Laboratory and Clinical Monitoring of Direct Acting Oral Anticoagulants: What Clinicians Need to Know

The direct acting oral anticoagulants (DOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban, have favorable pharmacokinetic and pharmacodynamic properties and equal or superior efficacy and an improved safety profile compared with warfarin. Noted shortcomings with DOACs are shorter half‐lives requiring stricter adherence, lack of standardized laboratory monitoring, lack of anticoagulation reversal agents, and loss of routine coagulation monitoring leading to fewer patient–clinician interactions. This review addresses many of these limitations including monitoring of DOACs for efficacy and toxicity, an assessment of selected qualitative and quantitative tests, and development of monitoring strategies for special populations. Coagulation monitoring is generally recommended only in overdose situations, but once standardized assays are readily available, they could be helpful to ensure efficacy, assess bleeding, and aid in drug selection in a number of other patient scenarios. Coagulation tests that may provide qualitative assessment include activated partial thromboplastin time, prothrombin time, and thrombin time. Methods with potential utility for quantitative assessment of DOACs include plasma drug concentrations, ecarin clotting time, dilute thrombin time, and anti–factor Xa concentrations. Noncoagulation laboratory monitoring should include serum creatinine, liver function tests, and complete blood counts. Clinical monitoring of the DOAC‐treated patient should include routine assessment of adherence, bleeding risks, and drug interactions. Frequency of monitoring should be 1–3 months after initiation and then at least every 6 months, with more frequent follow‐up (i.e., 3 months) based on patient specific characteristics such as age, renal impairment, hepatic impairment, and concomitant drug therapy. The authors provide a practical tool to assist in DOAC monitoring and recommend that pharmacists collaborate with physicians in selecting appropriate patients and tailoring patient‐specific monitoring plans.     

Risk of gastrointestinal bleeding during anticoagulant treatment

Introduction: Gastrointestinal bleeding (GIB) is a major problem in patients on oral anticoagulation therapy. This issue has become even more pressing since the introduction of direct oral anticoagulants (DOACs) in 2009.

Areas covered: Here we review current evidence related to GIB associated with oral anticoagulants, focusing on randomized controlled trials, meta-analyses, and post-marketing observational studies. Dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily increase the risk of GIB compared to warfarin. The risk increase with edoxaban is dose-dependent, while apixaban shows apparently, no increased risk. We summarize what is known about GIB risk factors for individual anticoagulants, the location of GIB in patients taking these compounds, and prevention strategies that lower the risk of GIB.

Expert opinion: Recently there has been an important shift in the clinical presentation of GIB. Specifically, upper GIB has decreased with the decreased incidence of peptic ulcers due to the broad use of proton pump inhibitors and the decreased prevalence of H. pylori infections. In contrast, the incidence of lower GIB has increased, due in part to colonic diverticular bleeding and angiodysplasia in the elderly. In this population, the addition of oral anticoagulation therapy, especially DOACs, seems to increase the risk of lower GIB.     

A novel prothrombin time method to measure all non-vitamin K-dependent oral anticoagulants (NOACs)

Background: There is a clinical need for point-of-care (POC) methods for non-vitamin K-dependent oral anticoagulants (NOACs). We modified a routine POC procedure: Zafena’s Simple Simon? PT-INR, a room-temperature, wet-chemistry prothrombin time method of the Owren-type.

Methods: To either increase or decrease NOAC interference, two assay variants were devised by replacing the standard 10?µL end-to-end capillary used to add the citrated plasma sample to 200?µL of prothrombin time (PT) reagent by either a 20?µL or a 5?µL capillary. All assay variants were calibrated to show correct PT results in plasma samples from healthy and warfarin-treated persons.

Results: For plasmas spiked with dabigatran, apixaban, or rivaroxaban, the 20?µL variant showed markedly higher PT results than the 5?µL. The effects were even more pronounced at room temperature than at +37?°C. In plasmas from patients treated with NOACs (n?=?30 for each) there was a strong correlation between the PT results and the concentration of NOACs as determined by the central hospital laboratory. For the 20?µL variant the PT response of linear correlation coefficient averaged 0.90. The PT range was INR 1.1–2.1 for dabigatran and apixaban, and INR 1.1–5.0 for rivaroxaban. Using an INR ratio between the 20?µL and 5?µL variants (PTr20/5) made the NOAC assay more robust and independent of the patient sample INR value in the absence of NOAC. Detection limits were 80?µg/L for apixaban, 60?µg/L for dabigatran, and 20?µg/L for rivaroxaban.

Conclusions: A wet-chemistry POC PT procedure was modified to measure the concentrations of three NOACs using a single reagent.     

Idarucizumab for the treatment of hemorrhage and dabigatran reversal in patients requiring urgent surgery or procedures

Introduction: Idarucizumab is a specific antagonist for dabigatran etexilate (DE). The recent market authorization of idarucizumab in Europe and the USA may reassure prescribers of DE, as it can increase the safety of the emergency management of patients taking this anticoagulant. However, idarucizumab use should be limited to specific indications to avoid unnecessary risks to patients and costs to healthcare systems.

Areas covered: The authors provide an overview of idarucizumab development and its pharmacokinetic and pharmacodynamic properties. The results of the clinical phase III trial RE-VERSE AD and a review of recent case reports of idarucizumab use in emergency contexts are also discussed.

Expert opinion: Although idarucizumab has shown clear efficacy in reversing dabigatran-induced coagulopathy, its overall effects on patient outcome have not been proven. Information regarding the clinical context in which patients on DE are admitted for emergency treatment, and accurate laboratory tests of dabigatran plasma level during reversal may inform selection and help with the follow-up of patients who may benefit from idarucizumab. Idarucizumab should be integrated into protocol for the emergency management of patients on DE. Furthermore, the benefit of idarucizumab in specific indications such as acute ischemic stroke should be investigated.     

Drug interactions with new oral anticoagulants in elderly patients

Introduction: This review attempts to summarise what is known about Drug-drug interactions (DDIs) of the new oral anticoagulants (NOACs) in elderly patients. The literature was searched for: ‘CYP3A4’, ‘CYP2C9’, ‘P-glycoprotein’, ‘acetylsalicylic-acid’, ‘non-steroidal anti-inflammatory’, ‘clopidogrel’, ‘ticagrelor’, ‘prasugrel’ and ‘dabigatran’, ‘rivaroxaban’, ‘edoxaban’, or ‘apixaban’. ‘Elderly’ was defined as ≥75 years.

Areas covered: Publications about DDIs of NOACs were found for 35% of 140 potentially interacting drugs. Reports about DDIs of cardiovascular drugs, were most frequent, followed by anti-infective and nervous system drugs. Reports about elderly were found for only 47 patients. DDIs were reported most frequently in association with dabigatran. Dabigatran is the only NOAC interacting with proton-pump-inhibitors.

Expert commentary: Dabigatran was the first NOAC approved, so it is not possible to determine whether the higher number of reports about DDIs with dabigatran compared with other NOACs is due to a higher rate of DDIs or to the length of time during which this drug has been in use. Most of the data is derived from subgroup-analyses of trials, sponsored by NOAC manufacturers, consequently there is a lack of independent data. Because of the scarcity of data, the clinical relevance of DDIs of NOACs is uncertain at present, especially in elderly patients.     

Safety and efficacy of Direct Oral Anticoagulants in cerebral venous thrombosis: A meta-analysis

Cerebral venous thrombosis (CVT) is caused by partial or complete occlusion of the major cerebral venous sinuses or the smaller feeding cortical veins which predispose to the risk of venous infarction and hemorrhage. Current guidelines recommend treating CVT with either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) followed by an oral vitamin K antagonist (VKA) for 3–12 months. Direct oral anticoagulants (DOACs) have already established benefit over warfarin as a long-term treatment of symptomatic venous thromboembolic disorder like deep vein thrombosis (DVT), and pulmonary embolism (PE) given its equal efficacy and better safety profile. The benefit of DOACs over warfarin as a long-term anticoagulation for CVT has likewise been extensively studied, yet it has not been approved as first-line therapy in the current practice. We therefore performed a systematic review and meta-analysis of relevant studies to generate robust evidence regarding the safety and efficacy of DOACs in CVT. This meta-analysis demonstrates that the use of DOACs in CVT has similar efficacy and safety compared to VKAs with better recanalization rate.     

Estimation Based on Emission Wavelength of Dabigatran Etexilate Mesylate in Bulk and Capsule Dosage Form

A simple, rapid, specific and highly sensitive spectrofluorimetric method has been developed for the quantification of dabigatran etexilate mesylate in bulk and capsule dosage form. A linear relationship was found between fluorescence intensity and concentration in the range of 0.01-1.0 μg/ml in dimethyl sulphoxide as solvent at an emission wavelength of 391 nm after excitation at 334 nm, with a good correlation coefficient (0.989). The detection and quantification limits were found to be 0.005 and 0.015 μg/ml, respectively. The proposed method was applied for dabigatran etexilate mesylate capsules, results reveal with percentage recovery of 102% and percentage relative standard deviation values were found to be less than 2 for accuracy and precision studies. The proposed method was validated for linearity, range, accuracy, precision, limit of detection and quantification according to International Conference on Harmonization guidelines. Statistical analysis of the results revealed high accuracy and good precision. The suggested procedures could be used for the determination of dabigatran etexilate mesylate in bulk and capsule dosage form in quality control laboratories of industries as well as in academic institutions.     

Dabigatran can cause eosinophilic pleural and pericardial effusion with blood eosinophilia

Eosinophilic pleural effusions (EPE) account for 5%–8% of all exudative pleural effusions. A pleural effusion is defined as eosinophilic if it contains 10% or more eosinophils. We present the case of a 70‐year‐old man with EPE, blood eosinophilia and pericardial effusion due to dabigatran, a novel anti‐thrombin agent.     

达比加群酯联合替格瑞洛对老年心房颤动合并不稳定型心绞痛患者的治疗效果

目的 探讨在治疗老年心房颤动合并不稳定型心绞痛时使用达比加群酯联合替格瑞洛对其凝血功能及临床疗效的影响.方法 120例老年心房颤动合并不稳定型心绞痛患者,按照入院的先后顺序分成观察组和对照组,每组60例.对照组在常规治疗的基础上口服华法林、替格瑞洛进行治疗,观察组在常规治疗的基础上加用达比加群酯联合替格瑞洛进行治疗.比...     

新型口服抗凝药在非瓣膜性房颤中的应用进展

目的:对新型口服抗凝药(NOACs)在非瓣膜性房颤抗凝治疗中的临床应用和发展进行探讨。方法:收集最新发表的相关文章,对新型口服抗凝药的药理学特性、临床试验结果和临床应用进行分析总结。结果与结论:房颤是临床中最常见的心律失常,对于CHA_2DS_2-VASc评分≥2或既往曾有一过性脑缺血发作(TIA)或有卒中史的患者,应该使用抗凝药物。新型口服抗凝药,与维生素K拮抗剂(VKA)相比,有相似甚至更好的抗凝效果、安全性和便利性。它们具有快速起效,更多可预测的药动学特征,与其他药物相互作用少,饮食对其无明显影响,比华法林导致颅内出血的风险更低。