Vitamin K antagonists (VKA, e.g. warfarin) should be reversed in a timely fashion and according to established readily accessible departmental protocols. Intravenous vitamin K on admission facilitates reliable reversal, and platelet complex concentrate (PCC) should be reserved for extreme scenarios.Direct oral anticoagulants (DOAC) must be discontinued prior to hip fracture surgery but the length of time depends on renal function ranging traditionally from two to four days.Recent evidence suggests that early surgery (within 48 hours) can be safe. No bridging therapy is generally recommended.There is an urgent need for development of new commonly available antidotes for every DOAC as well as high-level evidence exploring DOAC effects in the acute hip fracture surgical setting.Cite this article: EFORT Open Rev 2020;5:699-706. DOI: 10.1302/2058-5241.5.190071

Comprehensive review of the impact of direct oral anticoagulants on thrombophilia diagnostic tests: Practical recommendations for the laboratory.

There is a laboratory and clinical need to know the impact of direct oral anticoagulants (DOACs) on diagnostic tests to avoid misinterpretation of results. Although the regulatory labelling documents provide some information about the influences of each DOAC on diagnostic tests, these are usually limited to some of the most common tests and no head to head comparison is available. In this paper, we report the impact of DOACs on several thrombophilia tests, including assessment of antithrombin, protein S and protein C activity assays, detection of activated protein C resistance and assays used for lupus anticoagulant. Results are compared and discussed with data obtained from literature. The final goal of this comprehensive review is to provide practical recommendations for laboratories to avoid misdiagnosis due to oral direct factor Xa (FXa) or IIa (FIIa) inhibitors. Overall, oral direct FXa (apixaban, betrixaban, edoxaban and rivaroxaban) and FIIa (dabigatran) antagonists may affect clot-based thrombophilia diagnostic tests resulting in false-positive or false-negative results. An effect on FIIa-based thrombophilia diagnostic tests is observed with dabigatran but not with anti-FXa DOACs and conversely for FXa-based thrombophilia diagnostic tests. No impact was observed with antigenic/chromogenic methods for the assessment of protein S and C activity. In conclusion, interpretation of thrombophilia diagnostic tests results should be done with caution in patients on DOACs. The use of a device/chemical compound able to remove or antagonize the effect of DOACs or the development of new diagnostic tests insensitive to DOACs should be considered to minimize the risk of false results.

Updating the Cost Effectiveness of Oral Anticoagulants for Patients with Atrial Fibrillation Based on Varying Stroke and Bleed Risk Profiles.

Previous investigations into the cost effectiveness of direct oral anticoagulants only considered individual stroke risk but not bleed risk even though bleeding is an important and potentially fatal side effect for anticoagulated patients. This study aimed to evaluate the cost effectiveness of dabigatran, rivaroxaban, apixaban, and edoxaban vs warfarin in patients with atrial fibrillation with varying stroke/bleed risk profiles over a lifetime horizon. A Markov micro-simulation was adapted to examine the lifetime costs and quality-adjusted survival of five anticoagulants from a US private payer's perspective. The study hypothetical cohort consisted of 10,000 patients with atrial fibrillation with age, CHA2DS2-VASc, and HAS-BLED scores similar to a commercially insured patient with atrial fibrillation cohort. Model input parameters including the efficacy and safety of each strategy, utilities, and cost were estimated from public sources, published literature, and analysis conducted in the IBM MarketScan database. Lifetime cost, quality-adjusted life-years, and incremental cost-effectiveness ratios were assessed for each treatment strategy. Subgroup analyses stratified by age, stroke risk score alone, bleed risk score alone and both were performed. Uncertainty was assessed by a deterministic sensitivity analysis and a probabilistic sensitivity analysis. The base-case analysis suggested dabigatran was the optimal treatment with an incremental cost-effectiveness ratio of $35,055 per quality-adjusted life-year relative to warfarin. Subgroup analyses stratified by age, stroke risk score, and bleed risk score alone were largely consistent with the base-case analysis. Subgroup analyses stratified by both stroke and bleed risk score showed edoxaban was the preferred treatment in patients with a low stroke and a low or medium bleed risk, and patients with a high stroke and low bleed risk. Apixaban was the preferred treatment in patients with a medium stroke and high bleed risk. Results of the deterministic sensitivity analysis indicate the model results were most sensitive to the drug cost and hazard ratio for stroke and bleeding event. Results of the probability sensitivity analysis showed dabigatran is cost effective vs. other treatments in 32.8% and 42.4% of iterations at a willingness to pay of $50,000/quality-adjusted life-year and a willingness to pay of $100,000/quality-adjusted life year, respectively. From a US private payer's perspective, dabigatran appears cost effective compared with other anticoagulants. This study indicated risk stratification especially considering both stroke and bleed risk simultaneously is important not only in clinical practice but also in health technology assessment exercises among patients with atrial fibrillation.

Effectiveness and Safety of Direct Oral Anticoagulants in the Secondary Stroke Prevention of Elderly Patients: Ljubljana Registry of Secondary Stroke Prevention

The results of randomised clinical trials (RCTs) on direct oral anticoagulants (DOACs) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) can mostly be applied to primary prevention in relatively young patients, since only a minority of patients included in these trials were receiving DOACs for secondary prevention. The real-life secondary prevention subgroup, comprising mostly elderly and high-risk patients, remains a point of interest where further exploration is needed. Our objective was to explore the effectiveness and safety of DOACs for secondary prevention in the real-life conditions. In a six-year (2012-2018) period all consecutive patients with a history of transient ischaemic attack (TIA) or stroke, recorded NVAF and prescription of DOAC, were included in this single-centre registry. Choice of the DOAC and dose was based on the discretion of the attending clinician. Data regarding recurrent stroke/TIA or other embolic events, intracranial haemorrhage, other major bleeding, adherence and potential changes of therapy were collected and analysed. During the study period, 566 patients were prescribed a DOAC for secondary stroke prevention, and follow-up data were available for 510 patients, with an average observational time of 2.6years. The mean age of patients was 77.9 ± 8.7years. The mean CHA2DS2-VASc and HAS-BLED scores were 5.1 ± 1.2 and 2.4 ± 0.6, respectively. Dabigatran was prescribed in 66%, apixaban in 21% and rivaroxaban in 13% of patients; 58% of patients were prescribed the reduced dose of DOAC. The overall yearly incidence of recurrent stroke, major bleeding and intracranial bleeding was 1.7%, 1.6% and 0.2%, respectively. Thus, we found similar effectiveness and safety of both standard and reduced dose of DOACs for secondary stroke prevention, compared to the RCT and large registries. Our real-life data study suggests that secondary stroke prevention with DOACs is as effective and safe as primary prevention, both in standard and reduced doses, in a typical group of patients who are older than patients included in RCTs.

Monitoring DOACs with a Novel Dielectric Microsensor: A Clinical Study.

There are acute settings where assessing the anticoagulant effect of direct oral anticoagulants (DOACs) can be useful. Due to variability among routine coagulation tests, there is an unmet need for an assay that detects DOAC effects within minutes in the laboratory or at the point of care. We developed a novel dielectric microsensor, termed ClotChip, and previously showed that the time to reach peak permittivity (T peak) is a sensitive parameter of coagulation function. We conducted a prospective, single-center, pilot study to determine its clinical utility at detecting DOAC anticoagulant effects in whole blood. We accrued 154 individuals: 50 healthy volunteers, 49 rivaroxaban patients, 47 apixaban, and 8 dabigatran patients. Blood samples underwent ClotChip measurements and plasma coagulation tests. Control mean T peak was 428 seconds (95% confidence interval [CI]: 401-455 seconds). For rivaroxaban, mean T peak was 592 seconds (95% CI: 550-634 seconds). A receiver operating characteristic curve showed that the area under the curve (AUC) predicting rivaroxaban using T peak was 0.83 (95% CI: 0.75-0.91, p < 0.01). For apixaban, mean T peak was 594 seconds (95% CI: 548-639 seconds); AUC was 0.82 (95% CI: 0.73-0.91, p < 0.01). For dabigatran, mean T peak was 894 seconds (95% CI: 701-1,086 seconds); AUC was 1 (p < 0.01). Specificity for all DOACs was 88%; sensitivity ranged from 72 to 100%. This diagnostic study using samples from "real-world" DOAC patients supports that ClotChip exhibits high sensitivity at detecting DOAC anticoagulant effects in a disposable portable platform, using a miniscule amount of whole blood (<10 µL).

Atrial fibrillation and cognitive impairment: cerebral microbleeds as a new risk factor and possibilities of anticoagulant therapy (Part 2)

Atrial fibrillation (AF) and cognitive impairment (CI) are among the most important problems of the modern health care system, which are characterized by an extremely high prevalence with the increasing trend of the latter; they lead to lower quality of life, shorter duration, and a larger number of disabled people. The specific feature of AF and CI is the presence of common risk factors. To date, the data of an increasing number of studies allow cerebral microbleeds (CMBs) to be considered as a new risk factor for CI, inter alia in patients with AF. In recent years, special attention has been paid to the role of oral anticoagulants (OACs) in the prevention of CI in AF, which is reflected in a number of studies and meta-analyses. In terms of the effect of OACs on the risk of CMBs, there is reason to believe that the latter increases with the use of warfarin, the effects of direct OACs (DOAC) in this regard require further investigation. At the same time, among the DOACs, apixaban is the only drug that has been proven to have no negative effect on the risk of CMBs in a randomized controlled clinical trial. In general, the available data indicate the positive effect of OACs in reducing the risk of CI and dementia in AF; moreover, DOACs have an advantage in this respect. Among the DOACs, apixaban is promising due to its optimal efficacy and safety profile.

The Risks of Exfoliative Esophagitis in Patients with Atrial Fibrillation: A retrospective observational study.

The aging of the population has resulted in atrial fibrillation (AF) becoming increasingly prevalent. Treatment focuses on the prevention of thromboembolism through the use of catheter ablation or drug therapy with anticoagulants, such as warfarin or direct oral anticoagulants (DOACs). Dabigatran-induced exfoliative esophagitis has been reported as a rare side effect of DOACs. Although most cases are mild, some result in severe outcomes. However, the etiology of exfoliative esophagitis remains incompletely understood. The aim of this study is to investigate the etiology of exfoliative esophagitis and identify its risk factors by observational study.The participants were 524 patients using anticoagulants who received catheter ablation for AF and subsequently underwent upper gastrointestinal endoscopy at University of Tsukuba Hospital. Exfoliative esophagitis was noted in 21 (4.0%) patients. Potential risk factors for exfoliative esophagitis were examined retrospectively by comparing patients with and without this condition across the following parameters that were extracted retrospectively from the electronic medical records: physical characteristics, comorbidities, blood-based cardiac markers, echocardiographic and endoscopic findings, and current medications.Regarding physical characteristics, patients with exfoliative esophagitis had significantly higher body weight and BMI. No association was observed between exfoliative esophagitis and comorbidities. Associations were also not found for cardiac markers, echocardiographic findings, or endoscopic findings. In terms of current medications, patients receiving oral dabigatran showed the highest prevalence of exfoliative esophagitis at 8.8% (13/148). The adjusted odds ratio of dabigatran for exfoliative esophagitis was 10.3 by multivariable logistic regression analysis.Obesity and oral dabigatran were found to be significant risk factors for exfoliative esophagitis.

Prognosis of the influence of direct oral anticoagulants on the direct medical expenses in patients with atrial fibrillation

Aim. To evaluate clinical-economical effectiveness of direct oral anticoagulants (DOAC) dabigatran, rivaroxaban, and apixaban in comparison with warfarin in atrial fibrillation (AF) therapy. Materials and Methods. Mathematical modeling (tree derivation of solutions) on a temporary 5-year horizon from the medical healthcare system perspective. Methods of clinical-economic analysis: analysis “cost-effectiveness”, “budget impact”, and “the analysis of unseized opportunities”. Results. Total direct costs (DC) were lower by 10.3% when dabigatran was used, by 5.2%, when rivaroxaban was used, and by 10.9%, when apixaban was used in comparison with warfarin. The most significant difference was observed due to different cost of therapy for bleeding complications (in the structure of the costs, it occupied 30-38%). In the group of dabigatran, DC on bleeding complications were lower than in the group of warfarin by 22.0%, in the group of rivaroxaban – by 10.9%, in the group of apixaban – by 36.8%. Besides, in the group of dabigatran, the costs associated with the treatment for ischemic stroke were lower by 28.1% The strategy of the application of DOAC in comparison with warfarin provided more adjusted life years (ALY), complications adjusted life years (CALY), and its lower cost. The application of DOAC saves significant funds. At the same time, the saved funds will provide the purchase of additional modern drugs for patients. The cost-cutting reaches 12% for 5 years and up to 33 patients out of 1000 can receive additional treatment. Conclusion . Due to the prevention of thromboembolic complications in patients that received direct oral anticoagulants, the direct costs can be reduced by 28.1% and due to the prevention of bleeding complications – by 36.8% in comparison with the application of warfarin. Direct oral anticoagulants provide more adjusted life years and complications adjusted life years at a lower cost.

Rates of Bleeding and Discontinuation of Direct Oral Anticoagulants in Patients With Decompensated Cirrhosis

Studies of the effects of direct oral anticoagulants (DOACs) in patients with cirrhosis have been limited by their small sample size, inclusion of patients with well-compensated cirrhosis, short follow-up times, inadequate validation of cirrhosis diagnoses, and non-standard definitions of bleeding. We aimed to systematically determine the characteristics, indications, and outcomes of patients with cirrhosis of all severity classes who received DOACs. We performed a retrospective study of 138 patients with confirmed cirrhosis (93 with Child-Turcotte-Pugh scores of B or C) at a single center who started DOAC therapy (58,984 person-days; median, 181 days per patient) from September 2011 through April 2019. We collected data on clinical characteristics, indications for DOAC use, and outcomes. Standardized and validated definitions for bleeding complications were used. Twenty-nine patients (21%) stopped therapy due to a diagnosis of or perceived bleeding. The most common bleeding events were non-variceal upper and lower intestinal bleeding. No pretreatment laboratory parameters were associated with bleeding while patients received treatment, including platelet count (P = .50), international normalized ratio (P = .34), creatinine (P = .27), and model for end-stage liver disease score (P = .22). Frequency of bleeding events related to DOAC did not differ significantly among patients of different Child-Turcotte-Pugh classes (P = .81), DOAC indications (P = .60), or DOAC dosages (P = .10). Higher proportions of patients with hepatocellular carcinoma (P = .01) had major bleeding while receiving. Patients with decompensated cirrhosis have significant bleeding and rates of discontinuation of DOACs when they take them long term. Pretreatment laboratory parameters, DOAC dose, and Child-Turcotte-Pugh class were not associated with bleeding; hepatocellular carcinoma was associated with major bleeding.

Factor Xa and thrombin induce endothelial progenitor cell activation. The effect of direct oral anticoagulants

Factor Xa (FXa) and thrombin exert non-hemostatic cellular actions primarily mediated through protease-activated receptors (PARs). We investigated the effect of FXa and thrombin on human late-outgrowth endothelial cells (OECs), a type of endothelial progenitor cells (EPCs), and on human umbilical vein endothelial cells (HUVECs). The effect of direct oral anticoagulants (DOACs), rivaroxaban and dabigatran, was also studied. The membrane expression of intercellular adhesion molecule-1 (ICAM-1) and the secretion of monocyte chemoattractant protein-1 (MCP-1) were used as cell activation markers. FXa and thrombin increase the ICAM-1 expression and the MCP-1 secretion on both cells, being higher on OECs. Vorapaxar, a specific PAR-1 antagonist, completely inhibits FXa-induced activation of both cells and thrombin-induced HUVEC activation, but only partially thrombin-induced OEC activation. Furthermore, thrombin-receptor activating peptide; TRAP-6, only partially activates OECs. OECs do not membrane-express PAR-4, therefore it may not be involved on thrombin-induced OEC activation. Rivaroxaban and dabigatran inhibit OEC and HUVEC activation by FXa and thrombin, respectively. Rivaroxaban enhances thrombin-induced OEC and HUVEC activation, which is completely inhibited by vorapaxar. The inhibition of OEC and HUVEC activation by vorapaxar and DOACs may represent a new pleiotropic effect of these drugs. The pathophysiological and clinical significance of our findings need to be established.

Unveiling the complex effects of direct oral anticoagulants on dilute Russell's viper venom time assays

IntroductionDilute Russell viper venom time (dRVVT) assays can be affected by direct oral anticoagulants (DOACs), which may cause false‐positive results. However, there are conflicting results indicating significant differences between different reagents and DOACs. ObjectivesTo evaluate the effect of DOACs on dRVVT assays. Material and MethodsSamples were prepared by adding DOAC (dabigatran, rivaroxaban, apixaban, or edoxaban) to pooled normal plasma in the concentration range 0 to 800 µg/L. Six integrated dRVVT reagents were used, all composed of a screen assay (low phospholipid content) and a confirm assay (high phospholipid content). The screen/confirm dRVVT results were expressed as normalized ratios. To further evaluate the observed differences between tests and DOACs, addition of synthetic phospholipids was used. ResultsThe dRVVT ratios increased dose dependently for all DOACs, with four of the six tests and the DOAC rivaroxaban having the greatest effect. With one test, the ratios were almost unaffected with increasing DOAC concentration, whereas another test revealed a negative dose dependency for all DOACs. Variable DOAC effects can be explained by different effects on dRVVT screen and confirm clotting time. Adding synthetic phospholipids to samples containing rivaroxaban resulted in greatly reduced screen clotting times and thereby lower calculated dRVVT ratios. ConclusionsThere is a great variability in the dRVVT test result with different DOACs. The dRVVT ratios are unaffected for some reagents and this can be explained by an equal dose‐dependent effect on both screen and confirm assays. The phospholipid type and content of the different reagents may contribute to the observed differences.

Patterns and factors influencing oral anticoagulant prescription in people with atrial fibrillation and dementia: Results from UK primary care.

Oral anticoagulant (OAC) is recommended for preventing stroke in atrial fibrillation (AF). However, the OAC utilisation in AF patients with dementia or cognitive impairment (CI) is limited. This study aimed to examine the prevalence of OAC prescriptions in AF patients with dementia/CI and to identify factors associated with OAC treatment within 180 days after dementia/CI diagnosis. Using The Health Improvement Network database, the annual trends of OAC between 2000 and 2015 were calculated. Multivariable logistic regression was performed to identify factors associated with OAC treatment. The prevalence rate of OAC prescriptions increased from 6.1% in 2000 to 45.9% in 2015. Among OAC users, the proportion of direct oral anticoagulants (DOACs) use increased significantly from 0.1% in 2011 to 33.8% in 2015 (P-trend < 0.001), while the proportion of vitamin K antagonist use decreased by 28.6% from 100% in 2000 to 71.4% in 2015 (P-trend < 0.001). In the multivariable analysis, younger age, very old age, female sex, higher Charlson Comorbidity Index, having a HAS-BLED score ≥3, a history of intracranial bleeding, falls and polypharmacy were significantly associated with lower odds of receiving OAC. In UK primary care, OAC use increased from 2000 to 2015 in AF patients with dementia/CI, with a substantial increase in use of DOACs. Characteristics related to frailty are associated with lower odds of OAC prescription. Given the increasing use of DOACs in patients with dementia/CI, further studies are needed to investigate the safety and effectiveness of DOACs in this important patient group.

Gastrointestinal Bleeding in Antithrombotic Therapy in Patients with Coronary Heart Disease: Risk Factors, Pathogenesis and Treatment

Aim. Description of risk factors, pathogenesis and treatment strategies of gastrointestinal bleeding (GIB) in the course of antithrombotic therapy in patients with coronary heart disease (CHD).Key points. Risk factors of GIB during antithrombotic therapy in CHD patients include: GIB, gastric and/or duodenal ulcer in the history, reflux esophagitis, presence of H. pylori, inflammatory bowel disease, diverticula, haemorrhoids, angiodysplasia, gastrointestinal neoplasia, age above 65 years, concomitant treatment with non-steroidal anti-inflammatory drugs (NSAIDs), glomerular filtration rate &lt;50 mL/min, high doses of direct oral anticoagulants (DOACs) ≥3 in HAS-BLED score. Pathogenesis of GIB in the course of antithrombotic therapy is associated with systemic hypocoagulation and local damaging effects of these drugs. Strategies of GIB treatment during DOAC therapy in patients with CHD are determined by severity of bleeding and threat to life. Aside to standard conservative measures, endoscopic or surgical haemostasis requires usage of antidotes to suppress effects of DOACs and other specific drugs in severe cases.Conclusion. GIB associated with antithrombotic therapy in CHD patients poses a serious medical problem of growing importance with wider application of anticoagulant drugs. Antithrombotic therapy requires accurate decision making, risk assessment, careful monitoring of the patient’s condition and timely diagnosis of gastrointestinal disorders following good rationale in GIB prevention.

Effect of Direct Oral Anticoagulant, Patient, and Surgery Characteristics on Clinical Outcomes in the Perioperative Anticoagulation Use for Surgery Evaluation Study.

Introduction The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) Study assessed a standardized perioperative management strategy in patients with atrial fibrillation who were taking a direct oral anticoagulant (DOAC) and required an elective surgery or procedure. The aim of this substudy is to analyze the safety of this management strategy across different patient subgroups, according to four presurgical variables: (1) DOAC type and dose, (2) surgery/procedure bleed risk, (3) patient renal function, and (4) age. Methods Clinical outcomes analyzed included major bleeding (MB), arterial thromboembolism, any bleeding, and any thromboembolism. We used descriptive statistics to summarize clinical outcomes, where the frequency, proportion, and 95% confidence interval were reported. Fisher's exact tests were used for testing the null hypothesis of independence between the clinical outcome and patient characteristic, where the test p -values were reported. Results There were 3,007 patients with atrial fibrillation requiring perioperative DOAC management. There was no significant difference in bleeding or thromboembolic outcomes according to DOAC type/dose regimen, renal function, or patient age. The rate of MB was significantly higher with high bleed risk procedures than low bleed risk procedures in apixaban-treated patients (2.9 vs. 0.59%; p < 0.01), but not in dabigatran-treated patients (0.88 vs. 0.91%; p = 1.0) or rivaroxaban-treated patients (2.9 vs. 1.3%; p = 0.06). The risk for thromboembolism did not differ according to surgery/procedure-related bleed risk. Conclusion Our results suggest that in DOAC-treated patients who received standardized perioperative management, surgical bleed risk is an important determinant of bleeding but not thromboembolic outcomes, although this finding was not consistent across all DOACs. There were no differences in bleeding and thromboembolism according to DOAC type and dose, renal function, or age.

Direct oral anticoagulants for patients aged over 80 years in nonvalvular atrial fibrillation: the impact of frailty.

In patients aged at least 80 years, atrial fibrillation is responsible for significant morbidity and mortality, with a high incidence of stroke. Four new direct oral anticoagulants (DOACs) have been introduced in Italy for the prevention of thromboembolism. Their safety and efficacy in the elderly have already been confirmed. Frailty is frequently associated with aging, but only a few studies have paid attention to interactions between frailty and anticoagulation therapy. We retrospectively evaluated the effectiveness and safety of DOACs in a population aged at least 80 years. Frailty was appraised using an adaptation of the Reported Edmonton Frail Scale, considering a value at least 8 (on a scale from 0 to 18). The majority (644/731) of patients remained on DOACs for more than 1 year. A total of 19 patients experienced a thrombotic event while on anticoagulation (1.11 events per 100 person-years) and 26 patients a major bleeding episode (1.52 events per 100 person-years). The probability of interrupting therapy increased significantly with frailty [hazard ratio 2.91 with confidence interval (CI) 2.15-3.92 at univariate analysis, hazard ratio 2.80 with CI 2.03-3.86 at multivariate]; frailty showed a significant impact also on major bleeding (hazard ratio 3.28 with CI 1.45-7.37 at univariate analysis, hazard ratio 3.56 with CI 1.58-8.01 at multivariate). Our study highlights how DOACs are a safe and effective option for anticoagulation, even in frail elderly people; the introduction of these drugs is leading to an increased use of anticoagulation therapy in this population. Prospective trials will be needed to reinforce these results and to consider new variables in the thrombotic and hemorrhagic risk scores underlying the prescription of DOACs.