Safety and Efficacy Evaluation of Antithrombotic Therapy with Rivaroxaban and Clopidogrel After PCI in Chinese Patients.

OBJECTIVE: To investigate the efficacy and safety of the antithrombotic therapy using the oral anticoagulant rivaroxaban and clopidogrel in Chinese patients with acute coronary syndrome complicated with atrial fibrillation after percutaneous coronary intervention. METHODS: A total of 100 patients were selected. Patients were randomly divided into two groups: the treatment group (rivaroxaban group) received a therapy of rivaroxaban and clopidogrel. The control group (warfarin group) receivied a combined treatment of warfarin, clopidogrel, and aspirin. The primary outcome endpoint was evaluated based on the adverse cardiac and cerebrovascular events within 12 months. RESULTS: A total of 8 (8.00%) main adverse cardiac and cerebrovascular events occurred during the 12 months of follow-up, including 5 (9.80%) in the warfarin group and 3 (6.10%) in the rivaroxaban group. The risk of having main adverse cardiac and cerebrovascular events in the two groups was comparable (P = 0.479). A total of 9 patients (9.00%) were found to have bleeding events, among which 8 patients (15.7%) were in the warfarin group, whereas only 1 patient (2.00%) was in the rivaroxaban group. Therefore, the risk of bleeding in the warfarin group was significantly higher than that in the rivaroxaban group (P = 0.047). CONCLUSIONS: In Chinese patients with acute coronary syndrome complicated with atrial fibrillation, the efficacy of the dual therapy of oral anticoagulant rivaroxaban plus clopidogrel after percutaneous coronary intervention was similar to that of the traditional triple therapy combined with warfarin, aspirin and clopidogrel, but it has a better safety property, which has potential to widely apply to antithrombotic therapy after PCI.

Effect of Rivaroxaban and Clopidogrel Combination Therapy on In-Stent Responses After Everolimus-Eluting Stent Implantation in a Porcine Coronary Model.

AIM: According to recent clinical trials, a combination of direct oral anticoagulants with antiplatelet drugs is often recommended for atrial fibrillation patients who receive drug-eluting stents (DESs). Although the optimal combination comprises direct factor Xa inhibitors and a P2Y12 receptor antagonist (or aspirin), their influence on vascular responses to DESs remains unclear. METHODS: Pigs were given either aspirin and clopidogrel (dual antiplatelet therapy [DAPT] group), aspirin and rivaroxaban (AR group), or clopidogrel and rivaroxaban (CR group), followed by everolimus-eluting stent (Promus Element) implantation into the coronary artery. Stented coronary arteries were evaluated via intravascular optical coherence tomography (OCT) and histological analysis at 1 and 3 months. RESULTS: OCT revealed lower neointimal thickness in the DAPT group and comparable thickness among all groups at 1 and 3 months, respectively. Histological analyses revealed comparable neointimal area among all groups and the smallest neointimal area in the CR group at 1 and 3 months, respectively. In the DAPT and AR groups, the neointima continued to grow from 1 to 3 months. A shortened time course for neointima growth was observed in the CR group, with rapid growth within a month (maintained for 3 months). A higher incidence of in-stent thrombi was observed in the AR group at 1 month; no thrombi were found in either group at 3 months. More smooth muscle cells with contractile features were found in the CR group at both 1 and 3 months. CONCLUSIONS: Our results proved the noninferiority of the combination of rivaroxaban with an antiplatelet drug, particularly the dual therapy using rivaroxaban and clopidogrel, compared to DAPT after DES implantation.

Cancer-associated thrombosis - treatment and prevention with direct oral factor Xa inhibitors.

BACKGROUND: Venous thromboembolism (VTE) is a frequent cause of morbidity and mortality in patients with cancer. Moreover, management of VTE is frequently connected with complications, namely risk of recurrent VTE and bleeding. Low molecular weight heparins (LMWH) therapy administrated for 3-6 months is currently considered a standard for the treatment of cancer-associated VTE (CA-VTE). Direct oral factor Xa inhibitors (FXaI) apixaban, edoxaban and rivaroxaban have emerged as a new possibility for long-term antithrombotic therapy for VTE. These agents expose several advantages in individuals with cancer, and might overcome several disadvantages connected with LMWH therapy. PURPOSE: First clinical studies with oral FXaI for the treatment of CA-VTE with very promising results were recently published. The article summarizes current data regarding the use of oral FXaI in the treatment of CA-VTE.

Medically Ill hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis with rivaroxaban ThErapy: Rationale and Design of the MICHELLE Trial.

BACKGROUND: The devastating Coronavirus disease (COVID-19) pandemic is associated with a high prothrombotic state. It is unclear if the coagulation abnormalities occur because of the direct effect of SARS-CoV-2 or indirectly by the cytokine storm and endothelial damage or by a combination of mechanisms. There is a clear indication of in-hospital pharmacological thromboprophylaxis for every patient with COVID-19 after bleed risk assessment. However, there is much debate regarding the best dosage regimen, and there is no consensus on the role of extended thromboprophylaxis. DESIGN: This study aims to evaluate the safety and efficacy of rivaroxaban 10 mg once daily for 35 ± 4 days versus no intervention after hospital discharge in COVID-19 patients who were at increased risk for VTE and have received standard parenteral VTE prophylaxis during hospitalization. The composite efficacy endpoint is a combination of symptomatic VTE, VTE-related death, VTE detected by bilateral lower limbs venous duplex scan and computed tomography pulmonary angiogram on day 35 ± 4 posthospital discharge and symptomatic arterial thromboembolism (myocardial infarction, nonhemorrhagic stroke, major adverse limb events, and cardiovascular death) up to day 35 ± 4 posthospital discharge. The key safety outcome is the incidence of major bleeding according to ISTH criteria. SUMMARY: The MICHELLE trial is expected to provide high-quality evidence around the role of extended thromboprophylaxis in COVID-19 and will help guide medical decisions in clinical practice.1.

Comparison of Low and Full Dose Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Renal Dysfunction (from a National Registry).

The use of direct oral anticoagulants for stroke prevention in patients with non-valvular atrial fibrillation (NVAF) is robust. However, the efficacy and safety of different dosage in patients with renal dysfunction is still a clinical challenge. We aimed to evaluate the clinical characteristics and outcomes of patients treated with apixaban in its different doses. A multicenter prospective cohort study, where consecutive eligible apixaban or warfarin treated patients with NVAF and renal impairment, were registered. Patients were followed-up for clinical events over a mean period of 1 year. Analyses were performed according to the dose of apixaban given, with consideration to the standard indications for dose reduction. Primary outcome was a composite of 1-year mortality, stroke or systemic embolism, major bleeding and myocardial infarction, while secondary outcomes included those components separated. Among the study population (n = 2,140), risk of composite outcome was significantly lower in the high dose apixaban group (10%, n = 491) than the low dose group (18%, n = 673) and the warfarin group (18%, n = 976) p <0.001. Results of 1-year mortality were similar. Apixaban dosing analysis revealed 65% of patients were appropriately dosed, while 31% were under-dosed and 4% were over-dosed. Furthermore, 53% of patients treated with low dose apixaban were under-dosed. Propensity score analysis revealed that patients who were appropriately treated with low-dose apixaban had a trend towards better composite outcome and mortality than 1:1 matched warfarin treated patients (18% vs 24%, p = 0.09 and 16% vs 23%, p = 0.06, respectively). Overall, appropriately dosed apixaban treated patients at any dose had significantly better outcomes than matched warfarin treated patients (composite outcome probability of 13.1% vs 18.6%, p = 0.007). In conclusion, apixaban at any dose is a reasonable alternative to warfarin in patients with renal impairment, possibly associated with improved outcomes.

Comparison of Low-Dose Direct Acting Anticoagulant and Warfarin in patients Aged ≥80 years With Atrial Fibrillation.

Low dose direct acting oral anticoagulants (LDDOACS) were approved for elderly atrial Fibrillation (AF) patients with limited information. A retrospective analysis collecting baseline characteristics and outcomes in AF patients ≥ 80 prescribed LDDOAC or warfarin (W), from a multidisciplinary practice between 1/1/11 (First LDDOAC available) and 5/31/17 was conducted. From 9660 AF patients, 514 ≥ 80 received a LDDOAC and 422 W. A multivariable comparison found LDDOAC patients were older (p <0.001), had lower creatinine clearance (CrCl) (p = 0.006), used more anti-platelet drugs (p <0.001), and more often had new onset AF verses those prescribed W (p <0.001). There were no clinically significant differences among those patients receiving Dabigatran 75 mgs BID (D), Rivaroxaban 15mgs (R) or Apixaban 2.5mgs BID (A). Forty-eight and 50% of the patients remained on their LDDOAC or W for the observation period (p = 0.55). Stroke/systemic embolism (SSE) and CNS bleeds were 1.16 vs 2.22%/yr., (p = 0.143) and 1.46 vs 0.93%/yr., (p = 0.24). Mortality and major bleeds were 6.26 vs 1.67%/yr., and 12.3vs 3.77%/yr. (p <0.001). SSE were 1.1%/yr for D, R, and A (p = 0.94). CNS bleeds were 2.2 for D, 1.7 for R and 0.8%/yr. for A: p = 0.53. Major bleeding was: 14.3 for D, 14.1 for R and 9.1%/yr. for A, p = 0.048 (with A < R, p = 0.01). Mortality was 5.5 for D, 4.2 for R and 9.5% for A, p = 0.031. In conclusion, half the patients remained on their assigned anti-coagulant. SSE and intracranial bleed rates were similar and low. Major bleeds and deaths were different between groups emphasizing the need for prospective randomized trials in this growing population with AF.

Intranasal In Situ Gel of Apixaban-Loaded Nanoethosomes: Preparation, Optimization, and In Vivo Evaluation.

The present study was conducted to formulate ethosomal thermoreversible in situ gel of apixaban, an anticoagulant drug, for nasal delivery. Ethosomes were formed, of lecithin, cholesterol, and ethanol, by using thin-film hydration method. The prepared ethosomes were characterized by Zetasizer, transmission electron microscope, entrapment efficiency, and in vitro study. The selected ethosomal formula (API-ETHO2) was incorporated in gel using P407 and P188 as thermoreversible agents and carbopol 934 as mucoadhesive agent. Box-Behnken design was used to study the effect of independent variables (concentration of P407, P188, and carbopol 934) on gelation temperature, mucoadhesive strength, and in vitro cumulative percent drug released at 12h (response variables). The optimized formulation was subjected to compatibility study, ex vivo permeation, histopathological examination for the nasal mucosa, and in vivo study. API-ETHO2 was spherical with an average size of 145.1±12.3 nm, zeta potential of -20±4 mV, entrapment efficiency of 67.11%±3.26, and in vitro % release of 79.54%±4.1. All gel formulations exhibited an acceptable pH and drug content. The optimum gel offered 32.3°C, 1226.3 dyne/cm2, and 53.50% for gelation temperature, mucoadhesive strength, and in vitro percent released, respectively. Apixaban ethosomal in situ gel evolved higher ex vivo permeation (1.499±0.11 µg/cm2h) through the nasal mucosa than pure apixaban gel. Histopathological study assured that there is no necrosis or tearing of the nasal mucosa happened by ethosomal gel. The pharmacokinetic parameters in rabbit plasma showed that intranasal administration of optimized API-ethosomal in situ gel achieved higher Cmax and AUC0-∞ than unprocessed API nasal gel, nasal suspension, and oral suspension. The ethosomal thermoreversible nasal gel established its potential to improve nasal permeation and prolong anticoagulant effect of apixaban.

Treatment with direct oral anticoagulants or warfarin and the risk for incident diabetes among patients with atrial fibrillation: a population-based cohort study.

BACKGROUND: Diabetes mellitus is a common comorbidity of atrial fibrillation (AF), which can complicate the management of AF. The pharmacology of oral anticoagulants (OACs) have been implicated in pathogenesis of diabetes, but the relationship between different OACs and risk of diabetes remains unexamined. This study aimed to evaluate the risk of diabetes with use of different OACs in AF patients. METHODS: Population-based retrospective cohort study using an electronic healthcare database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with AF from 2014 through 2018 and prescribed OACs were included and followed till December 31, 2019. Inverse probability of treatment weighting based on the propensity score (PS) is used to address potential bias due to nonrandomized allocation of treatment. The risks ofdiabetes were compared between different new OAC users using propensity score-weighted cumulative incidence differences (CID). RESULTS: There were 13,688 new users of OACs (warfarin: n = 3454; apixaban: n = 3335; dabigatran: n = 4210; rivaroxaban: n = 2689). The mean age was 75.0 (SD, 11.2), and 6,550 (47.9%) were women. After a median follow-up of 0.93 years (interquartile range, 0.21-1.92 years), 698 incident diabetes cases were observed. In Cox-regression analysis, dabigatran use was significantly associated with reduced risk of diabetes when compared with warfarin use [HR 0.69 (95% CI 0.56-0.86; P < 0.001)], with statistically insignificant associations observed for use of apixaban and rivaroxaban. The corresponding adjusted CIDs at 2 years after treatment with apixaban, dabigatran, and rivaroxaban users when compared with warfarin were - 2.06% (95% CI - 4.08 to 0.16%); - 3.06% (95% CI - 4.79 to - 1.15%); and - 1.8% (- 3.62 to 0.23%). In head-to-head comparisons between women DOAC users, dabigatran was also associated with a lower risk of diabetes when compared with apixaban and rivaroxaban. CONCLUSIONS: Among adults with AF receiving OACs, the use of dabigatran had the lowest risk of diabetes when compared with warfarin use.

Safety and Efficacy of Vitamin K Antagonists versus Rivaroxaban in Hemodialysis Patients with Atrial Fibrillation: A Multicenter Randomized Controlled Trial.

BACKGROUND: In patients with normal renal function or early stage CKD, the risk-benefit profile of direct oral anticoagulants (DOACs) is superior to that of vitamin K antagonists (VKAs). In patients on hemodialysis, the comparative efficacy and safety of DOACs versus VKAs are unknown. METHODS: In the Valkyrie study, 132 patients on hemodialysis with atrial fibrillation were randomized to a VKA with a target INR of 2-3, 10 mg rivaroxaban daily, or rivaroxaban and vitamin K2 for 18 months. Patients continued the originally assigned treatment and follow-up was extended for at least an additional 18 months. The primary efficacy end point was a composite of fatal and nonfatal cardiovascular events. Secondary efficacy end points were individual components of the composite outcome and all-cause death. Safety end points were life-threatening, major, and minor bleeding. RESULTS: Median (IQR) follow-up was 1.88 (1.01-3.38) years. Premature, permanent discontinuation of anticoagulation occurred in 25% of patients. The primary end point occurred at a rate of 63.8 per 100 person-years in the VKA group, 26.2 per 100 person-years in the rivaroxaban group, and 21.4 per 100 person-years in the rivaroxaban and vitamin K2 group. The estimated competing risk-adjusted hazard ratio for the primary end point was 0.41 (95% CI, 0.25 to 0.68; P=0.0006) in the rivaroxaban group and 0.34 (95% CI, 0.19 to 0.61; P=0.0003) in the rivaroxaban and vitamin K2 group, compared with the VKA group. Death from any cause, cardiac death, and risk of stroke were not different between the treatment arms, but symptomatic limb ischemia occurred significantly less frequently with rivaroxaban than with VKA. After adjustment for competing risk of death, the hazard ratio for life-threatening and major bleeding compared with the VKA group was 0.39 (95% CI, 0.17 to 0.90; P=0.03) in the rivaroxaban group, 0.48 (95% CI, 0.22 to 1.08; P=0.08) in the rivaroxaban and vitamin K2 group and 0.44 (95% CI, 0.23 to 0.85; P=0.02) in the pooled rivaroxaban groups. CONCLUSIONS: In patients on hemodialysis with atrial fibrillation, a reduced dose of rivaroxaban significantly decreased the composite outcome of fatal and nonfatal cardiovascular events and major bleeding complications compared with VKA. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Oral Anticoagulation in Hemodialysis, NCT03799822.

Outpatient management of chronic warfarin therapy at a pharmacist-run anticoagulation clinic during the COVID-19 pandemic.

As a result of infection control regulations during the coronavirus disease 2019 (COVID-19) pandemic, anticoagulation clinics have been required to adjust their practices in order to continue providing safe and effective services for their patients. In accordance with a guidance document issued by the Anticoagulation Forum, The Brooklyn Hospital Center (TBHC) anticoagulation clinic in Brooklyn, New York implemented measures including telemedicine follow-ups instead of in-person clinic visits, extending the interval of INR testing, and reviewing eligible candidates for transition from warfarin to direct oral anticoagulants. This study describes the outcomes of one hospital-based clinic location in the 3 months before and after COVID-19 became a significant concern in the New York City area. The primary outcome of time-in-therapeutic range (TTR) for patients receiving warfarin was 60.6 % and 65.8 % in the pre-COVID and post-COVID groups, respectively (p = 0.21). For secondary outcomes, there was no difference in percent of therapeutic INRs (51.5 % pre-COVID v. 44.8 % post-COVID, p = 0.75) or percent of INRs ≥ 4.5 (2.3 % pre-COVID v. 4 % post-COVID, p = 0.27). Based on the data reported in this study, the short-term changes implemented at TBHC's anticoagulation clinic did not appear to cause reductions in safety and efficacy of chronic warfarin therapy management.

Rivaroxaban monotherapy versus combination therapy according to patient risk of stroke and bleeding in atrial fibrillation and stable coronary disease: AFIRE trial subanalysis.

BACKGROUND: In the AFIRE trial, rivaroxaban monotherapy was noninferior to combination therapy with rivaroxaban and an antiplatelet agent for thromboembolic events or death, and superior for major bleeding in patients with atrial fibrillation (AF) and stable coronary artery disease. Little is known about impacts of stroke and bleeding risks on the efficacy and safety of rivaroxaban monotherapy. METHODS: In this subanalysis of the AFIRE trial, we assessed the risk of stroke and bleeding by the CHADS2, CHA2DS2-VASc, and HAS-BLED scores. The primary efficacy end point was the composite of stroke, systemic embolism, myocardial infarction (MI), unstable angina requiring revascularization, or death from any cause. The primary safety end point was major bleeding defined by the International Society on Thrombosis and Haemostasis. RESULTS: Rivaroxaban monotherapy significantly reduced the primary efficacy and safety end points with no evidence of differential effects by stroke risk (CHADS2, p for interaction = 0.727 for efficacy, 0.395 for safety; CHA2DS2-VASc, p for interaction = 0.740 for efficacy, 0.265 for safety) or bleeding risk (HAS-BLED, p for interaction = 0.581 for efficacy, 0.225 for safety). There was also no evidence of statistical heterogeneity across patient risk categories for other end points; stroke or systemic embolism, ischemic stroke, hemorrhagic stroke, MI, MI or unstable angina, death from any cause, any bleeding, or net adverse clinical events. CONCLUSIONS: The advantages of rivaroxaban monotherapy compared with those of combination therapy with respect to all prespecified end points, including thromboembolism, bleeding, and mortality were similar across patients with AF and stable coronary artery disease, irrespective of their risk for stroke and bleeding. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry number, UMIN000016612, and ClinicalTrials.gov number, NCT02642419.

A randomized clinical trial to evaluate the efficacy and safety of rivaroxaban in patients with bioprosthetic mitral valve and atrial fibrillation or flutter: Rationale and design of the RIVER trial.

The efficacy and safety of rivaroxaban in patients with bioprosthetic mitral valves and atrial fibrillation or flutter remain uncertain. DESIGN: RIVER was an academic-led, multicenter, open-label, randomized, non-inferiority trial with blinded outcome adjudication that enrolled 1005 patients from 49 sites in Brazil. Patients with a bioprosthetic mitral valve and atrial fibrillation or flutter were randomly assigned (1:1) to rivaroxaban 20 mg once daily (15 mg in those with creatinine clearance <50 mL/min) or dose-adjusted warfarin (target international normalized ratio 2.0-30.); the follow-up period was 12 months. The primary outcome was a composite of all-cause mortality, stroke, transient ischemic attack, major bleeding, valve thrombosis, systemic embolism, or hospitalization for heart failure. Secondary outcomes included individual components of the primary composite outcome, bleeding events, and venous thromboembolism. SUMMARY: RIVER represents the largest trial specifically designed to assess the efficacy and safety of a direct oral anticoagulant in patients with bioprosthetic mitral valves and atrial fibrillation or flutter. The results of this trial can inform clinical practice and international guidelines.

Eligibility for Low-Dose Rivaroxaban Based on the COMPASS Trial: Insights from the Veterans Affairs Healthcare System.

INTRODUCTION: Low-dose rivaroxaban reduced major adverse cardiac and limb events among patients with stable atherosclerotic vascular disease (ASCVD) in the COMPASS trial. The objective of our study was to evaluate the eligibility and budgetary impact of the COMPASS trial in a real-world population. METHODS: The VA administrative and clinical databases were utilized to conduct a cross-sectional study to identify patients eligible for low-dose rivaroxaban receiving care at all 141 facilities between October 1, 2014 and September 30, 2015. Proportion of patients with stable ASCVD eligible for low-dose rivaroxaban and prevalence of multiple risk enrichment criteria among eligible patients. Pharmaceutical budgetary impact using VA pharmacy pricing. Chi-squared and Student's t tests were used to compare patients eligible versus ineligible patients. RESULTS: From an initial cohort of 1,248,214 patients with ASCVD, 488,495 patients (39.1%) met trial eligibility criteria. Eligible patients were older (74.2 vs 64.5 years) with higher proportion of hypertension (84.1% vs 82.1%) and diabetes (46.2% vs 32.9) compared with ineligible patients (p < 0.001 for all comparisons). A median of 38.7% (IQR 4.6%) of total ASCVD patients per facility were rivaroxaban eligible. Estimated annual VA pharmacy budgetary impact would range from $0.47 billion to $1.88 billion for 25% to 100% treatment penetration. Annual facility level pharmaceutical budgetary impact would be a median of $12.3 million (IQR $8.0-$16.3 million) for treatment of all eligible patients. Among eligible patients, age greater than 65 years was the most common risk enrichment factor (86.9%). Prevalence of eligible patients with multiple enrichment factors varied from 34.2% (one factor) to 6.2% (four or more). CONCLUSION: Over one third of patients with stable ASCVD may qualify for low-dose rivaroxaban within the VA. Additional studies are needed to understand eligibility in other populations and a formal cost-effectiveness analysis is warranted.

Patterns of anticoagulation therapy in atrial fibrillation: results from a large real-life single-center registry.

AIM: To investigate the differences in the characteristics and clinical outcomes of recently diagnosed patients with atrial fibrillation (AF) receiving different types of anticoagulants in a real-life setting. METHODS: We retrospectively analyzed the charts of 1000 consecutive patients with non-valvular AF diagnosed at our institution or referred it to from 2013 to 2018. RESULTS: Over the observed period, the frequency of direct oral anticoagulation (DOAC) therapy use significantly increased (P = 0.002). Patients receiving warfarin had more unfavorable thromboembolic and bleeding risk factors than patients receiving DOAC. Predetermined stroke and major bleeding risks were similarly distributed among the dabigatran, rivaroxaban, and apixaban groups. Patients receiving warfarin had shorter time-to-major bleeding (TTB), time to thrombosis (TTT), and overall survival (OS) than patients receiving DOACs. After adjustment for factors unbalanced at baseline, the warfarin group showed significantly shorter OS (hazard ratio 2.27, 95% confidence interval 1.44-3.57, P<0.001], while TTB and TTT did not significantly differ between the groups. Only 37% of patients on warfarin had optimal dosing control, and they did not differ significantly in TTB, TTT, and OS from patients on DOACs. CONCLUSION: Warfarin and DOACs are administered to different target populations, possibly due to socio-economic reasons. Patients receiving warfarin rarely obtain optimal dosing control, and experience significantly shorter survival compared with patients receiving DOACs.

Successful management of portal vein thrombosis in a Yorkshire Terrier with protein-losing enteropathy.

BACKGROUND: Portal vein thrombosis (PVT) is a rare presentation in dogs with protein-losing enteropathy (PLE). Rivaroxaban, an oral, selective, direct factor Xa inhibitor, has not been reported to be administrated for canine PVT and the effect is unclear in dogs with PLE. CASE PRESENTATION: An 11-year-old Yorkshire Terrier presented with moderate ascites. The dog had severe hypoalbuminemia (1.2 g/dL), and a portal vein thrombus was confirmed on computed tomographic angiography (CTA). On endoscopic examination, it became apparent that the hypoalbuminemia was caused by PLE, which was consequent of lymphatic dilation and lymphoplasmacytic enteritis. Therefore, the dog was initially treated with oral administrations of spironolactone and clopidogrel, with dietary fat restriction. However, a follow-up CTA showed no changes in the ascites, thrombus, and portal vein to aorta (PV/Ao) ratio. Therefore, the dog was additionally prescribed rivaroxaban and low-dose prednisolone for the portal vein thrombus and hypoalbuminemia due to lymphoplasmacytic enteritis, respectively. Following the treatment, the PV/Ao ratio decreased because of a decrease in the thrombus and the ascites disappeared completely with an elevation of albumin concentration (1.9 g/dL). CONCLUSIONS: This case report demonstrated that oral administration of rivaroxaban combined with low-dose glucocorticoid was effective management for PVT in a dog with PLE.

Therapeutic Drug Monitoring of Direct Oral Anticoagulants May Increase Their Benefit-Risk Ratio.

The attractiveness of direct oral anticoagulants (DOACs) over vitamin K antagonists, in addition to a better benefit-risk ratio, stems from the fact that no therapeutic drug monitoring is deemed necessary. This has been recently mitigated by the fact that increased dabigatran (D) plasma levels have been associated with hemorrhages, and is currently under scrutiny of the European Medicines Agency. We aimed to evaluate, in real conditions of use, whether patients with out-of-range DOAC blood concentrations (too high or too low) were associated with bleeding or thrombosis. Patients treated with D or rivaroxaban (R) were prospectively included in a hospital cohort. D and R plasma levels were measured by high-pressure liquid chromatography-tandem mass spectrometry-at the physician's demand. We defined concentration range as "expected" within the 95% confidence interval of the mean concentration obtained from pivotal trials, and "out of range" when concentrations were outside of that interval. A blind assessment of concentrations versus occurrence of bleeding or thrombosis was performed by means of univariate and multivariate analysis. Three hundred and twenty-two patients (mean age 78.5 years ± 13.1), treated with D or R were included consecutively. They had a mean CHA2DS2-VASc at 4.4 ± 1.7 and a mean HAS-BLED score at 1.7 ± 0.9. Irrespective of the DOAC prescribed, patients presenting with out-of-range concentrations had significantly more bleeding or thrombosis than patients with expected concentrations (P < 0.001). Patients with bleeding were more prone to have concentrations beyond the 95 percentile (N = 62, P < 0.001), whereas patients with thrombosis were more likely to have concentrations below the fifth percentile (N = 26, P < 0.05). The main risks associated with hemorrhages were abnormal concentrations, a high HAS-BLED score, the patient's age, and the creatinine blood level. For thrombosis, a concentration below the fifth percentile was the only risk factor that was significant in our cohort. While D and R under current recommendation have a better benefit-risk ratio than warfarin, their safe usage could be further optimized by some degree of therapeutic monitoring.