Factor Xa Inhibitors Rivaroxaban Research Articles

Current Strategies for the Management of Bleeding Associated with Direct Oral Anticoagulants and a Review of Investigational Reversal Agents.

The management of life-threatening bleeding in patients who are receiving direct oral anticoagulants (DOACs) is a serious medical concern. This review provides a concise, balanced overview of the current and future approaches for reversing the anticoagulation effects of DOACs, particularly factor Xa (FXa) inhibitors. The anticoagulant activity of the direct thrombin inhibitor dabigatran can be reversed by idarucizumab, but until recently, options for the management of major bleeding in patients who were receiving FXa inhibitors were limited to nonspecific strategies, including supplementation of clotting factors with prothrombin complex concentrates (PCCs) or activated PCCs for attenuating anticoagulation effects. They appear as a treatment option in many hospital guidelines despite the lack of approval by the U.S. Food and Drug Administration and the lack of rigorous medical evidence supporting their use in this setting. The development of specific reversal agents may provide improved strategies for the management of bleeding. Andexanetalfa is a modified FXa molecule approved in the United States to reverse the anticoagulant effects of FXa inhibitors (rivaroxaban and apixaban) in patients with life-threatening or uncontrolled bleeding. Ciraparantag is a small-molecule inhibitor of multiple anticoagulants that has been investigated in healthy subjects. The current guidelines for management of DOAC-associated bleeding are being updated to reflect that the reversal agent for rivaroxaban and apixaban is now available. For other FXa inhibitors, in the absence of a reversal agent, nonspecific strategies that include PCCs are recommended. The population of patients anticoagulated with DOACs is growing, and we hope that specific reversal agents will improve the approach to management of major bleeding in this population.

Rivaroxaban does not affect growth of human pancreatic tumors in mice

BackgroundSome clinical studies have shown that low‐molecular‐weight heparins (LMWHs) prolong the survival of cancer patients. In addition, various anticoagulants have been shown to reduce growth of tumors in mice. However, there are no studies on the effect of the factor Xa inhibitor rivaroxaban on growth of human pancreatic tumors in nude mice. ObjectivesTo test the hypothesis that the factor Xa inhibitor rivaroxaban reduces the growth of tissue factor (TF)‐positive pancreatic tumors but not TF‐negative pancreatic tumors in mice. MethodsThe TF‐positive human pancreatic cancer cell line BxPc‐3 and the TF‐negative human pancreatic cancer cell line MIA PaCa‐2 were injected subcutaneously into nude mice and tumors grown to a mean volume of ~100 mm3. Mice were then divided into two groups. One group was fed chow containing rivaroxaban (0.5 g/kg chow) whereas the other group was fed chow without rivaroxaban. ResultsRivaroxaban significantly prolonged prothrombin time in tumor‐bearing mice. Rivaroxaban did not affect cell proliferation or growth of either BxPc‐3 or MIA PaCa‐2 tumors grown subcutaneously in nude mice. ConclusionOur results indicate that inhibition of factor Xa with rivaroxaban does not affect the growth of two human pancreatic tumors in nude mice.

Efficacy and Safety of Direct Oral Anticoagulants in Obese Patients with Venous Thromboembolism

Background: Obesity is a well-known risk factor for venous thromboembolism (VTE), however, obese patients are under-represented in clinical trials (1;2). Four direct oral anticoagulants (DOACs) have been approved for the treatment of acute VTE (3-6), including the direct Factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the direct thrombin inhibitor, dabigatran. Given the lack of data in this population, it is unclear if DOACs can be used safely. Objectives: To evaluate the efficacy and safety of DOACs for the treatment of VTE in obese patients. Methods: We conducted a retrospective, single-centre cohort study in London (Canada) to compare the efficacy and safety of DOACs for the treatment of acute VTE in obese patients. We screened electronic and hard copy charts of adult patients referred to our thrombosis clinic for treatment of an objectively confirmed acute VTE between January 2012 and December 2017. Patients treated with DOACs or Warfarin were selected and followed from diagnosis of the index event until cessation of anticoagulation or up to 1 year. Our study population was analyzed by BMI (BMI ≥ 30 kg/m2versus < 30 kg/m2) and body weight (≥120 kg vs. <120 kg). Patients were excluded if they were on anticoagulation therapy for conditions other than VTE (e.g; atrial fibrillation), cancer-associated thrombosis, or missing data. The primary outcome measure was VTE recurrence during the anticoagulation treatment period and was defined according to the ISTH criteria (7). Our secondary outcome was the occurrence of bleeding events A bleeding event is defined as: a) Major Bleeding: bleed resulting in a hemoglobin drop of > 20 g/L, clinically overt and requiring more than 2 units of packed red blood cells, a hemorrhage requiring permanent cessation of anticoagulation and any retroperitoneal or intracranial hemorrhage; b) Minor Bleeding: bleed with no or little clinical significance, associated with no cost and does not require medical evaluation; and c) clinically significant non-major bleeding: does not fulfill criteria for major or minor bleeding but requires patients to be seek medical attention and/or minor procedures (8). Groups were compared using Chi-square or Fisher's exact test for categorical variables, as appropriate. The significance level was set at 0.05. Risk ratios (RR) and 95% confidence intervals (95% CI) for VTE recurrence and bleeding among DOAC groups and patients treated with Warfarin were analyzed by logistic regression. All statistical analyses were conducted using IBM SPSS Statistics version 25 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). Results: Of 1143 potentially eligible patients, 777 fulfilled our inclusion criteria: 278 (35.8%) obese patients treated with DOACs, 266 (34.2%) non-obese patients on DOACS and 233 (30%) obese patients on Warfarin. Of the patients on DOACs, 80% (n= 436) were on rivaroxaban, while the remaining 20% were either on apixaban or edoxaban (n= 108). Among patients on DOACs VTE recurrence was observed in 2.1% (N=6) of patients with BMI ≥ 30 kg/m2 and 2.8% (N=2) of patients with 120 kg or more, with no differences in the risk of VTE recurrence (Table 1). The proportion of major bleeding events for patients on DOACs was 1.1% (N=3) for patients with BMI ≥ 30 kg/m2 and 1.4% (N=1) for patients with 120kg or more. There were no significant differences with respect to major and total bleeding risk (Table1). When comparing obese patients on DOACs vs Warfarin we did not find differences in the risk of VTE recurrence among patients with a BMI ≥ 30 kg/m2 [RR 2.59 95% IC (0.51-12.96), p= 0. 247] or body weight ≥120 kg [RR 4.33 95% IC (0.21-89.43), p= 0. 337] (Table 2). Among obese patients those treated with DOACs had a similar proportion and risk of total bleeding and major bleeding events compared to those on warfarin (Table 2). Conclusions: Our retrospective study suggests that DOACs at standard doses appear to have similar efficacy and safety in obese patients as defined herein. However, since most of our patients were treated with rivaroxaban, information on other agents is inconclusive. Information on patients with extreme body weight was limited. Disclosures Louzada: Bayer: Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Direct-Acting Oral Anticoagulants and Their Reversal Agents-An Update.

Background: Over the last ten years, a new class of drugs, known as the direct-acting oral anticoagulants (DOACs), have emerged at the forefront of anticoagulation therapy. Like the older generation anticoagulants, DOACs require specific reversal agents in cases of life-threatening bleeding or the need for high-risk surgery. Methods: Published literature was searched, and information extracted to provide an update on DOACS and their reversal agents. Results: The DOACs include the direct thrombin inhibitor—dabigatran, and the factor Xa inhibitors—rivaroxaban, apixaban, edoxaban, and betrixaban. These DOACs all have a rapid onset of action and each has a predictable therapeutic response requiring no monitoring, unlike the older anticoagulants, such as warfarin. Two reversal agents have been approved within the last five years: idarucizumab for the reversal of dabigatran, and andexanet alfa for the reversal of rivaroxaban and apixaban. Additionally, ciraparantag, a potential “universal” reversal agent, is currently under clinical development. Conclusions: A new generation of anticoagulants, the DOACs, and their reversal agents, are gaining prominence in clinical practice, having demonstrated superior efficacy and safety profiles. They are poised to replace traditional anticoagulants including warfarin.

P1901Use of direct thrombin inhibitor on the day of atrial fibrillation ablation decreases incidence of silent cerebral ischemia detected by magnetic resonance imaging

Abstract Background There is increasing evidence to use direct oral anticoagulants (DOACs) in atrial fibrillation (AF) ablation. Uninterrupted use of DOACs is recommended for peri-procedural anticoagulation; the ways of choosing and/or using DOACs depend on physicians' decisions and preferences. Uninterrupted dabigatran (DAB), a direct thrombin inhibitor, reportedly decreased the risk of major bleeding (MB) in AF ablation, compared to uninterrupted warfarin (NEJM 2017; 376:1627). Among DOACs, only regular-dose of DAB (150 mg b.i.d.), showed superiority to warfarin for preventing ischemic thromboembolism (TE) in patients with non-valvular AF, implicating the powerful anti-thrombotic agent. DAB may decrease the potential risk of procedure-related TE. Purpose To evaluate whether use of DAB on the day of AF ablation decreases the prevalence of silent cerebral ischemia (SCI) detected by magnetic resonance imaging (MRI). Methods 414 AF patients on DOACs were enrolled and admitted on the day before AF ablation. Among 354 patients on factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), the original DOACs were switched to DAB (150 mg b.i.d.) on the day of the procedure in 172 patients (Group D); the treatment remained unchanged in 182 patients (Group non-D). In both groups, DOACs were continuously used throughout the procedure. After propensity-score matching, procedure-related parameters/events and the incidence of MRI-detected SCI were compared between Group D (n=134) and Group non-D (n=134). These parameters in patients originally taking DAB, used without interruption during the procedure (uninterrupted DAB, n=55), were also compared to Group D (n=55) after propensity-score matching. Results Baseline activated clotting time (ACT) before initial heparin injection was increased in Group D vs. Group-non-D (179±25* vs. 146±23 sec, *p<0.05 vs. Group non-D). The time to achieve optimal ACT (>300 sec) was shorter in Group D (34±29* vs. 43±32 min). The amounts of heparin needed to achieve optimal ACT and the total amount of heparin used during the procedure were unchanged between Group D and Group non-D. The incidence of SCI decreased in Group D (13.1%* vs. 21.9%), suggesting the potential anti-thrombotic efficacy of DAB. No MB or symptomatic TE events were observed in either group. Baseline ACT, the time to achieve ACT >300 sec, and the incidence of SCI in Group D were comparable to those in uninterrupted DAB (183±38 vs. 181±32 sec, 39±31 vs. 42±28 min, and 14.5% vs. 16.4%, respectively). No MB or symptomatic TE events were observed either in Group D or uninterrupted DAB. Conclusions Temporarily switching to DAB from the other DOACs and using it on the day of procedure enable us to achieve optimal ACT quickly and decrease the incidence of SCI, showing similar potential anti-thrombotic efficacy to uninterrupted DAB. Use of DAB on the day of AF ablation also benefits from the availability of its antidote in the case of MB during the procedure.

Andexanet to reverse apixaban or rivaroxaban anticoagulation

Andexanet alfa (Ondexxya) is the first licensed antidote to the direct factor Xa inhibitors apixaban or rivaroxaban, for use when reversal of anticoagulation is needed due to life‐threatening or uncontrolled bleeding. This article summarises its indications, efficacy and safety.

Direct Oral Anticoagulants: Novel Approach for the Treatment of Thrombosis in Pediatric Patients?

Venous thromboembolism (VTE) is a rare, but life-threatening disease in those who have not reached their adulthood. This condition is usually treated with heparin or low molecular weight heparins which require parenteral administration and, in case of unfractionated heparin, also frequent laboratory monitoring and dose adjustment. Direct oral anticoagulants (DOACs)-direct thrombin inhibitor dabigatran, and direct oral factor Xa inhibitors rivaroxaban, apixaban, and edoxaban-are currently frequently used for the prevention and treatment of VTE in adult population. In fact, these agents offer several advantages compared to traditional agents, such as oral route of administration, short on-set and off-set of action, predictable pharmacologic profile with low risk of food and drug interactions, and no need for routine laboratory assessment of anticoagulant activity. However, clinical experience with these directly acting oral anticoagulants in pediatric population is very limited as these drugs had been tested and are used mostly in adult individuals. This article reviews the current data from pre- and post-marketing studies reporting the use of DOACs for the treatment of VTE in pediatric patients.

How can the results of the COMPASS trial benefit patients with coronary or peripheral artery disease in Poland?

Aspirin decreases the risk of recurrent thrombotic events in patients with coronary artery disease or peripheral artery disease but the risk of recurrent events remains high. Long‑term dual antiplatelet therapy or the combination of aspirin and warfarin further reduces the risk of recurrent events, but at the cost of increased bleeding, and neither of these treatments reduce mortality. The COMPASS (Cardiovascular Outcomes in People Using Anticoagulation Strategies) randomized controlled trial involving 27 395 patients from 602 sites in 33 countries (Poland: 9 sites, 518 patients) tested whether low‑dose anticoagulant therapy with the coagulation factor Xa inhibitor rivaroxaban given alone or combined with aspirin reduced thrombotic risk compared with aspirin in patients with apparently stable chronic coronary and/or peripheral artery disease. In patients treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily, compared with aspirin alone, the primary outcome of the composite of cardiovascular death, stroke, or myocardial infarction was decreased by 24% (hazard ratio, 0.76; 95% confidence interval, 0.66 to 0.86; P <0.001), and mortality by 18% at the cost of a 70% increase in major bleeding but no significant increase in fatal or intracranial bleeding. Results were consistent in patients with coronary artery disease or peripheral artery disease, and the greatest absolute benefit was evident in the highest risk patients, including those with polyvascular disease, mild or moderate heart failure, chronic kidney disease, or diabetes. These results establish the combination of low‑dose rivaroxaban and aspirin as a highly effective treatment to decrease morbidity and mortality rates in patients with atherosclerotic vascular disease..

Effectiveness and safety of selective and non - selective factor Xa inhibitors in antiphospholipid syndrome and systemic lupus erythematosus: anti - Xa - activity range

Clinical and laboratory data were analyzed retrospectively in SLE and APS patients who protractedly received low weight molecular heparins (LWMH) and selective factor Xa inhibitors fondaparinux and rivaroxaban. The study included 70 patients in the middle age 39 [31; 43] years: 15/70 (21%) - with SLE, 10/70 (14%) - with APS and 45/70 (65%) - with SLE and APS (SLE+APS). All the patients received anticoagulants: 29 patients - nadroparin (98.3 [67.8; 129.5] IU/kg/day), 29 patients - fondaparinux (5 [5; 7.5] mg/day), 3 patients - enoxaparin (1.2 [0.8; 1.5] mg/day) and 9 patients - rivaroxaban (20 mg/day). All the patients signed informed consents. aXa therapeutic range of 0.1-1.5 IU/ml was found in 43/70 (61%) patients, low aXa - in 14/70 (20%) and high aXa - in 13/70 (19%) patients. Patients with low aXa underwent anticoagulant dose correction. There were not any major bleedings and thrombosis relapses in the study. Increased aXa was more common in patients, who took fondaparinux (31%), than in those, who took nadroparin (7%) and rivaroxaban (23%), p=0.02. Patients with enoxaparin had normal aXa range. In the absence of bleeding in SLE and APS patients, received anticoagulants in standardized therapeutic dose, the next factors influenced the aXa range excess: valvular heart disease (VHD) with the 3rd stage of mitral valve insufficiency as a result of aseptic Libman-Sacks endocarditis (odds ratio - OR 9.02, 95% confidential interval - CI [1.53; 53.12], p=0.015), peripheral artery disease in analogy with arteritis obliterans (AO) (OR 6.86, 95% CI [1.25; 37.71], p=0.027), and also triple - positivity of all types of antiphospholipid antibodies (OR 4.93, 95% CI [1.11; 21.99], p=0.036). According to found logistic regression model, aXa range excess risk can be prognosticated by the next formula: Z = -3.98 + 2.2 × VHD (yes-1/no-0) + 1.9 × AO (yes-1/no-0) + 1.6 × Triple - positivity (yes-1/no-0). Classified function value Z=0.39 defines the patients group with aXa range excess. Thus the value Z>0.39 indicates aXa range excess in the absence of bleeding, herewith sensibility is of 77% and specificity is 86%, positive prognostic value is 84.3%. In SLE and APS patients the next clinical and immunologic manifestations influenced the aXa therapeutic range excess: peripheral artery disease in analogy with AO, earlier aseptic Libman-Sacks endocarditis with the 3rd stage of mitral valve insufficiency and triple - positivity of all types of antiphospholipid antibodies, that does not need LWMH and fondaparinux dose correction. In contrast, anticoagulant dose reduction can cause clinical symptoms progression. Therapeutic aXa range in such patients should be extended.

Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity

Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to ApoE-/- mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes (Alox12 or Alox15) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. Alox-deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that Alox deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with ApoE-/- deletion, and many were absent in Alox-/- mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development.

Real-world outcomes of the Xarelto Post-Authorization Safety & Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS)

BackgroundAlthough the efficacy and safety of the factor Xa inhibitor rivaroxaban for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) were shown in global and Japanese phase III clinical trials, safety and effectiveness data from unselected patients in everyday clinical practice are limited. The objective of the XAPASS (Xarelto Post-Authorization Safety & Effectiveness Study in Japanese Patients with Atrial Fibrillation) is to investigate the safety and effectiveness of rivaroxaban in Japanese real-world clinical practice. MethodsThe XAPASS is a prospective, single-arm, real-world observational study mandated by the Japanese authority as post-marketing surveillance. In total, 11,308 patients with NVAF who began treatment with rivaroxaban were enrolled from April 2012 to June 2014, and 9578 patients were analyzed to examine the one-year outcomes. ResultsThe mean treatment duration was 300±119 days. The patients’ age was 73.2±9.8 years, and their CHADS2 score was 2.2±1.3. Any bleeding and major bleeding occurred in 602 patients (7.6 events per 100 patient-years) and 143 patients (1.8 events per 100 patient-years), respectively. Stroke/non-central nervous system systemic embolism/myocardial infarction was observed in 144 patients (1.8 events per 100 patient-years). ConclusionsReal-world outcomes of the XAPASS showed incidence rates of major bleeding and thromboembolic events, suggesting that rivaroxaban is safe and effective in Japanese daily clinical practice (Clinicaltrials.gov: NCT01582737).

Management of bleeding associated with direct oral anticoagulants: update on reversal strategies

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban have at least comparable efficacy as vitamin K antagonists along with a better safety profile, reflected by a lower incidence of intracranial hemorrhage. Specific reversal agents have been developed in recent years. Namely, idarucizumab, a specific antidote for dabigatran, is currently approved in most countries. Andexanet, which reverses factor Xa inhibitors, has been recently approved by the FDA, and ciraparantag, a universal antidote targeted to reverse all DOACs, is still under investigation. In this review we provide an update on the pharmacology of DOACs, the risk of hemorrhagic complications associated with their use, the measurement of their anticoagulant effect and the reversal strategies in case of DOAC-associated bleeding.

Thrombin-Mediated Activation of PAR-1 Contributes to Microvascular Stasis in Mouse Models of Sickle Cell Disease Via Increased Endothelial Expression of P-Selectin and VWF

Sickle cell disease (SCD) is caused by a single nucleotide mutation in the β-globin gene, resulting in an altered red cell physiology that causes vascular complications such as hemolytic anemia, chronic inflammation, activation of coagulation, and vaso-occlusion. We have shown that infusion of hemin results in tissue factor (TF)-dependent activation of coagulation in mice. Furthermore, TF-dependent activation of coagulation contributes to inflammation in a mouse model of SCD. Interestingly, thrombin-dependent inflammation in sickle cell mice was not attenuated by deficiency of the main thrombin receptor protease activated receptor-1 (PAR-1). However, others have shown that the activation of endothelial cell PAR-1 with agonist peptide enhances interactions of these cells with sickle RBCs in a P-selectin-dependent manner. Importantly, P-selectin inhibition reduces microvascular stasis in mouse models of SCD and prevents vaso-occlusive crisis in sickle cell patients.We propose that thrombin-mediated PAR-1 activation promotes microvascular stasis in mouse models of SCD via increased expression of P-selectin and VWF on the endothelium, triggered by exocytosis of Weibel-Palade bodies.To investigate if the TF/thrombin/PAR-1 pathway contributes to microvascular stasis, dorsal skinfold chambers were implanted in NY1DD sickle mice 3 days before the experiment. Microvascular stasis was determined in 20-25 preselected micro-vessels in response to intravenous infusion of stroma-free hemoglobin (SFH, 1.6 µmol/kg) and was expressed as % non-flowing vessels (mean ± SEM). We previously demonstrated that infusion of SFH results in microvascular stasis that is inhibited by hemopexin in NY1DD mice, indicating that hemoglobin releases heme into the circulation. In NY1DD mice treated with control IgG antibody, SFH infusion caused stasis in 28.3 ± 1.7% and 36.7 ± 1.7% of preselected vessels at 1 and 4 hrs after infusion, respectively. Treatment with an inhibitory anti-TF antibody 1H1 (25 mg/kg; IP) 30 minutes before SFH infusion significantly reduced stasis to only 3.3 ± 1.5% and 2.8 ± 1.6% of vessels at 1 and 4 hrs, respectively (p<0.01). To investigate if TF contributes to SFH-induced microvascular stasis via generation of downstream coagulation proteases, NY1DD mice were fed with control chow or chow containing either Factor Xa (FXa) inhibitor rivaroxaban (0.4 mg/g chow) or thrombin inhibitor dabigatran (10 mg/g chow) ad libitum for 4 days prior to stasis experiments. We previously showed that these doses efficiently anticoagulated sickle mice without bleeding complications. FXa inhibition significantly reduced stasis at 1 hr (4.9 ± 0.1% versus 22.4 ± 3.8%, p<0.001) and 4 hrs (1.7 ± 1.6% versus 12.8 ± 1.9%, p<0.001) after SFH injection. Similarly, dabigatran also significantly attenuated SFH-induced stasis (3.1 ± 1.5% non-flowing vessels at 1 hour and 1.6 ± 1.6% non-flowing vessels at 4 hours). Next, to investigate if thrombin contributes to SFH-induced stasis through activation of PAR-1, we used bone marrow transplantation to generate sickle mice lacking PAR-1 expression in all non-hematopoietic cells. PAR-1+/+ and PAR-1-/- mice were lethally irradiated and transplanted with bone marrow from Townes sickle (SS) mice. Efficient reconstitution of bone marrow was confirmed by hemoglobin electrophoresis. We found that PAR-1-/- SS mice were significantly protected from SFH-induced stasis compared to PAR-1+/+ SS mice at both 1 hr (13.2 ± 3.4% versus 37.6 ± 3.9% stasis; P<0.001) and 4 hrs (6.6 ± 1.7% versus 18.0 ± 1.5% stasis; p<0.05) after hemoglobin challenge. We have previously shown that a monoclonal antibody to murine P-selectin or a polyclonal antibody to VWF markedly inhibit stasis in sickle mice. After the 4 hr stasis measurement, lungs were harvested from PAR-1+/+ SS and PAR-1-/- SS the mice and stained for P-selectin, VWF, and CD31 (a marker for endothelial cells). We found that intensity of P-selectin and VWF staining was markedly reduced in the lungs of PAR-1-/- SS mice compared to the staining observed in lungs of PAR-1+/+ SS mice.Our data indicates that SFH-induced microvascular stasis is significantly diminished by inhibition of TF, FXa, or thrombin activity or knockout of endothelial PAR-1, which leads to reduced expression of P-selectin and VWF on endothelium in a mouse model of SCD. We speculate that inhibiting the TF/thrombin/PAR-1 axis may reduce vaso-occlusive crises in SCD patients. DisclosuresVercellotti:CSL Behring: Research Funding. Belcher:CSL Behring: Research Funding.

Evaluation of direct oral anticoagulants for the treatment of cancer-associated thrombosis: an update.

Cancer is associated with an increased risk of venous thromboembolism of four to sixfold. Cancer-related interventions such as chemotherapy, hormonal therapy and indwelling central venous catheters also increase the risk of venous thromboembolism. Low molecular weight heparin for at least 3-6months is the current standard of care for the treatment of cancer associated venous thromboembolism. Anticoagulation should be continued as long as the cancer is active. Over the past few years, direct oral anticoagulants have emerged, including one direct thrombin inhibitor (dabigatran etexilate) and three factor Xa inhibitors (apixaban, edoxaban and rivaroxaban). In the randomized controlled trials comparing direct oral anticoagulants with vitamin K antagonists, the direct oral anticoagulants all provide non-inferior in prevention of thromboembolic events in patients with atrial fibrillation, for the prevention and treatment of venous thromboembolism and in acute coronary syndrome. In people with cancer, these drugs have emerged as attractive alternatives for the treatment of venous thromboembolism with the potential to overcome the limitations of low molecular weight heparin. Randomized controlled studies comparing direct oral anticoagulants to low molecular weight heparin in cancer patients are still limited and direct oral anticoagulants are not recommended for the treatment of cancer associated venous thromboembolism yet. However, new emerging data are supporting the use of direct oral anticoagulants in cancer-associated thrombosis. Here, we review recent data on the evidence related to the efficacy and safety of direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer.

Andexanet alfa in the treatment of acute major bleeding related to apixaban and rivaroxaban: a profile of its use in the USA

Andexanet alfa (Andexxa®), a first-in-class recombinant modified factor Xa protein, is currently the only specific agent available to reverse life-threatening or uncontrolled bleeding with the factor Xa inhibitors apixaban and rivaroxaban. Andexanet alfa acts as a decoy and competes with endogenous factor Xa to bind factor Xa inhibitors, thereby reversing the anticoagulant effects of factor Xa inhibitors, and restoring the activity of endogenous factor Xa. In adults with major bleeding associated with the use of apixaban or rivaroxaban, intravenous administration of andexanet alfa effectively and rapidly reduces anti-factor Xa levels, with reduced levels being maintained during continued treatment. The tolerability profile of andexanet alfa in patients is generally similar to that reported of other approved anticoagulation reversal agents. With the known increased risk of thromboembolic events following andexanet alfa treatment, anticoagulant therapy should be resumed as soon as medically appropriate.

PCV29 - REAL-WORLD DOAC AND VKA USE: THE PHARMO-ANTICOAGULATION COHORT

Anticoagulation with vitamin K antagonists (VKAs), including acenocoumarol, phenprocoumon and warfarin, has been the standard of care for more than 60 years, but has been associated with drug use-related hospital admissions due to bleeding events. Dosing requires close monitoring of therapeutic levels. Direct oral anticoagulants (DOACs), which have been on the market since 10 years, do not require close monitoring. DOACs include factor II inhibitors (dabigatran) and factor Xa inhibitors apixaban, rivaroxaban and edoxaban). A real-world dynamic prospective cohort of patients using DOACs and VKAs was created with the aim to set a basis for safety and efficacy outcome monitoring. Patients with recorded dispensings of DOAC or VKA between 2008 and 2017 were selected from the Out-patient Pharmacy Database of the PHARMO Database Network, resulting in the PHARMO- anticoagulation cohort. Outcome data are available from hospital admission records and for a subset of the patients, detailed patient information from the GP Database is available. During 2008-2017 a total of 77,189 patients using DOACs and 249,210 patients using VKAs were identified; 22,512 were in both groups. DOAC users were 69.9 ± 12.1 years at the time of first use; 44% used rivaroxaban, 27% dabigatran, 18% apixaban, 4% edoxaban and 7% had used multiple DOACs over time. VKA users (77% used acenocoumarol, 17% phenprocoumon and 5% used both over time) were 70.6 ± 14.1 years at the time of first dispensing in the study period; this is a mix of new and prevalent users. For about 25% of the population detailed medical information from GP records is available. The PHARMO-anticoagulation cohort provides real-world information on DOAC and VKA use in the Netherlands and delivers comprehensive insights in anticoagulation-related safety, efficacy and resource utilisation.

Limitations of Specific Coagulation Tests for Direct Oral Anticoagulants: A Critical Analysis.

BackgroundDuring treatment with direct oral anticoagulants (DOAC), coagulation assessment is required before thrombolysis, surgery, and if anticoagulation reversal is evaluated. Limited data support the accuracy of DOAC‐specific coagulation assays around the current safe‐for‐treatment threshold of 30 ng/mL.Methods and ResultsIn 481 samples obtained from 96 patients enrolled at a single center, DOAC concentrations were measured using Hemoclot direct thrombin inhibitor assay, Biophen direct thrombin inhibitor assay or ecarin clotting time for dabigatran, chromogenic anti‐Xa assay (AXA) for factor Xa inhibitors (rivaroxaban, apixaban) and ultraperformance liquid chromatography–tandem mass spectrometry as reference. All dabigatran‐specific assays had high sensitivity to concentrations >30 ng/mL, but specificity was lower for Hemoclot direct thrombin inhibitor assay (78.2%) than for Biophen direct thrombin inhibitor assay (98.9%) and ecarin clotting time (94.6%). AXA provided high sensitivity and specificity for rivaroxaban, but low sensitivity for apixaban (73.8%; concentrations up to 82 ng/mL were misclassified as <30 ng/mL). If no DOAC‐specific calibration for AXA is available, results 2‐fold above the upper limit of normal indicate relevant rivaroxaban concentrations. For apixaban, all elevated results should raise suspicion of relevant anticoagulation.Conclusions DOAC‐specific tests differ considerably in diagnostic performance for concentrations close to the currently accepted safe‐for‐treatment threshold. Compared with Biophen direct thrombin inhibitor assay and ecarin clotting time, limited specificity of Hemoclot direct thrombin inhibitor assay poses a high risk of unnecessary anticoagulation reversal or treatment delays in patients on dabigatran. While AXA accurately detected rivaroxaban, the impact of low apixaban levels on the assay was weak. Hence, AXA results need to be interpreted with extreme caution when used to assess hemostatic function in patients on apixaban.Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifiers: NCT02371044, NCT02371070.

D-Dimer Levels and Effect of Rivaroxaban on Those Levels and Outcomes in Patients With Acute Coronary Syndrome (An ATLAS ACS-TIMI 46 Trial Substudy)

D-dimer has been used as both a diagnostic and prognostic biomarker in the assessment of patients with venous thromboembolism, but its prognostic value in the setting of arterial acute coronary syndromes (ACS) and the ability of pharmacotherapy to reduce D-dimer in ACS is less well characterized. It was hypothesized that elevated baseline D-dimer would be associated with poor clinical outcomes in ACS, and that Factor Xa inhibition with Rivaroxaban would reduce D-dimer acutely and chronically. The ATLAS ACS TIMI-46 trial assessed the safety and efficacy of rivaroxaban compared with placebo in ACS patients. A subset of subjects had a D-dimer measured at baseline (n = 1,834, 52.5%). A univariate and multivariable logistic regression assessed the relation between baseline D-dimer and a composite end point of cardiovascular death, myocardial infarction, or stroke through 6 months. The Wilcoxon rank sum test was used to compare change in D-dimer level between the treatment groups from baseline. Baseline D-dimer was associated with the composite efficacy outcome in a univariate logistic regression (odds ratio 1.15, 95% confidence interval 1.03 to 1.29, p = 0.015) and a multivariable logistic regression (odds ratio 1.13, 95% confidence interval 1.00 to 1.28, p = 0.048). Rivaroxaban administration lowered D-dimer levels compared wth placebo after administration of the first dose of study drug (p = 0.026), at day 30 (p < 0.001) and day 180 (p < 0.001). In conclusion, elevated baseline D-dimer was associated with an increased risk of the composite outcome within 6 months of the ACS event and administration of the Factor Xa inhibitor rivaroxaban was associated with lower D-dimer levels compared with placebo after the first dose, at day 30 and day 180.

Pharmacokinetic drug interactions of the non-vitamin K antagonist oral anticoagulants (NOACs).

The use of warfarin, the most commonly prescribed oral anticoagulant, is being questioned by clinicians worldwide due to warfarin several limitations (a limited therapeutic window and significant variability in dose-response among individuals, in addition to a potential for drug-drug interactions). Therefore, the need for non-vitamin K antagonist oral anticoagulants (NOACs) with a rapid onset of antithrombotic effects and a predictable pharmacokinetic (PK) and pharmacodynamic (PD) profile led to the approval of five new drugs: the direct factor Xa (F-Xa) inhibitors rivaroxaban, apixaban, edoxaban and betrixaban (newly approved by FDA) and the direct thrombin (factor-IIa) inhibitor dabigatran etexilate. The advantages of NOACs over warfarin are a fixed-dosage, the absence of the need for drug monitoring for changes in anti-coagulation and fewer clinically significant PK and PD drug-drug interactions. NOACs exposure will likely be increased by the administration of strong P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4-inhibitors and may increase the risk of bleeds. On the contrary, P-gp inducers could significantly decrease the NOACs plasma concentration with an associated reduction in their anticoagulant effects. This manuscript gives an overview of NOACs PK profiles and their drug-drug interactions potential. This is meant to be of help to physicians in choosing the best therapeutic approach for their patients.

Factor Xa inhibitors differently modulate electrical activities in pulmonary veins and the sinoatrial node

Factor Xa inhibitors reduce stroke in patients with atrial fibrillation. Pulmonary veins (PVs) and the sinoatrial node (SAN) are crucial for genesis of atrial fibrillation. However, the electrophysiological effects of factor Xa inhibitors (edoxaban and rivaroxaban) on PVs and the SAN remain unclear. Conventional microelectrodes were used to record the action potential in isolated rabbit PVs and SAN preparations before and after administration of edoxaban (0.1, 0.3, and 1 μM) or rivaroxaban (0.01, 0.03, 0.1, and 0.3 μM). A whole-cell patch-clamp was used to record the late sodium current (INa-late) in isolated single rabbit PV cardiomyocytes. Edoxaban significantly reduced PV spontaneous beating rates at 0.3 and 1 μM (N = 6 rabbits, P < 0.05), and reduced SAN beating rates at 1 μM (N = 6, P < 0.05). Similarly, rivaroxaban reduced PV spontaneous beating rates at 0.1 and 0.3 μM (N = 7, P < 0.05), and reduced SAN beating rates at 0.3 μM (N = 6, P < 0.05). However, neither edoxaban (1 μM) nor rivaroxaban (0.3 μM) reduced PV spontaneous beating rates in the presence of 1 μM BMS200261 (an inhibitor of protease-activated receptors type 1, PAR1 inhibitor) or 10 μM ranolazine (an inhibitor of late sodium current, INa-late inhibitor). Edoxaban (0.3 and 1 μM) and rivaroxaban (0.1 and 0.3 μM) respectively decreased the INa-late by 47%, 47%, 36%, and 49% (n = 9 PV cardiomyocytes from 5 rabbits, P < 0.05). In conclusion, Factor Xa inhibitors reduce PV spontaneous activities and may modulate occurrence of atrial fibrillation by inhibiting PAR1 and reducing the INa-late in PVs.