Oral Direct Xa Inhibitor Research Articles

Primary Prevention of Cancer-Associated Thrombosis: Current Perspectives.

Over the past two decades, the incidence of cancer-associated thrombosis (CAT) has increased. It is nowadays a common and often serious complication among patients with cancer. Although medical thromboprophylaxis is recommended for most surgical and nonsurgical cancer patients, it has been infrequently used in ambulatory patients with cancer because of the burden of treatment and concerns about bleeding. However, various risk assessment scores are now available and randomized placebo-controlled trials have established the efficacy of low-molecular-weight heparin or the direct oral Xa inhibitors rivaroxaban and apixaban in ambulatory patients with cancer at high risk of venous thromboembolism (VTE). This review provides an overview of (1) primary thromboprophylaxis in the setting of hospitalized surgical and medical patients, (2) extended thromboprophylaxis after hospital discharge, (3) performance of risk assessment tools for CAT, and (4) primary thromboprophylaxis in ambulatory patients with cancer. The aim is to provide support to physicians in identifying ambulatory patients with cancer at high VTE risk who benefit most from medical thromboprophylaxis according to current recommendations from international guidelines.

Anti-Xa Monitoring of Apixaban (ZyQuis) in Venous Thrombo-Embolism and Atrial Fibrillation.

Apixaban is a direct oral Xa inhibitor and is indicated for the treatment of venous thrombo-embolism (VTE) and prevention of stroke in atrial fibrillation (AF). Recently, a generic (ZyQuis, Zydus Lifesciences Limited, India) has received Food and Drug Administration approval. While bioequivalence has been demonstrated with Eliquis (Bristol-Myers Squibb/Pfizer, UK), it is necessary to monitor its effectiveness prior to acceptance in medical practice. This prospective study independently evaluated Apixaban (ZyQuis) at two accredited laboratories. Participants were converted from Warfarin or Rivaroxaban to Apixaban 5 mg bd for a duration of one month. Peak anti-Xa levels were measured 3-4 h post the morning dose. The samples were processed on the Atellica COAG 360 (Siemens Healthineers, Marburg, Germany) analyzers with a chromogenic anti-Xa assay (Innovance, reference interval 69-321 ng/mL). There were 26 participants; 5 men, 21 women; mean ± standard deviation age of 46 ± 12 years. Indications for anticoagulation included: VTE (88.5%) and AF (11.5%). 69.2% of the participants had at least one comorbidity. 96.2% of the anti-Xa levels were within the laboratory's 95% reference interval. Mean anti-Xa activity was 191 ± 69 ng/mL and 186 ± 68 ng/mL measured at respective laboratories. Mean differences in anti-Xa measurements represented by Bland-Altman statistics were small (bias of -2.6%, 95% confidence interval -1.11 to -4.09) and a strong correlation was observed on Deming regression analysis (0.995). Apixaban (ZyQuis) was effective for the management of VTE and AF as evidenced by anti-Xa activity.

Safety and Efficacy of Rivaroxaban as Extended-Phase Anticoagulation in Patients with Cancer and Venous Thromboembolism: A Preliminary Data Analysis from the Mac Project.

Extended-phase anticoagulation with direct oral Xa inhibitors (OAXI) is suggested in patients with cancer-associated venous thromboembolism (CAT). We report on patients enrolled in the MAC (Monitoring AntiCoagulants) Project, given rivaroxaban as extended-phase anticoagulation after CAT. The primary efficacy outcome was the incidence of symptomatic recurrent VTE; the primary safety outcomes were incidence of major and non-major clinically relevant bleeding, adverse events, and all-cause mortality. The mean patients' follow-up was 19 months (SD 16); 64/604 (11%) had CAT. Recurrent VTE occurred in 9.3% and in 8.1% of patients with and without CAT (OR 1.2, 95% CI 0.5 to 2.9; p = 0.6). Major bleeding occurred in 4.7% and in 2.6%, respectively (OR = 1.8, 95% CI 0.5 to 6.6, p = 0.4), and non-major clinically-relevant bleeding in 4.7% and in 4.1% (OR = 1.2, 95% CI 0.3 to 3.9, p = 0.7). The relative figures for fatal haemorrhage and all-cause death were 1.6% versus 0%, and 1.6% versus 0.4%. Rivaroxaban appears to be effective and safe as extended-phase anticoagulation in patients with CAT. The mean treatment period was 3-times the standard 6-month course.

Prospective cohort study on the use of low molecular weight heparin calibrated anti-Xa assay for measurement of direct oral Xa inhibitors in ex vivo patient samples

Drug-specific anti-Xa chromogenic assays are recommended for measurement of direct anti-Xa inhibitor levels but are not routinely available in many institutions. We performed a prospective study to determine: (1) the relationship between low molecular weight heparin (LMWH) calibrated anti-Xa measurements and apixaban or rivaroxaban levels measured using drug-specific anti-Xa assays and, (2) if a LMWH calibrated anti-Xa assay can be used to detect clinically significant apixaban or rivaroxaban levels. Haematology outpatients on rivaroxaban or apixaban for at least 72 h were recruited for this study. Anti-Xa LMWH assay was performed using the Innovance Heparin Anti-Xa kit/calibrator. Drug-specific levels were determined using STA-Liquid anti-Xa kit/STA-Apixaban or STA-Rivaroxaban calibrators. Serial dilutions with pooled normal plasma were performed for specimens with anti-Xa LMWH activity greater than 1.50 ng/mL to obtain anti-Xa levels within the reportable range (0.10-1.50 ng/mL) and multiplied by the dilution factor to determine actual anti-Xa level. Seventy-five (39 rivaroxaban, 36 apixaban) specimens from 67 patients (mean age 60.3 years; 53.3% males) were available for analysis. Rivaroxaban levels ranged from <25 to 500 ng/mL while apixaban levels ranged from <20 to 236.1 ng/mL. For both rivaroxaban and apixaban, there was linear and good correlation (R2= 0.96) between direct oral anticoagulants and anti-Xa LMWH levels. Using the correlation equation from our data, a rivaroxaban concentration of 50 ng/mL [International Society on Thrombosis and Haemostasis (ISTH) threshold for consideration of antidotes in bleeding patients] and 30 ng/mL (ISTH threshold for consideration of reversal agents prior to interventions), corresponds to anti-Xa LMWH levels of 0.50 and 0.35 IU/mL, respectively. For apixaban the corresponding anti-Xa LMWH levels were 0.35 and 0.20 IU/mL, respectively. In conclusion, LWWH calibrated anti-Xa assay can be used in emergency situations to screen for clinically significant apixaban or rivaroxaban levels when drug-specific calibrators are not available.

Bleeding After Gastric Endoscopic Submucosal Dissection Focused on Management of Xa Inhibitors.

PurposeThe use of direct oral Xa inhibitors (DXaIs) to prevent venothrombotic events is increasing. However, gastrointestinal bleeding, including that related to endoscopic resection, is a concern. In this study, we evaluated bleeding and coagulation times during the perioperative period of gastric endoscopic submucosal dissection (ESD).Materials and MethodsPatients who consecutively underwent gastric ESD from August 2016 to December 2018 were analyzed. Bleeding rates were compared among the 3 groups (antiplatelet, DXaIs, and control). DXaI administration was discontinued on the day of the procedure. Prothrombin time (PT), activated partial thromboplastin time, and the ratio of inhibited thrombin generation (RITG), which was based on dilute PT, were determined before and after ESD.ResultsDuring the study period, 265 gastric ESDs were performed in 239 patients, where 23 and 50 patients received DXaIs and antiplatelets, respectively. Delayed bleeding occurred in 17 patients (7.4%) and 21 lesions (7.1%). The bleeding rate in the DXaI group was significantly higher than that in the other groups (30.4%, P<0.01), and the adjusted odds ratio of bleeding was 5.7 (95% confidence interval, 1.4–23.7; P=0.016). In patients using DXaIs, there was a significant (P=0.046) difference in the median RITG between bleeding cases (18.6%) and non-bleeding cases (3.8%).ConclusionsA one-day cessation of DXaIs was related to a high incidence of bleeding after gastric ESD, and monitoring of residual coagulation activity at trough levels might enable the predicted risk of delayed bleeding in patients using DXaIs.

Direct oral Xa inhibitors versus warfarin in patients with cancer and atrial fibrillation: a meta-analysis.

Patients with cancer are at higher risk of atrial fibrillation, thromboembolic complications and bleeding events compared with the general population. The aim of the present meta-analysis was to compare the efficacy and safety of direct oral Xa inhibitor anticoagulants versus warfarin in patients with cancer and atrial fibrillation. We searched electronic databases for randomized controlled trials comparing direct oral Xa inhibitor anticoagulants and warfarin in cancer patients. The primary efficacy outcome was stroke or systemic embolism. The primary safety outcome was major bleeding. A subgroup analysis was performed to explore the outcome differences between patients with active cancer or history of cancer. Three trials with a total of 3029 cancer patients were included in the analysis. There was no statistically significant difference in the risk of stroke or systemic embolism [risk ratio (RR) 0.76; 95% confidence interval (CI) 0.52-1.10] between the two therapeutic strategies. Direct oral Xa inhibitors significantly reduced the incidence of major bleeding compared with warfarin (RR 0.79; 95% CI 0.63-0.99; P = 0.04; number needed to treat = 113). These results were consistent both in patients with active cancer and in those with history of cancer. In patients with cancer and atrial fibrillation, direct oral Xa inhibitors have a similar efficacy and may be safer compared with warfarin. These results are consistent both in patients with active cancer and history of cancer.

P569Efficacy and safety of direct Xa oral inhibitors versus warfarin in patients with atrial fibrillation and cancer: a meta-analysis of randomized controlled trials

Abstract Background Patients with cancer are at higher risk of atrial fibrillation (AF) compared with the general population. Furthermore, cancer per se and anti-cancer treatments have been associated with thromboembolic complications and increased bleeding risk. Considering that only 12% of cancer patients can achieve a stable International Normalized Ratio target and the frequent need for invasive procedures, warfarin is not an ideal option. Direct oral anticoagulants may theoretically represent a valid alternative although their use in this population has been scarcely investigated. Purpose To compare efficacy and safety of direct oral Xa inhibitors (DOXaI) versus warfarin in patients with atrial fibrillation and cancer. Methods We searched electronic databases for randomized controlled trials (RCTs) that analyzed the use of DOXaI versus warfarin in patients with AF and cancer. The primary efficacy outcome was stroke or systemic embolism (SE). The secondary efficacy outcomes were ischemic stroke, myocardial infarction and all-cause death. The primary safety outcome was major bleeding; secondary safety outcomes were major or clinically relevant non-major bleeding, intracranial bleeding and any bleeding. The net clinical benefit was estimated as the composite of the two primary outcomes. A sensitivity analysis was performed to better define the incidence of these outcomes in patients with active cancer. The statistical software ProMeta 3 was used to estimate the risk ratio with a random-effect model. Results 3 RCTs counting a total of 3029 cancer patients (1682 on DOXaI and 1347 on warfarin), 1354 of whom with active cancer (856 on DOXaI and 502 on warfarin), were included in the analysis. Mean age was 75.6 ± 1.2 years, and 32% were female. Mean follow-up period was 2.2 ± 0.6 years. The most common cancer sites were prostate (23%), gastrointestinal tract (22.2%), breast (12.1%) and genitourinary tract (10.6%). The mean CHADS2 score was 2.9 ± 0.6 and the mean HAS-BLED score was 2.6 ± 0.4. There were no significant differences in the risk of stroke or SE (RR 0.76; 95% CI 0.52-1.10) as well as for all the other secondary efficacy outcomes. DOXaI significantly reduced the incidence of major bleeding in the overall cancer population (RR 0.79; 95% CI 0.63-0.99; p = 0.039); this finding was consistent also in patients with active cancer (RR 0.79; 95% CI 0.59-1.05) although the effect was not statistically significant. DOXaI also significantly reduced intracranial bleeding in overall cancer population (RR 0.12; 95% CI 0.02-0.63; p = 0.013) and any bleeding in active cancer patients (RR 0.87; 95% CI 0.77-0.98; p = 0.026). Furthermore, DOXaI significantly reduced the composite endpoints of major bleeding and stroke or SE in overall cancer population (RR 0.78; 95% CI 0.64-0.94; p = 0.008). Conclusions Our metanalysis shows that, in patients with atrial fibrillation and cancer, DOXaI are safer and have a similar efficacy compared with warfarin. Abstract Figure. Primary efficacy and safety outcomes

Incidence of residual perfusion defects by lung scintigraphy in patients treated with rivaroxaban compared with warfarin for acute pulmonary embolism

Residual perfusion defects (RPD) as detected by lung scintigraphy occur in over 50% of patients with acute pulmonary embolism (PE) treated with vitamin K antagonists but there is lack of data in patients treated with direct oral anticoagulants. The aim of this retrospective study was to estimate the incidence of RPD detected by ventilation perfusion (VQ) scan at 3-6 months in patients with first acute symptomatic PE treated with rivaroxaban compared to warfarin. Consecutive eligible patients treated with rivaroxaban as part of a previous study were identified. The Monash Health Radiology database was used to identify a historical cohort of age matched (± 5 years) patients treated with warfarin. Follow-up VQ scans were classified as normal (no perfusion defect) or abnormal (matched or unmatched perfusion defects) by two independent nuclear medicine physicians blinded to treatment. Any disagreement was resolved by consensus. One hundred and ninety patients with PE (95 in each cohort) were included (mean age 56.8 years; 41.1% males; 54.2% unprovoked). In the overall cohort, 31.1% had RPD with a significantly lower incidence of RPD in rivaroxaban treated patients 23.2% (95% CI 15.8-32.6), compared to warfarin 38.9% (95% CI 29.8-49.0). Treatment with rivaroxaban was associated with a significantly lower incidence of RPD detected by VQ scan at 3-6 months compared to warfarin. This supports recent in-vitro data suggesting an indirect enhancement of fibrinolysis by direct oral Xa inhibitors but requires confirmation in larger studies.

Effects of the oral, direct factor Xa inhibitor edoxaban on routine coagulation assays, lupus anticoagulant and anti-Xa assays

Edoxaban is an oral direct factor Xa inhibitor for prophylaxis and treatment of thromboembolic disorders. The effects on common coagulation assays are clinically valuable information and in certain clinical situations a quick assessment of the anticoagulant is wanted. Our aim was to investigate the effect of edoxaban on routine coagulation methods and evaluate anti-Xa assays, commonly used for other direct factor Xa inhibitors, for estimation of the drug concentration. Edoxaban was spiked to plasma samples from healthy subjects in the concentration range 0–742 µg/L and analyzed using different reagents for activated partial thromboplastin time (APTT) and prothrombin time (PT). Assays for antithrombin, activated protein C resistance, lupus anticoagulant (LA) and chromogenic anti-Xa assays were also included. Edoxaban displayed similar effects in vitro to other oral direct Xa inhibitors. The concentration needed to double the coagulation time varied between assays and reagents; 539–758 µg/L for the APTT and between 329 and 2505 µg/L for the PT. Edoxaban gave false high antithrombin activities in assays based on Xa-inhibition. Two integrated assays for LA, both based on activation with dilute Russell’s viper venom, displayed different results. Chromogenic anti-Xa assays displayed linear dose-response curves with edoxaban up to approximately 500 µg/L. In conclusion, therapeutic concentrations of edoxaban variably affect different coagulation assays, and even different reagents within an assay group. In comparison with other oral Xa-inhibitors, the in vitro effects of edoxaban were more similar to rivaroxaban than apixaban. For measurement of edoxaban concentration in plasma, it is possible to use the chromogenic anti-Xa assays.

Low molecular weight heparin versus rivaroxaban in the treatment of venous thromboembolism in gastrointestinal malignancies

: Due to their ease of use, the direct oral anticoagulants (DOACs) are an attractive treatment option for cancer-associated venous thromboembolism (VTE) and have been readily adopted by many clinicians. A recent published study comparing a DOAC (edoxaban) to the current standard-of-care low molecular weight heparin dalteparin for the treatment of cancer-associated thrombosis showed that edoxaban was noninferior to dalteparin for recurrent VTE, but the risk of major bleeding was higher. We present three patients with high-risk gastrointestinal malignancies complicated by cancer-associated VTE with progression of thrombosis while treated with the oral direct Xa inhibitor rivaroxaban. Upon switching therapy to low molecular weight heparin, we found that these patients had clinical and radiologic improvement of VTE. More studies are needed to evaluate the efficacy of rivaroxaban in high-risk gastrointestinal-VTE. We suggest that in some patients, DOACs may not be sufficient for the treatment of VTEs related to high-risk gastrointestinal malignancies.

Comparative effectiveness of venous thromboembolism prophylaxis options for the patient undergoing total hip and knee replacement: a network meta‐analysis

Background There are numerous trials and several meta-analyses comparing venous thromboembolism (VTE) prophylaxis options after total hip and knee replacement (THR and TKR). None have included simultaneous comparison of new with older options. Objective To measure simultaneously the relative risk of VTE and hemorrhage for 12 prophylaxis options. Methods We abstracted VTE and hemorrhage information from randomized controlled trials published between January 1990 and June 2016 comparing 12 prophylaxis options. We then constructed networks to compute the relative risk for each option, relative to once-daily dosing with low-molecular-weight heparin (LMWH) Low. Results Main: Relative to LMWH Low, direct oral Xa inhibitors had the lowest risk of total deep vein thrombosis (DVT)-asymptomatic and symptomatic- (odds ratio [OR], 0.45; 95% confidence interval [CI], 0.35-0.57), translating to 53-139 fewer DVTs per 1000 patients. Vitamin K antagonists (VKAs) titrated to International Normalized Ratio [INR] 2-3 predicted 56% more DVT events (OR, 1.56; 95% CI, 1.14-2.14). Aspirin performed similarly (OR, 0.80; 95% CI, 0.34-1.86), although small numbers prohibit firm conclusions. Direct oral Xa inhibitors did not lead to significantly more bleeding (OR, 1.21; 95% CI, 0.79-1.90). Secondary: Relative to LMWH Low, direct oral Xa inhibitors prevented 4-fold more symptomatic DVTs (OR, 0.25; 95% CI, 0.13-0.47). Conclusions Relative to LMWH Low, direct oral Xa inhibitors had a more favorable profile of VTE and hemorrhage risk, whereas VKAs had a less favorable profile. The profile of other agents was not more or less favorable. Clinicians should consider these profiles when selecting prophylaxis options.

Edoxaban: A Comprehensive Review of the Pharmacology and Clinical Data for the Management of Atrial Fibrillation and Venous Thromboembolism.

Historically, vitamin K antagonists have been the only class of oral anticoagulants available. Despite our experience with warfarin over the past 60 years, its use is associated with several pharmacokinetic and clinical disadvantages including unpredictable dosing, frequent monitoring, and delayed onset and offset. Edoxaban, an oral direct Xa inhibitor, may provide clinicians with an additional option in patients requiring chronic anticoagulation. This review examines the pharmacology and clinical data of edoxaban as a therapeutic alternative.

Efficacy and Safety of Four Factor Prothrombin Complex Concentrates As a Reversal Agent for Oral Xa Inhibitors

INTRODUCTION: FDA had approved three oral Xa inhibitors (OXI) Rivaroxaban (R), Apixaban (A) and Edoxaban for the treatment of venous thromboembolism (VTE) and cardiac thromboembolism prophylaxis in patients with non-valvular atrial fibrillation (NV A fib). The incidence of major bleeding and intracranial hemorrhage (ICH) is lesser with OXI's compared to warfarin but due to lack of appropriate reversal agents, management of such situations are very difficult. In the healthy human volunteer studies Andexanet alfa, Activated or non-activated prothrombin complex concentrates (PCC) and recombinant factor VIIa have been studied but there is lack of good real time data due to which practices are diverse. KCentra (K) was FDA approved in 2013 for urgent reversal of warfarin in cases of acute major bleeding or emergent surgery and consists of inactive factors II, VII, IX, X, Protein C and Protein S. Our institution uses Kcentra to reverse OXIs starting in November 2014.METHODS: After IRB approval, all requests for KCentra from November 2014 to June 2015 were reviewed. For patients who were on an OXI and had acute life threatening bleeding or needed urgent surgery, the following variables were analyzed: demographics, clotting assays, dose and type of OXI, length of hospital stay, mortality, thrombotic events and medications.RESULTS: 12 requests for Kcentra were placed and at physicians discretion ten patients ultimately received it of which none died during that hospitalization. One of the two patients who didn't receive rapidly died (hepatic bleeding). Results include: Median age of 74 years (65-86 y), 6 were male (50%). Indications for OXI therapy- NV A fib (n=6), unprovoked VTE (n=2), provoked VTE (n=1), cancer associated VTE (n=1). The OXIs used were R (n=5) and A (n=5). Median time of administration of K from the last intake of the drug was 10 hours (8-15 h) and median length of hospital stay was 8 days (4-26). In 9 patients with available data, the pre-K median INR and PT was 1.4 (1.1-2.5)/20.6 s (11.8- 21.8s) and the median post-K INR and PT was 1.1 (1-1.8), 16.9 s (13.4-30.2 s), median activated partial thromboplastin time (aPTT) before K is 30.6 s (27.5-40.2 s). Anti Xa activity was tested in only 3 patients before K administration with a median of 0.66 IU/mL (0.54-1.48) and In 2 patients after K with a mean of 0.51 (0.32-0.71). Indications included emergent surgery in two (20%), ICH (20%)-1 spontaneous subdural hemorrhage (SDH) and 1 SDH after fall, 1 patient each on A and R, gastrointestinal bleeding (30%)- 1 gastric ulcer, 1 diverticular bleeding and 1 spontaneous with 2 of these 3 patients on R, Trauma (30%) causing spinal fractures (n=2) and hepatic bleeding (n=1). Median estimated glomerular filtration rate (eGFR), AST and ALT at the time of bleeding were 62 ml/min, 24 U/L and 17 U/L respectively. Median number of packed red blood cells (PRBC) transfused was 3 U with median hemoglobin at admission of 8.9 gm/dL (7-13.3) and median platelet count of 195 x10E3/cmm (163-356). The median K dose was 25 U/kg once (25-50) and one patient (10%) had acute VTE 14 days after administration (Lower extremity femoral DVT. 6 patients were on Aspirin (60%), 7 on p-glycoprotein (p-gp) inhibitors (70%), 3 (30%) on p-gp substrates & 2 (20%) on Selective Serotonin Reuptake Inhibitors.CONCLUSION: Kcentra use was observed to be safe as a reversal agent with acceptable risk of thrombosis. Advanced age, concurrent use of P-glycoprotein inhibitors, antiplatelet agents appear to be risk factors for bleeding and use of OXI's with such risk factors should be cautioned.TableAgeSexIndication of A/CDrugHospital daysIndication for Kcentra# of PRBCASAP-gp-XP-gp used64MNV AfibRivaroxaban 20 mg QD7Spontaneous SDH0YesYesAtorvastatin65MUnprovokedVTE/PERivaroxaban 20 mg QD9Trauma-Liver cyst rupture1NoNoNo76FProvokedVTERivaroxaban 20 mg QD4Spontaneous GI bleeding Diverticular7NoNoNo70MCancer AssociatedVTERivaroxaban 20 mg QD9Bleeding penile cancer-surgery4YesYesEsomeprazolePravastatin74MUnprovokedVTERivaroxaban 20 mg QD5GI bleeding-gastric ulcer3NoNoNo84FNV AfibApixaban5 mg BID4Fall-SDH0YesYesPropafenone73FNV AfibApixaban5 mg BID26Fall-Spinal trauma2NoYesOmeprazole68MNV AfibApixaban5 mg BID13Surgery-Type A Aortic aneurysm6YesYesAmiodoroneSimvastatin84FNV AfibApixaban5 mg BID23Trauma-Facial/spine fracture3YesYesPravastatin86MNV AfibApixaban5 mg BID5Spontaneous GI bleeding6YesYesAmiodorone DisclosuresOff Label Use: Kcentra is not FDA approved as a reversal agent for oral direct Xa inhibitors.

Rivaroxaban

Rivaroxaban

Laboratory Assays for Monitoring Rivaroxaban: In House in-Vitro Analysis and Review of Literature

Abstract 4320 Introduction:Rivaroxaban an oral direct Xa inhibitor has recently been approved for VTE prophylaxis. It doesn't require monitoring but in special circumstances like bleeds a monitoring tool will be useful. Also, it is prudent to know its effect on various routine coagulation tests. Currently, there is no commercially available method for monitoring of Rivaroxaban. Aim: We conducted an In house- in-vitro analysis to (a)determine the effects of rivaroxaban locally on a range of commercially available coagulation assays, lupus anticoaugulant, factor VIII level, thrombin generation time and (b) measure it by two anti-Xa assays. Materials: Rivaroxaban (Xeralto) tablet, strength-10 mg. Plasma samples: Citrated normal human platelet poor plasma procured and freezed at −70 degree centigrade, Baxter sterile water. Method:The tablet was dissolved over 72 hours in a litre of sterile water to make 10 ug/ml of solution. Despite stirring a fine particulate compound remained which settled on standing. Samples were vortexed prior to each assay. This stock solution was used to spike citrated normal human platelet-poor plasma (PPP) at increasing concentrations of rivaroxaban from 0.1,0.2, 0.3, 0.4, upto 0.5 ug/ml to see the effect on the following tests and to determine rivaroxaban concentration by two 1.anti-Xa methods. All method were run using standard protocols taken from manufacturers' instructions.Anti-Xa assay:a) BIOPHEN DiXaI kit for 2-stage chromogenic assay of Direct Xa inhibitors; Ref 221030 b) Rotachrome using 1:2 dilution and further using 1:10 and 1:20 dilutions; catalogue Number-00612.2.PT & INR (STAGO neoplastin CI Plus MNPT-13.2 s, ISI-1.30 s).3.aPTT (Triniclot aPTT reagent)4.LAC-dRVVT screening and confirm (STAGO).5.Factor VIII assay (Siemens- Factor VIII deficient plasma)6. TT (STAGO-Thrombin)7. Factor VIII assay- Helena SARP.8.TGT: Thrombinoscope 5 picomolar TF and standard CAT method.Values described for Xarelto/ Rivaroxaban on patients with thromboprophylaxis in orthopedic surgery are usually of about 0.1–0.2 ug /ml in plasma.Result & Discussion: Concentration dependent prolongation of PT was observed. We used a single reagent (STAGO neoplastin CI Plus) which was sensitive at 0.1ug/ml concentration. Samama et al found that the results of PT were variable with reagent and not corrected by conversion to INR.We found that aPTT at lower concentrations of Rivaroxaban was not significantly different. Hillarp et al used five different reagents and found a reagent dependent dose response of APTT to rivaroxaban.The effect on Thrombin Time was non concentration dependent with no prolongation of TT at lower levels.There was fall in FVIII level in concentration dependent manner with 35% fall at 0.5ug/ml. We did not come across any literature till date about FVIII levels in Rivaroxaban therapy and our conclusion emphasises the importance of drug history.The LAC by DRVVT test showed positive result at the lowest concentration with an ILR of 1.23 and a dose dependent prolongation of clotting time. Thus making thrombophilia screening difficult.Thrombin generation time showed dose dependent effect on all parameters with almost complete suppression of thrombin generation. The initiation and propagation phase of TGT was affected at the lowest concentration (Green et al).The two anti-Xa tests used for measuring the concentration of Rivaroxaban in spiked plasma showed that Biophen DiXAI method has a broad range of sensitivity (0.1–0.5ug/ml) with calibration curve almost identical to that of manufacturer's with an excellent R value through out.The Rotachrome method at the standard 1:2 dilution was unable to measure concentration beyond 0.2ug/ml and at 1:20 dilution could only measure upto 0.4ug/ml. Thus, this method needs modification to determine a broad range of concentration.There was a variable result with 0.5ug/ml concentration of Rivaroxaban despite repeated vortex with unclear cause. This could be due to instability or settling of non-dissolved particles of the sample.The calibration curves were linear throughout with an acceptable R-value but there was a progressive drop in assay over a period of time. Conclusion:Anti-Xa assay with Biophen DiXAI method is a promising candidate for measurement of concentration of Rivaroxaban in special circumstances. Our findings show a trend towards prolongation of global clotting assays. The tablet is not stable as a calibrator. Disclosures:Pathak: BIOPHEN-DIXAI: Research Funding. McRae:BIOPHEN-DIXAI: Research Funding.

Rivaroxaban (Xarelto®) : efficacité et tolérance

The oral direct Xa inhibitor rivaroxaban (Xarelto) shows great promise for prevention of venous thromboembolic events after major elective orthopedic surgery. Its consistent and predictable pharmacokinetics and pharmacodynamics across a wide range of patient populations allow administration with fixed dosing and with no coagulation monitoring. In 4 orthopaedic surgery clinical trials (12,700 patients), 10mg postoperative (6-10 hours after the end of surgery) dose, once daily, of oral rivaroxaban, achieved superior efficacy and similar safety to enoxaparin, whatever the dose of enoxaparin. Indeed, 40 mg once a day in Europe and 30 mg bid in US of enoxaparin were compared to the same dose of 10mg once daily of rivaroxaban. Furthermore, there is no difference according to liver enzymes elevation and cardio-vascular adverse events. Although the risk of spinal haematoma after neuraxial anaesthesia is rare, it is increased by concomitant use of anticoagulants. In orthopedic surgery trials with rivaroxaban to date, complications such as spinal haematoma have not been reported. The pharmacokinetic profile of rivaroxaban suggests that concurrent use with neuraxial anaesthesia should require no further precautions than currently necessary with low-molecular-weight heparin.