Routine Coagulation Monitoring Research Articles

Rivaroxaban for Treatment of Suspected or Confirmed Heparin-Induced Thrombocytopenia Study

▪Rivaroxaban is an ideal potential alternative for treatment of heparin-induced thrombocytopenia because it is administered orally by fixed dosing, requires no routine coagulation monitoring and has been proven effective in the treatment of venous and arterial thromboembolism in other settings. The Rivaroxaban for HIT Study prospectively evaluated the efficacy and safety of patients with suspected or confirmed HIT who were treated with rivaroxaban [NCT01598168 - investigator sponsored study funded by Bayer]Methods: Canadian multicenter, single-arm, prospective cohort study of patients with confirmed or suspected HIT (4Ts score ≥4) treated with rivaroxaban 15 mg bid until the diagnosis was supported or refuted using the local HIT assay. Participants with HIT (positive local assay result) received rivaroxaban 15 mg bid until platelet recovery (or until Day 21 if the patient had acute thrombosis; HITT) then stepped down to rivaroxaban 20 mg daily until Day 30. Central testing with the serotonin-release assay (SRA) was performed (not in real-time at all centres). HIT positive was defined as a 4Ts score ≥4 plus serotonin release ≥50%.The primary outcome measure was the incidence of new symptomatic, objectively-confirmed venous and arterial thromboembolism in the combined cohort of patients with suspected and confirmed HIT at 30 days. Secondary objectives included incidence of symptomatic thromboembolism while on treatment with rivaroxaban (combined cohort) and the following outcomes among SRA-positive participants while on treatment with rivaroxaban: incidence of venous and arterial thromboembolism, incidence of major bleeding, and time to platelet recovery.Sample size of 200 participants (10 to 30 with SRA-confirmed HIT) was based on feasibility and an anticipated thrombotic event rate in the study population (combined cohort) of 6.5% at 30 days (5% in HIT negative; 11% in HIT positive while on rivaroxaban).Results: 22 participants (12 HIT positive) were enrolled between January 2013 and July 2015. The study was terminated early due to poor recruitment, but after enrolling the minimum expected number of HIT positive participants. Of the 12 HIT positive participants (SRA, mean release 95%), 3(25%) had HITT at time of study entry and 6 had received at least one dose of fondaparinux prior to study enrolment. Half of the HIT positive participants were enrolled in study after the SRA result had already been reported as positive.After 371 days of exposure to rivaroxaban (combined cohort), 1 HIT positive participant had possible symptomatic recurrent VTE (4.5%, 95% CI: 0 to 23.5%), 1 HIT positive participant had major bleeding (9 days after rivaroxaban was held) and there were 4 deaths (cancer 2, sepsis 1, end-stage COPD 1).The single episode of possible recurrent VTE was extension of previously documented apheresis catheter-related arm DVT in a HIT positive participant who presented on Day 7 with worsening arm pain. A repeat ultrasound showed extension of DVT; however a baseline scan had not been performed at time of study entry. Interestingly, the same participant failed treatment with fondaparinux prior to study enrolment (development of erythematous plaques at injection sites and failure of platelets to rise). His apheresis catheter was removed on Day 8, rivaroxaban was continued and complete resolution of his symptoms as well as platelet recovery was achieved.One HIT positive participant presented with evidence of bilateral lower limb arterial ischemia (HIT-related acute arterial thrombosis on documented chronic peripheral vascular disease) at the time of study enrolment. Despite achieving platelet recovery, he underwent bilateral below knee amputation on Day 16.Out of the 12 HIT positive participants, 11 achieved platelet recovery with mean time to recovery 9 days. The single participant who did not achieve platelet recovery received only 2 doses of rivaroxaban before it was held due to a transient rise in liver enzymes. Rivaroxaban was never restarted because he bled while receiving fondaparinux as an alternative.Conclusions: Rivaroxaban appears to be effective for treating patients with confirmed HIT, although lack of a comparator and a small sample size are limitations of our findings. The advantages of rivaroxaban over other agents currently used to treat HIT such as ease of administration, lack of routine coagulation monitoring and low cost make it an attractive option. DisclosuresLinkins:Pfizer: Honoraria; Bayer: Honoraria, Research Funding. Off Label Use: rivaroxaban has not been approved for treatment of heparin-induced thrombocytopenia. Warkentin:W.L. Gore: Consultancy, Research Funding; Instrumentation Laboratory: Consultancy, Honoraria; Pfizer: Consultancy. Pai:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS-Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Shivakumar:Bayer: Honoraria. Wells:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS-Pfizer: Research Funding. Wu:Pfizer Canada: Membership on an entity's Board of Directors or advisory committees; Leopharma: Membership on an entity's Board of Directors or advisory committees.

Edoxaban: A Review in Deep Vein Thrombosis and Pulmonary Embolism.

Edoxaban (Lixiana, Savaysa) is an oral, direct factor Xa inhibitor which has recently been approved for use in the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) [collectively, venous thromboembolism (VTE)] and for the prevention of recurrent VTE. This article reviews the pharmacological properties of edoxaban as well as its tolerability and therapeutic efficacy in the treatment and prevention of recurrent VTE events. As demonstrated in the pivotal Hokusai-VTE phase III trial, once-daily edoxaban after initial treatment with heparin was non-inferior to standard therapy with heparin/warfarin in preventing recurrent VTE events and was associated with a significantly lower risk of clinically relevant bleeding than the traditional therapy. Edoxaban shares the advantages of other direct oral anticoagulants (DOACs) over traditional therapies, including the lack of requirement for routine coagulation monitoring, a rapid onset and offset of action, and few drug-drug interactions. It offers the convenience of once-daily dosing, can be taken without regard to food and allows for a dose reduction in patients with certain clinical features, such as moderate renal impairment or low body weight. In conclusion, edoxaban represents an effective and potentially safer alternative to traditional vitamin K antagonist therapy for the treatment and prevention of recurrent VTE. Its recent approval expands the range of DOAC agents for recurrent VTE, further facilitating treatment individualization.

Laboratory measurement of the direct oral anticoagulants.

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor, dabigatran, and the direct factor Xa (FXa) inhibitors, rivaroxaban, apixaban and edoxaban, are approved for thromboembolism prevention and treatment. These drugs do not require routine coagulation monitoring but, in some circumstances, measurement of drug level or anticoagulant effect may be necessary. Although traditional coagulation tests lack analytical sensitivity and specificity, they are widely available and inexpensive, and can provide useful information regarding the residual anticoagulant effect of DOACs. Hemoclot® and ecarin-based assays can be used to quantify dabigatran level and calibrated chromogenic anti-FXa assays are suitable for measuring rivaroxaban, apixaban and edoxaban levels, but these tests are not yet widely available.

Management of Bleeding Associated with New Oral Anticoagulants

In the last few years, a great improvement in the management of clinical thromboembolism has been made thanks to the availability of novel oral anticoagulants. These drugs, which act by directly inhibiting thrombin (dabigatran) or activated factor X (apixaban, rivaroxaban, and edoxaban), offer several practical advantages over the traditional vitamin K antagonists (VKA), such as a more predictable anticoagulant effect with no need for routine coagulation monitoring and a limited drug and food interaction. Several phase III clinical trials have now been completed, overall demonstrating that non-VKA oral antagonists (NOACs) are at least as efficacious and safe as VKA in the prevention and treatment of thromboembolism. Nevertheless, patients receiving NOACs represent a new challenge because no antidotes are currently available for these drugs. In this review, after a description of the main pharmacologic characteristics and the main results of the clinical trials of NOACs, we will focus on the management of bleeding associated with these anticoagulant agents. A treatment algorithm of NOACs-associated bleeding is finally provided, with the aim of helping physicians in their daily care activity.

Diluted thrombin time reliably measures low to intermediate plasma dabigatran concentrations.

Direct oral anticoagulant dabigatran was first introduced as a fixed-dose drug without routine coagulation monitoring, but current recommendations suggest that diluted thrombin time can be used to estimate plasma drug level. The aim of this study was to assess a diluted thrombin time assay based on the same thrombin reagent already used for traditional thrombin time measurements that reliably measure low to intermediate plasma dabigatran levels. We included 44 patients with atrial fibrillation who started treatment with dabigatran 150 mg (23 patients) or 110 mg (21 patients) twice a day. Blood samples were collected at baseline (no dabigatran) and 2-4 weeks after the beginning of dabigatran therapy at trough and at peak. Plasma dabigatran levels were measured with diluted thrombin time and compared to liquid chromatography with tandem mass spectrometry as the reference method. The performance of the diluted thrombin time was compared to Hemoclot® Thrombin Inhibitor and Ecarin Chromogenic Assay. In ex vivo plasma samples, diluted thrombin time highly correlated with the liquid chromatography with tandem mass spectrometry (Pearson's R = 0.9799). In the low to intermediate range (dabigatran concentration ≤ 100 µg/L) diluted thrombin time correlated significantly more closely to the liquid chromatography with tandem mass spectrometry (R = 0.964) than Hemoclot® Thrombin Inhibitor (R = 0.935, p = 0.05) or Ecarin Chromogenic Assay (R = 0.915, p < 0.01). It was also the only functional assay without any significant bias in the low to intermediate range. Both trough and peak diluted thrombin time values were similar to liquid chromatography with tandem mass spectrometry. We conclude that the diluted thrombin time assay presented in this study reliably detects dabigatran and that it is superior to the Hemoclot® Thrombin Inhibitor assay in the low to intermediate range.

Clinical implication of monitoring rivaroxaban and apixaban by using anti-factor Xa assay in patients with non-valvular atrial fibrillation

BackgroundAlthough patients taking non-vitamin K antagonist oral anticoagulants (NOACs) do not require routine coagulation monitoring, high-risk patients require monitoring to assess pharmacodynamics. MethodsWe measured (1) anti-factor Xa activity (AXA), using chromogenic assay with the HemosIL Liquid Heparin kit, (2) prothrombin time (PT), and (3) activated partial thromboplastin time (aPTT) in 188 blood samples from 70 patients with non-valvular atrial fibrillation, of whom 36 received rivaroxaban once daily and 34 received apixaban twice daily. ResultsAfter the rivaroxaban therapy, AXA ranged from 0 to 3.65IU/mL; PT, from 9.6 to 44.5s; and APTT, from 19.3 to 69.7s. After the apixaban therapy, AXA ranged from 0.02 to 3.18IU/mL; PT, from 10.2 to 20.8s; and APTT, from 21.8 to 59.8s. At peak time, the AXA of patients who received rivaroxaban and apixaban were almost the same (2.08±0.91IU/mL vs. 1.71±0.57IU/mL), but the PT and APTT of patients who received rivaroxaban were more prolonged than those of patients who received apixaban (18.1±5.6s vs. 13.8±0.9s, p<0.001 and 40.9±7.3s vs. 35.5±7.5s, p<0.01, respectively). At trough time, the AXA and PT of patients who received rivaroxaban were respectively lower and shorter than those of patients who received apixaban (0.28±0.31IU/mL vs. 1.04±0.72IU/mL, p<0.001 and 11.9±2.0s vs. 13.7±2.4s, p<0.01, respectively), but the APTT of patients who received rivaroxaban and apixaban did not significantly differ (32.3±4.3s vs. 34.3±3.8s). ConclusionsMeasurement of AXA might be useful to assess the pharmacodynamics of high-risk patients, such as high age, low body weight, and/or low renal function, and to assess the intensity of anticoagulation by using different methods of administration, such as crushed tablet via the nasogastric tube.

How to Monitor Patients Receiving Direct Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Practice Tool Endorsed by Thrombosis Canada, the Canadian Stroke Consortium, the Canadian Cardiovascular Pharmacists Network, and the Canadian Cardiovascular Society

Ideas and Opinions1 September 2015How to Monitor Patients Receiving Direct Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Practice Tool Endorsed by Thrombosis Canada, the Canadian Stroke Consortium, the Canadian Cardiovascular Pharmacists Network, and the Canadian Cardiovascular SocietyDavid J. Gladstone, MD, PhD, William H. Geerts, MD, James Douketis, MD, Noah Ivers, MD, PhD, Jeff S. Healey, MD, and Kori Leblanc, PharmDDavid J. Gladstone, MD, PhDFrom the University of Toronto Department of Medicine; Sunnybrook Regional Stroke Prevention Clinic, Hurvitz Brain Sciences Program, Dr. Thomas and Harriet Black Rapid TIA Clinic, and Anticoagulant Management Clinic and Thromboembolism Service, Sunnybrook Health Sciences Centre; University of Toronto Stroke Program; Family Practice Health Centre, Women's College Research Institute, and Institute for Health Systems Solutions and Virtual Care, Women's College Hospital;and University Health Network and OpenLab, University Health Network, Toronto, Ontario, Canada, and McMaster University, Population Health Research Institute, and Canadian Stroke Prevention Intervention Network, Hamilton, Ontario, Canada.Search for more papers by this author, William H. Geerts, MDFrom the University of Toronto Department of Medicine; Sunnybrook Regional Stroke Prevention Clinic, Hurvitz Brain Sciences Program, Dr. Thomas and Harriet Black Rapid TIA Clinic, and Anticoagulant Management Clinic and Thromboembolism Service, Sunnybrook Health Sciences Centre; University of Toronto Stroke Program; Family Practice Health Centre, Women's College Research Institute, and Institute for Health Systems Solutions and Virtual Care, Women's College Hospital;and University Health Network and OpenLab, University Health Network, Toronto, Ontario, Canada, and McMaster University, Population Health Research Institute, and Canadian Stroke Prevention Intervention Network, Hamilton, Ontario, Canada.Search for more papers by this author, James Douketis, MDFrom the University of Toronto Department of Medicine; Sunnybrook Regional Stroke Prevention Clinic, Hurvitz Brain Sciences Program, Dr. Thomas and Harriet Black Rapid TIA Clinic, and Anticoagulant Management Clinic and Thromboembolism Service, Sunnybrook Health Sciences Centre; University of Toronto Stroke Program; Family Practice Health Centre, Women's College Research Institute, and Institute for Health Systems Solutions and Virtual Care, Women's College Hospital;and University Health Network and OpenLab, University Health Network, Toronto, Ontario, Canada, and McMaster University, Population Health Research Institute, and Canadian Stroke Prevention Intervention Network, Hamilton, Ontario, Canada.Search for more papers by this author, Noah Ivers, MD, PhDFrom the University of Toronto Department of Medicine; Sunnybrook Regional Stroke Prevention Clinic, Hurvitz Brain Sciences Program, Dr. Thomas and Harriet Black Rapid TIA Clinic, and Anticoagulant Management Clinic and Thromboembolism Service, Sunnybrook Health Sciences Centre; University of Toronto Stroke Program; Family Practice Health Centre, Women's College Research Institute, and Institute for Health Systems Solutions and Virtual Care, Women's College Hospital;and University Health Network and OpenLab, University Health Network, Toronto, Ontario, Canada, and McMaster University, Population Health Research Institute, and Canadian Stroke Prevention Intervention Network, Hamilton, Ontario, Canada.Search for more papers by this author, Jeff S. Healey, MDFrom the University of Toronto Department of Medicine; Sunnybrook Regional Stroke Prevention Clinic, Hurvitz Brain Sciences Program, Dr. Thomas and Harriet Black Rapid TIA Clinic, and Anticoagulant Management Clinic and Thromboembolism Service, Sunnybrook Health Sciences Centre; University of Toronto Stroke Program; Family Practice Health Centre, Women's College Research Institute, and Institute for Health Systems Solutions and Virtual Care, Women's College Hospital;and University Health Network and OpenLab, University Health Network, Toronto, Ontario, Canada, and McMaster University, Population Health Research Institute, and Canadian Stroke Prevention Intervention Network, Hamilton, Ontario, Canada.Search for more papers by this author, and Kori Leblanc, PharmDFrom the University of Toronto Department of Medicine; Sunnybrook Regional Stroke Prevention Clinic, Hurvitz Brain Sciences Program, Dr. Thomas and Harriet Black Rapid TIA Clinic, and Anticoagulant Management Clinic and Thromboembolism Service, Sunnybrook Health Sciences Centre; University of Toronto Stroke Program; Family Practice Health Centre, Women's College Research Institute, and Institute for Health Systems Solutions and Virtual Care, Women's College Hospital;and University Health Network and OpenLab, University Health Network, Toronto, Ontario, Canada, and McMaster University, Population Health Research Institute, and Canadian Stroke Prevention Intervention Network, Hamilton, Ontario, Canada.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M15-0143 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Anticoagulation for atrial fibrillation with direct oral anticoagulants (DOACs)—apixaban, dabigatran, edoxaban, and rivaroxaban—is one of the most powerful stroke prevention interventions (1) and is now being prescribed to millions worldwide. Guidelines, however, have focused primarily on patient selection and therapy initiation, with little guidance on patient follow-up and monitoring for these long-term therapies. Given the increasing use of these agents, their associated risks for bleeding and nonadherence (one quarter of patients in recent reports was less than 80% adherent [2–4]), the absence of routine coagulation monitoring, and variable follow-up practices, we advocate regular, standardized clinical monitoring of patients receiving these ...

Cost-effectiveness analysis of treatment of venous thromboembolism with rivaroxaban compared with combined low molecular weight heparin/vitamin K antagonist.

BackgroundVenous thromboembolism (VTE) is a burden on healthcare systems. Standard treatment involves parenteral anticoagulation overlapping with a vitamin K antagonist, an approach that is effective but associated with limitations including the need for frequent coagulation monitoring. The direct oral anticoagulant rivaroxaban is similarly effective to standard therapy as a single-drug treatment for VTE and does not require routine coagulation monitoring. The objective of this economic evaluation was to estimate the cost-effectiveness of rivaroxaban compared with standard VTE treatment from a UK perspective.MethodsA Markov model was constructed using data and probabilities derived from the EINSTEIN DVT and EINSTEIN PE studies of rivaroxaban and other published sources. Health outcomes included VTE rates, bleeding events avoided, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs).ResultsThere was greater discounted quality-adjusted life expectancy with rivaroxaban than with standard therapy, irrespective of indication and treatment duration. Rivaroxaban was associated with per-patient cost savings for each treatment duration modelled (3, 6 and 12 months), and these were greatest with shorter durations. Rivaroxaban was found to be dominant (cheaper and more effective) and, therefore, cost-effective, in both patients with deep vein thrombosis and pulmonary embolism in all three treatment duration groups, and was also cost-effective in patients requiring lifelong anticoagulation (ICERs: £8677 per QALY and £7072 per QALY in patients with index deep vein thrombosis and pulmonary embolism, respectively). The cost-effectiveness of rivaroxaban was largely insensitive to variations in one-way sensitivity analysis. Probabilistic sensitivity analysis demonstrated that at a threshold of £20,000 per QALY, rivaroxaban had a consistent probability of being cost-effective, compared with LMWH/VKA treatment, of around 80% regardless of index VTE or duration of anticoagulation therapy (3, 6, 12 months or lifelong).ConclusionsThis analysis suggests that rivaroxaban represents a cost-effective choice for acute treatment of deep vein thrombosis and pulmonary embolism and secondary prevention of VTE in the UK, compared with LMWH/VKA treatment, regardless of the required treatment duration.Electronic supplementary materialThe online version of this article (doi:10.1186/s12959-015-0051-3) contains supplementary material, which is available to authorized users.

Rivaroxaban for the treatment and prevention of thromboembolic disease.

A number of direct oral anticoagulants are now available and offer alternative strategies for anticoagulation therapy. Rivaroxaban, a direct oral Factor Xa inhibitor, is approved for use across several thromboembolic indications. This article aims to provide an overview of the key pharmacological characteristics of rivaroxaban and the rationale and evidence for the use of different dose regimens across its licenced indications, and offer practical guidance to healthcare professionals on responsible use. References were sourced via PubMed searches using the search string (rivaroxaban AND (pharmacokinetics OR pharmacodynamics OR (clinical studies) OR (drug interaction)) NOT review NOT (children OR pediatrics OR paediatrics OR adolescent)). Rivaroxaban exhibits predictable pharmacokinetics and pharmacodynamics, and thus does not require routine coagulation monitoring, unlike vitamin K antagonists (e.g. warfarin). Rivaroxaban also has a lower potential for drug-drug and food-drug interactions compared with warfarin; however, co-administration with strong inhibitors of both cytochrome P450 3A4 and P-glycoprotein is not recommended. The data indicate that dose adjustment is not necessary for age, gender or body weight. The dosing regimens of rivaroxaban vary depending on the indication, and phase III studies have demonstrated a favourable benefit-risk profile of rivaroxaban compared with traditional standard of care. Rivaroxaban may offer an anticoagulant option that could simplify and improve the management of patients with thromboembolic disorders.

Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism.

Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a common and potentially preventable cause of morbidity and mortality. Unfractionated heparin, low-molecular-weight heparin, and warfarin have been the cornerstone of VTE prevention and treatment but are being replaced by recently approved non-vitamin K antagonist oral anticoagulants (NOACs): dabigatran, rivaroxaban, apixaban, and edoxaban. The NOACs are at least as effective and as safe as heparins and warfarin for VTE prevention and treatment and are more convenient because they have a low propensity for food and drug interactions and are given in fixed doses without routine coagulation monitoring. The remaining limitations of currently available NOACs include their dependence on renal and hepatic function for clearance, and the lack of an approved antidote. Betrixaban is a new NOAC with distinct pharmacological characteristics: minimal renal clearance, minimal hepatic metabolism, and long half-life. It has undergone successful Phase II studies in orthopedic thromboprophylaxis, and in stroke prevention in atrial fibrillation. Currently, it is being evaluated in a Phase III trial of extended thromboprophylaxis in medical patients (APEX study). In this article, we describe the development of betrixaban, review its pharmacological profile, discuss the results of clinical trials, and examine its potential for VTE prevention and treatment.

Target-specific oral anticoagulants: should we switch from warfarin?

Target-specific oral anticoagulants: should we switch from warfarin?

Direct oral anticoagulants: key considerations for use to prevent stroke in patients with nonvalvular atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide. Strokes that occur as a complication of AF are usually more severe and associated with a higher disability or morbidity and mortality rate compared with non-AF-related strokes. The risk of stroke in AF is dependent on several risk factors; AF itself acts as an independent risk factor for stroke. The combination of effective anticoagulation therapy, risk stratification (based on stroke risk scores, such as CHADS2 and CHA2DS2-VASc), and recommendations provided by guidelines is essential for decreasing the risk of stroke in patients with AF. Although effective in preventing the occurrence of stroke, vitamin K antagonists (VKAs; eg, warfarin) are associated with several limitations. Therefore, direct oral anticoagulants, such as apixaban, dabigatran etexilate, edoxaban, and rivaroxaban, have emerged as an alternative to the VKAs for stroke prevention in patients with nonvalvular AF. Compared with the VKAs, these agents have more favorable pharmacological characteristics and, unlike the VKAs, they are given at fixed doses without the need for routine coagulation monitoring. It remains important that physicians use these direct oral anticoagulants responsibly to ensure optimal safety and effectiveness. This article provides an overview of the existing data on the direct oral anticoagulants, focusing on management protocols for aiding physicians to optimize anticoagulant therapy in patients with nonvalvular AF, particularly in special patient populations (eg, those with renal impairment) and other specific clinical situations.

Implementation of non-vitamin K antagonist oral anticoagulants in daily practice: the need for comprehensive education for professionals and patients.

Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used for the prevention and treatment of venous thromboembolism and for stroke prevention in patients with atrial fibrillation. NOACs do not require routine coagulation monitoring, creating a challenge to established systems for patient follow-up based on regular blood tests. Healthcare professionals (HCPs) are required to cope with a mixture of patients receiving either a vitamin K antagonist or a NOAC for the same indications, and both professionals and patients require education about the newer drugs. A European working group convened to consider the challenges facing HCPs and healthcare systems in different countries and the educational gaps that hinder optimal patient management. Group members emphasised the need for regular follow-up and noted national, regional and local variations in set-up and resources for follow-up. Practical incorporation of NOACs into healthcare systems must adapt to these differences, and practical follow-up that works in some systems may not be able to be implemented in others. The initial prescriber of a NOAC should preferably be a true anticoagulation specialist, who can provide initial patient education and coordinate the follow-up. The long-term follow-up care of patients can be managed through specialist coagulation nurses, in a dedicated anticoagulation clinic or by general practitioners trained in NOAC use. The initial prescriber should be involved in educating those who perform the follow-up. Specialist nurses require access to tools, potentially including specific software, to guide systematic patient assessment and workflow. Problem cases should be referred for specialist advice, whereas in cases for which minimal specialist attention is required, the general practitioner could take responsibility for patient follow-up. Hospital departments and anticoagulation clinics should proactively engage with all downstream HCPs (including pharmacists) to ensure their participation in patient management and reinforcement of patient education at every opportunity. Ideally, (transmural) protocols for emergency situations should be developed. Last but not least, patients should be well-informed about their condition, the treatment, possible risk scenarios, including the consequences of non-adherence to prescribed therapy, and the organisation of follow-up care.

The temporal pattern of postoperative coagulation status in patients undergoing major liver surgery

IntroductionAfter major liver surgery, there are risks of both postoperative bleeding and thrombosis. Routine coagulation monitoring is indicated, but may not provide adequate clinical guidance. Thus, we described the clotting status in a pilot study using broader coagulation testing. We analysed the temporal pattern of coagulation tests to assess whether thromboelastometry (ROTEM®) would improve the quality of the postoperative monitoring of the coagulation status in patients undergoing major hepatic resections. Material and methodsSixteen patients undergoing major liver resections were examined prior to surgery, on postoperative day 1, and subsequently, every three postoperative days during hospitalization. At the same time, the clinical signs of bleeding and thrombotic complications were monitored. ResultsOn postoperative day 1, increases in bilirubin, PT-INR, APTT, and D-dimers were observed, together with concomitant decreases in fibrinogen, platelet count, antithrombin (AT), protein C and protein S compared to preoperative values. On postoperative days 4 and 7, all of the variables had returned to the normal range except for D-dimers, AT and protein C. The ROTEM® median values remained within the normal range. There were no significant episodes of postoperative bleeding. Two patients were diagnosed with a pulmonary embolism. ConclusionDespite the abnormalities observed in routine coagulation monitoring, thromboelastometry indicated a balanced coagulation status following major hepatic surgery. The levels of both pro- and anticoagulant proteins changed over time during this period. The exact clinical role for thromboelastometry in major hepatic surgery remains to be established.

Non-VKA oral anticoagulants: an update for the clinical biologists

Non-VKA oral anticoagulants (NOACs), thanks to their ease of use and their similar or superior safety/efficacy profiles versus warfarin, have now widely reached the lucrative market of anticoagulation. However, while the marketing authorization holders always claim, in a quite unclear way that no monitoring is required, accumulative evidence and cases of major bleeding have been described in the literature and reported by spontaneous reporting systems at the regulator's level. These compounds are usually given at fixed doses without routine coagulation monitoring. However, new data suggests that an assessment of the response at the individual level could improve the benefit-risk ratio of, at least dabigatran. Therefore, in certain patient populations, i.e. acute or chronic renal impairment or multiple drug interactions, measurement of drug exposure may be useful to ensure an optimal treatment response. More specific circumstances such as patients experiencing a haemorrhagic or thromboembolic event during the treatment duration, patients who require urgent surgery or an invasive procedure, or patient with a suspected overdose could benefit from such a measurement. This article aims at providing guidance on how to best estimate the intensity of anticoagulation using laboratory assays in daily practice.

Initiation of rivaroxaban in patients with nonvalvular atrial fibrillation at the primary care level:: The Swiss Therapy in Atrial Fibrillation for the Regulation of Coagulation (STAR) Study

BackgroundRivaroxaban has become an alternative to vitamin-K antagonists (VKA) for stroke prevention in non-valvular atrial fibrillation (AF) patients due to its favourable risk–benefit profile in the restrictive setting of a large randomized trial. However in the primary care setting, physician's motivation to begin with rivaroxaban, treatment satisfaction and the clinical event rate after the initiation of rivaroxaban are not known. MethodsProspective data collection by 115 primary care physicians in Switzerland on consecutive nonvalvular AF patients with newly established rivaroxaban anticoagulation with 3-month follow-up. ResultsWe enrolled 537 patients (73±11years, 57% men) with mean CHADS2 and HAS-BLED-scores of 2.2±1.3 and 2.4±1.1, respectively: 301(56%) were switched from VKA to rivaroxaban (STR-group) and 236(44%) were VKA-naïve (VN-group). Absence of routine coagulation monitoring (68%) and fixed-dose once-daily treatment (58%) were the most frequent criteria for physicians to initiate rivaroxaban. In the STR-group, patient's satisfaction increased from 3.6±1.4 under VKA to 5.5±0.8 points (P<0.001), and overall physician satisfaction from 3.9±1.3 to 5.4±0.9 points (P<0.001) at 3months of rivaroxaban therapy (score from 1 to 6 with higher scores indicating greater satisfaction). In the VN-group, both patient's (5.4±0.9) and physician's satisfaction (5.5±0.7) at follow-up were comparable to the STR-group. During follow-up, 1(0.19%; 95%CI, 0.01–1.03%) ischemic stroke, 2(0.37%; 95%CI, 0.05–1.34%) major non-fatal bleeding and 11(2.05%; 95%CI, 1.03–3.64%) minor bleeding complications occurred. Rivaroxaban was stopped in 30(5.6%) patients, with side effects being the most frequent reason. ConclusionInitiation of rivaroxaban for patients with nonvalvular AF by primary care physicians was associated with a low clinical event rate and with high overall patient's and physician's satisfaction.

Recent Advances in the Development of Specific Antidotes for Target-Specific Oral Anticoagulants

Warfarin, a vitamin K antagonist, has been the only orally available anticoagulant for>60years. During the past decade, the U.S. Food and Drug Administration has approved several target-specific oral anticoagulants (TSOACs) for the prophylaxis and treatment of arterial and venous thromboembolism and stroke prevention in patients with nonvalvular atrial fibrillation. These new agents have several advantages over warfarin including more predictable pharmacokinetics and pharmacodynamics, fewer food and drug interactions, and lack of need for routine coagulation monitoring. However, unlike warfarin, currently no antidotes are available to reverse the anticoagulant effect of TSOACs. Specific antidotes for TSOACs may not be needed in most situations due to their short half-life, yet the absence of antidotes for these agents is a concern, especially in emergent situations such as life-threatening major bleeding or nonelective major surgery. Several specific antidotes for TSOACs including idarucizumab, andexanet alfa, and aripazine have been developed and have shown promise in early clinical trials evaluating their efficacy and safety. In this narrative review, the progress made in developing specific antidotes for TSOACs is summarized based on the latest available preclinical and clinical data.

Effects of Rivaroxaban Therapy on ROTEM Coagulation Parameters in Patients with Venous Thromboembolism.

Rivaroxaban (Xarelto) does not require routine coagulation monitoring; however, in certain clinical situations (overdose, drug accumulation, urgent surgery) measurement of its plasma concentration is highly recommended. Currently, there is no single hemostasis test that shows a direct correlation between rivaroxaban plasma levels and anticoagulant efficacy. This study was intended to assess the value of ROTEM in determining rivaroxaban administration. Thirteen patients with venous thromboembolism and 13 healthy volunteers were compared with regard to certain ROTEM parameters and anti-FXa activity. The tests were done before the administration of 20 mg rivaroxaban (i.e. 24 h after previous administration) and 2.5 h afterwards. The study group demonstrated residual activity of rivaroxaban in plasma (20 ± 11.3 ng/mL) 24 h following the previous administration, which did not cause marked changes in clotting assays compared to controls. In the group, 2.5 h after rivaroxaban administration, prolongation of PT (PTratio 1.51 ± 0.22), APTT (APPTratio: 1.30 ± 0.14) and ROTEM CT (CTratio - EXTEM: 2.45 ± 1.06, CTratio - 1.32 ± 0.21) were observed. The cut-off values for particular tests were created to determine if the patient had achieved desirable anticoagulant effect after rivaroxaban administration. The mean anti-FXa values were significantly lower in patients before rivaroxaban dosing than after. PT demonstrated better diagnostic value than APTT in rivaroxaban administration. The ROTEM clotting time (CT) according to EXTEM may be used to determine the anticoagulation effect of rivaroxaban, but is not sensitive enough to measure the residual activity of this drug.

Massive Life-Threatening Hemorrhages Due to Toxic Oral Intake of 3750 Mg Dabigatran Etexilate As a Suicide Attempt and the Clinical Management

The direct thrombin inhibitor dabigatran etexilate is a novel oral anticoagulant agent. The drug is used for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. There is no specific antidote for the reversal of the anticoagulant effects of dabigatran etexilate. Therefore, the management of the clinical bleeding due to dabigatran etexilate represents a great challenge for the clinician. We would like to share our experience regarding the massive life-threatening hemorrhages due to toxic oral intake of 3750 mg dabigatran etexilate as a suicide attemp and the clinical management.A 83-year-old man with a medical history of atrial fibrillation, coronary artery disease, hypertension and myelodisplastic syndrome presented to the emergency room with massive hematuria. Because of atrial fibrilation, he was using dabigatran etexilate as a prophylaxis of stroke or systemic embolism. He had received about 50 capsules of dabigatran etexilate (3750 mg) with the purpose of suicide, 30 hours before transfer to hospital. On the admission, physical assessment showed hypotension, massive hematuria and spontaneous pethechial areas and purpuras on the skin. The thrombin clotting time (TT) was 130 s (normal range 20- 30 s), activated partial thromboplastine time (aPTT) was 59 s (normal 22-35 s), prothrombin time - international normalized ratio (INR) was 1,4. Complete blood count showed that hemoglobin was 7,4 g/dL and platelets were 30000 /µL. The patient received 1000 U prothrombin complex concentrates (PCC), for two days. And 2 units of erytrocyte suspensions were administered. The bleeding ceased within the first day and the thrombin time normalized 3 days later.Dabigatran etexilate is a safer drug than the other anticoagulants. When compared to the warfarin and enoxaparin, dabigatran etexilate has been shown to reduce the rates of bleeding. However, the patients receving dabigatran etexilate have still a risk of bleeding. Because of the predictable pharmacokinetic and pharmacodynamic profile of dabigatran etexilate, there is no need for routine therapeutic coagulation monitoring while using the drug. In case of active bleeding, a possible overdose, or the need for an invasive procedure, the monitoring gains importance. TT and aPTT are the most sensitive laboratory assays to determine the dabigatran etexilate levels. Since the prothrombin time is not affected by dabigatran etexilate, it is not sensitive. There is a strong correlation between the TT measurements and dabigatran etexilate plasma levels. So in monitoring effectivity of therapy or determining the dabigatran etexilate levels in plasma, thrombin clotting time is very useful. However, at dabigatran etexilate concentrations above 600 ng/mL, the maximum measurement of the test is exceeded, correlating to a TT of greater than 120 seconds. Our patient on admission had an elevated TT of >120 seconds indicating accumulation of dabigatran etexilate with levels >600 ng/mL and massive hematuria. There were a bleeding associated dabigatran etexilate and overdose of drug. In order to stop bleeding we need to reverse anticoagulant effects of dabigatran etexilate. There is no specific antidote for dabigatran etexilate and there is limited guidance for treatment in these situations. Fortunately, dabigatran etexilate has short half-life which provides a relatively quick decline in plasma concentrations after discontinuance of the drug in a patient with normal renal function In case of overdose, it is suggested that discontinuing dabigatran etexilate therapy, initiating supportive care, the potential use of hemodialysis, and investigating the source of the bleed. In patients who require more urgent reversal of their anticoagulation, the use of prothrombin complex concentrates (PCCs) may be helpful. PCCs contain vitamin K–dependent coagulation factors II, VII, IX, and X. We started the patient PCCs at the dose of 1000 IU/d and supportive care. The bleeding was ceased in the first day and there was no need to hemodialysis.Thus, the advantages of using dabigatran etexilate instead of warfarin will lead to widespread use. But it must be kept in mind that dabigatran etexilate is not completely innocent drug and the patients using dabigatran etexilate still have the significant risk of bleeding. And acute reversal of the effects of dabigatran etexilate in the actively bleeding patient is a significant challenge. DisclosuresNo relevant conflicts of interest to declare.

Development and Validation of a Chromogenic Direct Thrombin Inhibitor Assay on the ACL Top 700 for Quantifying Dabigatran Levels in Plasma

Dabigatran is a potent, competitive, and reversible direct thrombin inhibitor, that binds to the active site of thrombin, inhibiting both free and clot-bound thrombin. It is the active form of dabigatran etexilate, which is a low molecular weight prodrug metabolized to its active form after oral administration. Although patients on therapeutic doses of dabigatran do not require routine coagulation monitoring due to its dose dependent and predictable pharmacological profile, there may be situations in which it may be beneficial to be able to accurately measure the degree of anticoagulation (ie. urgent surgery, severe bleeding, thrombosis despite treatment, overdose, bridging with other anticoagulants, patients with a high risk of dabigatran accumulation or potential drug interactions). Accordingly, we developed and validated a chromogenic direct thrombin inhibitor assay on the ACL TOP 700 automated hemostasis analyzer for quantifying dabigatran levels in human plasma.Our test principle was based on the in vitro thrombin inhibition by dabigatran, in which excess thrombin was added to the plasma sample, the thrombin in the sample was neutralized in proportion to the amount of dabigatran, and the residual thrombin hydrolyzed the chromogenic substrate releasing pNA which was measured photometrically at 405 nm on the ACL TOP 700. This assay was calibrated with purchased dabigatran calibration samples (Aniara). Each calibration curve consisted of five points, used a 3rd order polynomial curve fit, and was performed each time an assay was run. For all runs, an r2 of 1.0 was observed and all calibrators demonstrated an acceptable accuracy and precision (± 10% from assigned value for samples ≥ 100 ng/mL or < 10 ng/mL of assigned values for all other samples).Validation of this dabigatran level assay for accuracy, intra- and inter-assay precision, analytical specificity, analytical sensitivity, analyte stability, and robustness was completed and reportable result ranges established. To evaluate accuracy, three plasma samples containing dabigatran in the range of expected concentrations (high, medium, low) were compared to the value determined by mass spectrometry. Intra- and inter-assay precision was determined by analyzing these 3 samples over multiple assay runs spanning multiple days. All determined values were within 15% of the assigned values for samples ≥ 100ng/mL and within 10ng/mL of the assigned values for all other samples. Analytical specificity was confirmed by running sample pairs (plasma/serum, citrate/EDTA, hemolyzed/non-hemolyzed, icteric/non-icteric, lipemic/cleared-lipemic, 1 U/mL unfractionated heparin and 2 U/mL low molecular weight heparin-containing samples). Only the serum sample resulted in >10% difference from the standard plasma, indicating assay interference. Assay results were not affected by unfractionated heparin up to 1 U/mL and low molecular weight heparin up to 2 U/mL. Analytical sensitivity was established by assaying normal plasma containing no or low levels of dabigatran. The limit of blank was determined to be 3 ng/mL, limit of detection 10 ng/mL, and limit of quantitation (LoQ) 20 ng/mL. Analyte stability studies established samples thawed and refrozen up to 2 times were acceptable. Assay robustness was determined to be acceptable. The reportable range was determined to be 20-900 ng/mL based on the calibration curve and LoQ.In summary, we have developed and validated an accurate, precise, sensitive and robust chromogenic assay on the ACL TOP 700 for the determination of dabigatran concentration in human plasma. This assay may prove useful in certain clinical circumstances (urgent surgery, severe bleeding, or thrombosis despite treatment) for the assessment of anticoagulation status. DisclosuresNo relevant conflicts of interest to declare.