Direct Oral Anticoagulants: New Drugs and New Concepts

Direct oral anticoagulants (DOACs) are approved for multiple thromboembolic disorders and provide advantages over existing agents. As with all anticoagulants, management protocols for the eventuality of bleeding are important. Randomized phase III studies generally show that DOACs have a similar risk of clinically relevant bleeding compared with standard anticoagulants, with reductions in major bleeding in some cases. This may be particularly important in patients with atrial fibrillation, for whom the rate of intracranial hemorrhage was approximately halved with DOACs compared with warfarin. Conversely, the risk of gastrointestinal bleeding may be increased. Specific patient characteristics, such as renal impairment, comedications, and particular aspects of each drug, including the proportion eliminated by the kidneys, must be taken into account when assessing the risk of bleeding. Although routine coagulation monitoring of DOACs is not required, it may be useful under some circumstances. Of the traditional clotting assays, a sensitive and calibrated prothrombin time may be useful for detecting the presence or absence of clinically relevant factor Xa inhibitor concentrations (rivaroxaban or apixaban), but specific anti–factor Xa assays can measure drug levels quantitatively. For dabigatran, the results of an activated partial thromboplastin time test may exclude a clinically relevant pharmacodynamic effect, but a calibrated dilute thrombin time assay can be used for quantification of drug levels. In the event of mild or moderate bleeding, normal hemostatic support measures are recommended. For life-threatening bleeding, use of nonspecific prohemostatic agents may be considered, although clinical evidence is scarce. Specific antidotes are in development.     

依度沙班预防骨科大手术后静脉血栓栓塞的meta分析

目的 比较依度沙班与低分子肝素预防骨科大手术后静脉血栓栓塞（venous thromboembolism,VTE）的有效性和安全性。方法 检索Cochrane Library、PubMed、EMBASE、中国知网、万方和维普科技期刊等数据库。收集依度沙班与低分子肝素预防骨科大手术后VTE随机对照试验。应用RevMan 5.3.5软件进行分析。结果 最终纳入5项研究,涉及2 585例患者。依度沙班组总VTE发生率[RR=0.47,95% CI（0.38,0.56）,P<0.000 01]、无症状性深静脉血栓发生率[RR=0.47,95% CI（0.31,0.71）,P=0.000 4]均低于低分子肝素组。依度沙班组总出血事件发生率高于低分子肝素组[RR=1.22,95% CI（1.01,1.49）,P=0.04]。亚组分析发现依度沙班不同剂量组总VTE发生率均低于低分子肝素组,15 mg组、30 mg组与低分子肝素组总出血事件发生率差异均无统计学意义。结论 依度沙班预防骨科大手术后VTE优于低分子肝素,但增加了总出血事件发生率。15,30 mg依度沙班可能为较安全剂量。     

Comprehensive review of the impact of direct oral anticoagulants on thrombophilia diagnostic tests: Practical recommendations for the laboratory

There is a laboratory and clinical need to know the impact of direct oral anticoagulants (DOACs) on diagnostic tests to avoid misinterpretation of results. Although the regulatory labelling documents provide some information about the influences of each DOAC on diagnostic tests, these are usually limited to some of the most common tests and no head to head comparison is available. In this paper, we report the impact of DOACs on several thrombophilia tests, including assessment of antithrombin, protein S and protein C activity assays, detection of activated protein C resistance and assays used for lupus anticoagulant. Results are compared and discussed with data obtained from literature. The final goal of this comprehensive review is to provide practical recommendations for laboratories to avoid misdiagnosis due to oral direct factor Xa (FXa) or IIa (FIIa) inhibitors. Overall, oral direct FXa (apixaban, betrixaban, edoxaban and rivaroxaban) and FIIa (dabigatran) antagonists may affect clot-based thrombophilia diagnostic tests resulting in false-positive or false-negative results. An effect on FIIa-based thrombophilia diagnostic tests is observed with dabigatran but not with anti-FXa DOACs and conversely for FXa-based thrombophilia diagnostic tests. No impact was observed with antigenic/chromogenic methods for the assessment of protein S and C activity. In conclusion, interpretation of thrombophilia diagnostic tests results should be done with caution in patients on DOACs. The use of a device/chemical compound able to remove or antagonize the effect of DOACs or the development of new diagnostic tests insensitive to DOACs should be considered to minimize the risk of false results.     

口服抗凝剂Edoxaban

深静脉血栓（DVT）及相关并发症已成为影响公众健康的主要杀手之一。由于目前临床使用的抗凝疗法均存在局限性，人们正在积极开发强效稳定的新型口服小分子抗凝药。活化因子FXa为一种丝氨酸蛋白酶，可将凝血酶原转化为凝血酶，是一个极具价值的抗凝作用靶点，它在内源性和外源性两条凝血途径的会聚点发挥作用，现已成为开发新一代抗凝药物的主要靶点。     

Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians

Click to hear Dr Baglin's perspective on the role of the laboratory in treatment with new oral anticoagulants

Summary

One of the key benefits of the direct oral anticoagulants (DOACs) is that they do not require routine laboratory monitoring. Nevertheless, assessment of DOAC exposure and anticoagulant effects may become useful in various clinical scenarios. The five approved DOACs (apixaban, betrixaban, dabigatran etexilate, edoxaban and rivaroxaban) have different characteristics impacting assay selection and the interpretation of results. This article provides an updated overview on (i) which test to use (and their advantages and limitations), (ii) when to assay DOAC levels, (iii) how to interpret the results relating to bleeding risk, emergency situations and perioperative management, and (iv) what is the impact of DOACs on routine and specialized coagulation assays. Assays for anti‐Xa or anti‐IIa activity are the preferred methods when quantitative information is useful, although the situations in which to test for DOAC levels are still debated. Different reagent sensitivities and variabilities in laboratory calibrations impact assay results. International calibration standards for all specific tests for each DOAC are needed to reduce the inter‐laboratory variability and allow inter‐study comparisons. The impact of the DOACs on hemostasis testing may cause false‐positive or false‐negative results; however, these can be minimized by using specific assays and collecting blood samples at trough concentrations. Finally, prospective clinical trials are needed to validate the safety and efficacy of proposed laboratory thresholds in relation to clinical decisions. We offer recommendations on the tests to use for measuring DOACs and practical guidance on laboratory testing to help patient management and avoid diagnostic errors.     

Safety of non-vitamin K antagonist oral anticoagulants - coronary risks

ABSTRACT

Introduction: Since the approval and commercialization of non-vitamin K antagonist oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban, and rivaroxaban) several studies and meta-analyses have raised safety concerns regarding myocardial infarction (MI) risk among NOAC-treated patients, particularly with dabigatran. Uncertainty remains regarding the coronary risk associated with dabigatran, and whether this putative risk also applies to the other NOACs.

Areas covered: In this review, the coronary risks of NOACs based on findings from placebo-controlled trials are discussed, and randomized controlled trials and major cohort studies in AF patients are also appraised. We performed a random-effect meta-analysis, including both interventional trials and observational studies (“real-world” data). Further estimates were retrieved from the meta-analysis of coronary risk among NOAC-treated patients with concomitant AF and coronary disease.

Expert opinion: Currently, the best available data from both clinical trials and observational studies do not support the claim that patients treated with NOACs, including dabigatran, are at increased coronary risk. However, a definitive conclusion cannot be made (especially regarding dabigatran) and further data are required to address the coronary risks, mostly of high-risk patients. As with any therapeutic intervention, the possible complications should be balanced against the potential benefits at an individual patient level.