Reversal of Dabigatran with Idarucizumab

Introduction: The use of novel oral anticoagulants such as dabigatran has been increasing over the last five years. Indicated for use in the prevention of thromboembolic complications from non-valvular atrial fibrillation and for the treatment and prevention of venous thromboembolic disease, dabigatran is increasingly encountered clinically. Lack of an efficacious reversal agent has been a challenge for increased clinical 10 adoption, and for management of patients with bleeding complications while taking dabigatran, or those requiring urgent procedures while taking dabigatran. Idarucizumab, a monoclonal antibody fragment, has recently been approved for use to reverse anticoagulation with dabigatran in patients with serious bleeding.

Areas covered: Herein we discuss the development and early clinical data evaluating the use of idarucizumab for dabigatran reversal.

Expert commentary: Idarucizumab has been shown to be an efficacious reversal agent for patients receiving dabigatran. The drug provides a novel and clinically useful agent for patients with significant bleeding while receiving dabigatran, or those needing urgent invasive procedures.     

Best Clinical Practice: Controversies in Outpatient Management of Acute Pulmonary Embolism

Background

Pulmonary embolism (PE) is a common condition managed in the emergency department (ED), with a wide range of morbidity and mortality. Patients are classically admitted for treatment and monitoring of anticoagulation.

Prediction of hemorrhagic and thrombotic events in patients with mechanical heart valve prostheses treated with oral anticoagulants

Summary.  Background:  Variability in the intensity of anticoagulant therapy is considered a risk factor for complications, but it is unclear how best to quantify variability. Objective:  We evaluated the association of three methods to measure variability with complications of oral anticoagulant therapy. Methods:  We conducted a nested case–control study within a cohort of patients with prosthetic heart valves. 210 patients with a first hemorrhagic or thrombotic event during follow-up were selected with two controls per case, matched on age and sex. We calculated the time spent at an International Normalized Ratio below, above, and between 2.5 and 4.0, and the variance growth rate according to three different methods (A, B1, B2); method A combines variability and time in range, and methods B1 and B2 purely look at variability. Results:  Odds ratios of the variance growth rates for thrombotic events for patients in the second and third tertiles varied between 2 and 3, with the highest odds ratio for complications for the method that purely looked at variability. For hemorrhagic complications, the highest odds ratios were found for method A, which also incorporated time in range, with odds ratios of 2.6 (95% CI: 1.3–5.1) and 3.1 (95% CI: 1.6–6.0) for the second and third tertiles as compared to the first. The combination of time spent out of range with the highest tertile of variability increased the risk 2.6-fold (95% CI: 1.6–4.2) as compared to subjects with stable anticoagulation within the target range. Conclusion:  Unstable anticoagulation was associated with hemorrhagic and thrombotic complications. Method A was best associated with complications, but methods B1 and B2, in combination with time spent in range, were equally well associated. As we prefer to disentangle variability and intensity of anticoagulation, we propose to use methods B1 or B2 to reflect pure variability of oral anticoagulant therapy.     

The Effect of Direct Oral Anti-Coagulants on Delayed Traumatic Intracranial Hemorrhage After Mild Traumatic Brain Injury: A Systematic Review

BackgroundThe use of anticoagulant medications leads to a higher risk of developing traumatic intracranial hemorrhage (tICH) after a mild traumatic brain injury (mTBI). The management of anticoagulated patients can be difficult to determine when the initial head computed tomography is negative for tICH. There has been limited research on the risk of delayed tICH in patients taking direct oral anticoagulant (DOAC) medications.ObjectiveOur aim was to determine the risk of delayed tICH for patients anticoagulated with DOACs after mTBI.MethodsWe conducted a systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searched several medical databases to examine the risk of delayed tICH in patients on DOACs.ResultsThere were 1252 nonduplicate studies that were identified through an initial database search, 15 of which met our inclusion and exclusion criteria and were included in our analysis after full-text review. A total of 1375 subjects were combined among the 15 studies, with 20 instances of delayed tICH after mTBI. Nineteen of the 20 patients with a delayed tICH were discharged without any neurosurgical intervention, and 1 patient on apixaban died due to a delayed tICH.ConclusionsThis systematic review confirms that delayed tICH after mTBI in patients on DOACs is uncommon. However, large, multicenter, prospective studies are needed to confirm the true incidence of clinically significant delayed tICH after DOAC use. Due to the limited data, we recommend using shared decision-making for patients who are candidates for discharge.     

The Safety of Ultrasound-Guided Thoracentesis in Patients on Novel Oral Anticoagulants and Clopidogrel: A Single-Center Experience

ObjectiveTo assess the risk of hemorrhagic complications in patients taking novel oral anticoagulants (NOACs) and/or clopidogrel who underwent an ultrasound-guided thoracentesis.Patients and MethodsA retrospective analysis was performed of ultrasound-guided thoracenteses completed at an academic institution between January 1, 2016, and November 14, 2017. All patients who underwent a thoracentesis while actively receiving treatment with an NOAC and/or clopidogrel were included in the study. Primary endpoints are any significant post-procedure bleeding complication; defined as a hemoglobin decrease of greater than 2 g/dL in 48 hours, hemothorax, chest wall hematoma, and bleeding requiring transfusion, surgery, or chest tube placement.ResultsA total of 115 thoracenteses were performed in 103 patients actively taking an NOAC (n=43) and/or clopidogrel (n=69). All patients used either the NOAC or clopidogrel within 24 hours before the procedure and continued using it daily thereafter. There were no bleeding complications.ConclusionThe overall risk of significant hemorrhage in patients taking an NOAC and/or clopidogrel while undergoing ultrasound-guided thoracentesis is very low. Albeit the total number of procedures reviewed may be insufficient to prove definitive safety, it is sufficient to provide a measure of relative risk when assessing benefits of thoracentesis in these patients.     

Detecting nonvalvular atrial fibrillation and anticoagulant therapy in cardioembolic ischemic stroke

Nonvalvular Atrial fibrillation (NVAF) is the most common cardiac arrhythmia associated with an increase in risk of stroke and systemic thromboembolism. Strokes related to AF are associated with higher mortality, greater disability, longer hospital stays, and lower chance of being discharged home. The present review will focus on the current status of detecting NVAF and stroke prevention when there is AF. The CHA2DS2-VASc risk stratification scheme is discussed for the identification of patients who are at risk for thromboembolic stroke related to NVAF. Patient with a CHA2DS2-VASc score of 2 or greater are candidates for warfarin or a novel oral anticoagulant, irrespective of whether the strategy is for rate or rhythm control. Finally, guidelines and landmark clinical trials in NVAF patients with primary or secondary stroke prevention are discussed.     

The safety and effectiveness of a nurse-led anticoagulant service

AIM: The aim of this study was to compare the safety and effectiveness of anticoagulant nurses and a consultant haematologist in managing anticoagulant patients in a hospital outpatient setting. BACKGROUND: Nurses are increasingly developing roles traditionally undertaken by medical staff. As a result nurse-led practice has expanded in many areas including anticoagulant services. Previous studies have attempted to demonstrate the effectiveness of using other professionals to manage anticoagulant clinics over short periods of time. This research evaluates the safety and effectiveness of a consultant-led and a nurse-led service over two sequential 18-month periods. RESEARCH METHODS: A nonexperimental design was adopted. Data were collected retrospectively, from a random sample of 197 patients, who had been managed by both the consultant-led and nurse-led service. Two main outcome measures were selected: anticoagulant control between professional groups and interval between outpatient clinic appointments. RESULTS: No statistically significant difference in anticoagulant control was found between professional groups (P=0.137). There was evidence that patients attended anticoagulant clinics on significantly fewer occasions with nurse-led management (P < 0.0005). CONCLUSION: At the department within which this research was conducted, anticoagulant nurses were found to be at least as safe and effective as the consultant haematologist in managing outpatient anticoagulant patients over the study period. These findings are of importance in both shaping the future provision of anticoagulant care and also contributing to the wider area in evaluating the impact of nurse-led practice within health care.     

S35972, a direct‐acting thrombin inhibitor with high oral bioavailability and antithrombotic efficacy

Summary. Objectives: Dabigatran etexilate is the first oral thrombin inhibitor to demonstrate superior efficacy to warfarin for stroke prevention in patients with atrial fibrillation. This study describes the in vitro, ex vivo anticoagulant and in vivo antithrombotic effects of an oral thrombin inhibitor, S35972, in comparison with dabigatran etexilate. Methods: Enzyme assays with thrombin and related serine proteases were performed. Clotting times, including activated partial thromboplastin time (APTT) and thrombin time (TT), were measured in vitro in different species and ex vivo in dogs and rats to determine pharmacologic bioavailabilities. The formation of occlusive venous and arterial thrombi in the rat vena cava and aorta was induced with stasis plus thromboplastin or ferrous chloride, respectively. Results: S35972 inhibited human thrombin with an IC₅₀ of 3.7 nm , and did not inhibit other serine proteases. The anticoagulant activities of S35972 in vitro were comparable in dog and human plasmas, and the sensitivity of the clotting times to S35972 was TT > APTT > prothrombin time. In the fasted dog, oral administration of 3 mg kg^?1 S35972 increased TT rapidly and for at least 8 h, and its pharmacologic bioavailability was 75.4% ± 0.1%. In the rat venous thrombosis model, 3 mg kg^?1 oral S35972 or dabigatran etexilate significantly decreased the thrombus weight. In the rat aortic thrombosis model, oral S35972 at 10 mg kg^?1 significantly decreased thrombus weight, by approximately 50%, whereas, at this dose, no effect was obtained with dabigatran etexilate. Conclusions: S35972 is a non‐prodrug thrombin inhibitor with high selectivity, oral bioavailability, and antithrombotic efficacy.     

Is bleeding a necessary evil? The inherent risk of antithrombotic pharmacotherapy used for stroke prevention in atrial fibrillation

Current European atrial fibrillation (AF) guidelines have assigned a strong recommendation for the initiation of antithrombotic therapy to prevent thromboembolism in all but those AF patients at low risk (or with contraindications). Furthermore, the selection of antithrombotic therapy is based on the absolute risks of thromboembolism and bleeding, and the relative risk and benefit for a given patient. By their very mechanism of action, antithrombotic agents used for stroke prevention in AF will potentially increase the risk of bleeding events. Moreover, the introduction of novel oral anticoagulation agents have introduced new, hitherto ill-defined, deficiencies in the authors’ knowledge with respect to anticoagulation monitoring, availability of direct antidotes, drug–drug interactions and the ability to appropriately control and reverse their actions if bleeding events occur. The authors present a comprehensive review on all aspects of bleeding related to currently licensed antithrombotic agents used for stroke prevention in patients with AF.     

DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles

Summary.  Background:  Factor Xa (FXa), a key serine protease that converts prothrombin to thrombin in the coagulation cascade, is a promising target enzyme for the prophylaxis and treatment of thromboembolic diseases. DU-176b is a novel antithrombotic agent that directly inhibits FXa activity. Objective:  To evaluate the in vitro pharmacological profiles and in vivo effects of DU-176b in animal models of thrombosis and bleeding. Methods: In vitro , FXa inhibition, specificity and anticoagulant activities were examined. Oral absorption was studied in rats and cynomolgus monkeys. In vivo effects were studied in rat and rabbit models of venous thrombosis and tail bleeding. Results: DU-176b inhibited FXa with Ki values of 0.561 n m for free FXa, 2.98 n m for prothrombinase, and exhibited >10 000-fold selectivity for FXa. In human plasma, DU-176b doubled prothrombin time and activated partial thromboplastin time at concentrations of 0.256 and 0.508 μ m , respectively. DU-176b did not impair platelet aggregation by ADP, collagen or U46619. DU-176b was highly absorbed in rats and monkeys, as demonstrated by more potent anti-Xa activity and higher drug concentration in plasma following oral administration than a prototype FXa inhibitor, DX-9065a. In vivo , DU-176b dose-dependently inhibited thrombus formation in rat and rabbit thrombosis models, although bleeding time in rats was not significantly prolonged at an antithrombotic dose. Conclusions:  DU-176b is a more potent and selective FXa inhibitor with high oral bioavailability compared with its prototype, DX-9065a. DU-176b represents a promising new anticoagulant for the prophylaxis and treatment of thromboembolic diseases.     

In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939--an oral, direct Factor Xa inhibitor.

BAY 59-7939 is an oral, direct Factor Xa (FXa) inhibitor in development for the prevention and treatment of arterial and venous thrombosis. BAY 59-7939 competitively inhibits human FXa (K(i) 0.4 nm) with > 10 000-fold greater selectivity than for other serine proteases; it also inhibited prothrombinase activity (IC(50) 2.1 nm). BAY 59-7939 inhibited endogenous FXa more potently in human and rabbit plasma (IC(50) 21 nm) than rat plasma (IC(50) 290 nm). It demonstrated anticoagulant effects in human plasma, doubling prothrombin time (PT) and activated partial thromboplastin time at 0.23 and 0.69 microm, respectively. In vivo, BAY 59-7939 reduced venous thrombosis (fibrin-rich, platelet-poor thrombi) dose dependently (ED(50) 0.1 mg kg(-1) i.v.) in a rat venous stasis model. BAY 59-7939 reduced arterial (fibrin- and platelet-rich) thrombus formation in an arteriovenous (AV) shunt in rats (ED(50) 5.0 mg kg(-1) p.o.) and rabbits (ED(50) 0.6 mg kg(-1) p.o.). Slight inhibition of FXa (32% at ED(50)) reduced thrombus formation in the venous model; to affect arterial thrombosis in the rat and rabbit, stronger inhibition of FXa (74%, 92% at ED(50)) was required. Calculated plasma levels in rabbits at the ED(50) were 14-fold lower than in the rat AV shunt model, correlating with the 14-fold lower IC(50) of FXa inhibition in rabbit compared with rat plasma; this may suggest a correlation between FXa inhibition and antithrombotic activity. Bleeding times in rats and rabbits were not significantly affected at antithrombotic doses (3 mg kg(-1) p.o., AV shunt). Based on these results, BAY 59-7939 was selected for clinical development.     

Hereditary and acquired protein S deficiencies are associated with low TFPI levels in plasma

Summary. Background: Protein S and tissue factor pathway inhibitor (TFPI) act together in down‐regulating coagulation. Objective: To investigate the TFPI/protein S system in hereditary and acquired protein S deficiency. Methods: Plasma antigen levels of protein S and full‐length TFPI were determined in heterozygous type I protein S‐deficient individuals (n = 35), patients on oral anticoagulant treatment (OAT) (n = 29), oral contraceptive (OC) users (n = 10) and matched controls. Thrombin generation was determined using calibrated automated thrombography. Results: Full‐length TFPI levels were lower in type I protein S‐deficient individuals (76.8 ± 33.8%) than in age‐ and sex‐matched controls (128.0 ± 59.4%, P < 0.001). Among protein S‐deficient individuals with thrombosis, those on OAT had not only lower total protein S levels (25.7 ± 8.2% vs. 54.7 ± 8.2%, P < 0.001), but also lower full‐length TFPI levels (52.6 ± 15.0% vs. 75.4 ± 22.9%, P = 0.009) than those not on OAT. Similarly, OC users had lower protein S (73.8 ± 11.5% vs. 87.9 ± 10.8%, P = 0.005) and full‐length TFPI levels (73.7 ± 27.7% vs. 106.4 ± 29.2%, P = 0.007) than non‐users. When triggered with tissue factor, plasma from protein S‐deficient individuals generated 3–5‐fold more thrombin than control plasma. The difference was only partially corrected by normalization of the protein S level, full correction requiring additional normalization of the TFPI level. Protein S‐immunodepletion experiments indicated that free protein S and full‐length TFPI form a complex in plasma, and the protein S/TFPI interaction was confirmed by surface plasmon resonance analysis. Conclusions: Full‐length TFPI binds to protein S in plasma and is reduced in genetic and acquired protein S deficiency. The concomitant TFPI deficiency substantially contributes to the hypercoagulable state associated with protein S deficiency.     

Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study

Summary.  Background:  Apixaban, an oral potent reversible direct inhibitor of activated factor X, has shown promise in the prevention of venous thromboembolism following major orthopedic surgery. We conducted a dose-ranging study in patients with deep vein thrombosis. Methods:  Consecutive patients with symptomatic deep vein thrombosis were included and randomized to receive 84–91 days of apixaban 5 mg twice-daily, 10 mg twice-daily, or 20 mg once-daily, or low molecular weight heparin (LMWH) followed by a vitamin K antagonist (VKA). The primary efficacy outcome was the composite of symptomatic recurrent venous thromboembolism and asymptomatic deterioration of bilateral compression ultrasound or perfusion lung scan. The principal safety outcome was the composite of major and clinically relevant, non-major bleeding. Results:  The mean age of the 520 included patients was 59 years, and 62% were male. The primary outcome occurred in 17 of the 358 apixaban-treated patients [4.7%, 95% confidence interval (CI) 2.8–7.5%] and in five of the 118 LMWH/VKA-treated patients (4.2%, 95% CI  1.4–9.6%) who were evaluable. The incidence in all three apixaban groups was low and comparable without evidence of a dose response. The principal safety outcome occurred in 28 (7.3%) of the 385 apixaban-treated patients and in 10 (7.9%) of the 126 LMWH/VKA-treated patients. No dose response for apixaban was observed. Conclusion:  These observations warrant further evaluation of apixaban in phase III studies. The attractive fixed-dose regimen of this compound may meet the demand to simplify anticoagulant treatment in patients with established venous thromboembolism.     

Is there a need for an alternative in the era of novel anticoagulants?

With the development of the new direct oral anticoagulants, many of the unmet needs of the vitamin K antagonists were fulfilled, such as the absence of dietary interactions, few drug interactions, predictable effects and no need for monitoring. However, growing experience with the direct oral anticoagulants indicates there is still room for improvement. Developing antithrombotic agents that optimize their antithrombotic effect while producing little or no risk of bleeding is a long sought after goal. This and other enhanced attributes of candidate drugs are on the horizon.     

Fitting the right non-vitamin K antagonist oral anticoagulant to the right patient with non-valvular atrial fibrillation: an evidence-based choice

Atrial fibrillation (AF) is the most prevalent arrhythmia and is associated with an increased risk of ischemic stroke (IS) and systemic embolism (SE). Stroke prevention is a key element for the overall management of AF patients. The non-vitamin K antagonist oral anticoagulants (NOACs), such as dabigatran, rivaroxaban, apixaban and edoxaban, are at least as effective as warfarin in reducing IS/SE with a lower rate of major bleeding. Various analyses from the large Phase III randomized trials demonstrated different efficacy and safety of NOACs in specific subgroups of patients. The randomized trials are supplemented by effectiveness and safety data from real-world observational cohorts following the availability of these drugs for use in everyday clinical practice. Given the clinical heterogeneity of AF patients, the available data from trials and real-world studies allow us to fit the right NOAC to the particular patient’s characteristics, with the aim of optimizing outcomes for the individual patient. This review article aims to provide a summary of the evidence on the performance of NOACs in AF patients with specific clinical characteristics. Evidence-based suggestions are presented to provide a simple and viable strategy for clinicians for the choice of a particular NOAC.

• KEY MESSAGE

• Given the different performance of the new-oral anticoagulants in patients with the different clinical situation, evidence-based choice of fitting the right new-oral anticoagulants to the patients is provided in this review article.

     

International multicenter international sensitivity index (ISI) calibration of a new human tissue factor thromboplastin reagent derived from cultured human cells

Summary.  The international sensitivity index (ISI) of the first working standard of Simplastin HTF, a new human tissue factor thromboplastin derived from cultured human cells, has been assessed in a calibration exercise in two Canadian and five European laboratories. Calibrations against international reference preparations (IRP) were performed for the manual method and six types of automated coagulometers that cover the majority of clotting endpoint principles in routine use. The ISI was method-dependent and varied between 1.03 and 1.29 when calibrated against rTF/95 (human IRP). The ISI was also dependent on the route of calibration. Compared with calibration against rTF/95, the ISIs obtained by calibration against RBT/90 (rabbit IRP) were on average 4.4% higher ( P  < 0.005). Considering the principle of 'like vs. like', the ISIs obtained by calibration against rTF/95 should be preferred.     

Non-fatal major bleeding during treatment with vitamin K antagonists: influence of soluble thrombomodulin and mutations in the propeptide of coagulation factor IX.

BACKGROUND AND OBJECTIVES: The key complication of treatment with vitamin K antagonists (VKAs) is bleeding. The major determinant of VKA-induced bleeding is the intensity of anticoagulation. Individual patient characteristics may also influence bleeding risk. In addition, soluble thrombomodulin (s-TM) levels and mutations in the propeptide of factor (F)IX are important candidate risk factors in this respect. PATIENTS AND METHODS: A matched case-control study was designed to search for risk factors that predict bleeding during VKA treatment. We selected cases that had experienced major bleeding during treatment with VKA and matched controls without bleeding complications from the databases of two Thrombosis Services. The controls were matched for indication of treatment, age, gender, type of anticoagulant used and whether or not treatment with VKA was stopped. DNA and plasma were stored of all cases and controls. RESULTS AND CONCLUSIONS: In total 110 patients and 220 controls consented to participate. The results indicate that s-TM levels, measured by ELISA, may be a risk indicator for bleeding [crude odds ratio 3.25 for the highest quartile vs. the lowest quartile (95% confidence interval 1.40, 7.51)]. Three novel mutations, determined by direct sequencing, in the gene portion encoding the propeptide of FIX were identified that do not seem to play an important role in bleeding risk during treatment with VKAs.