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.     

Direct‐acting oral anticoagulants: pharmacology,indications, management,and future perspectives

In recent years, several direct‐acting oral anticoagulants (DOAC) have become available for use in Europe and other regions in indications related to prophylaxis and treatment of venous and arterial thromboembolism. They include the oral direct thrombin inhibitor dabigatran etexilate (Pradaxa^®, Boehringer Ingelheim) and the oral direct FXa inhibitors rivaroxaban (Xarelto^®, Bayer HealthCare), apixaban (Eliquis^®, Bristol‐Myers Squibb), and edoxaban (Lixiana^®/Savaysa^®, Daiichi‐Sankyo). The new compounds have a predictable dose response and few drug–drug interactions (unlike vitamin k antagonists), and they do not require parenteral administration (unlike heparins). However, they accumulate in patients with renal impairment, lack widely available monitoring tests for measuring its anticoagulant activity, and no specific antidotes for neutralization in case of overdose and/or severe bleeding are currently available. In this review, we describe the pharmacology of the DOAC, the efficacy, and safety data from pivotal studies that support their currently approved indications and discuss the postmarketing experience available. We also summarize practical recommendations to ensure an appropriate use of the DOAC according to existing data. Finally, we discuss relevant ongoing studies and future perspectives.     

Impact of four direct oral anticoagulants on rotational thromboelastometry (ROTEM)

Introduction

Rotational Thromboelastometry (ROTEM) is a point of care method used to monitor coagulation during surgery and to guide transfusion strategies in patients presenting with severe bleeding. The aim of our study was to determine the impact of four direct oral anticoagulants (DOACs) on 3 commonly used ROTEM tests.

Methods

Whole blood samples from 20 healthy donors were spiked in vitro with apixaban, edoxaban, rivaroxaban or dabigatran at 5 different plasma concentrations (0‐1000 ng/mL). EXTEM, INTEM and FIBTEM tests were systematically performed.

Results

There was a linear relationship between the increase in clotting time (CT) and plasma DOAC concentrations in both the EXTEM and INTEM tests. We found that the DOAC concentration required to double EXTEM CT was 1042 ± 225 ng/mL for apixaban, 134 ± 38 ng/mL for edoxaban, 176 ± 26 ng/mL for rivaroxaban and 284 ± 73 ng/mL for dabigatran. INTEM CT was less sensitive than EXTEM CT whatever the anticoagulant. EXTEM CT was above the normal range for 5 of 5 spiked samples when the plasma concentrations were ~1000 ng/mL for apixaban, ~100 ng/mL for edoxaban, ~200 ng/mL for rivaroxaban and ~200 ng/mL for dabigatran. Maximum Clot Firmness in EXTEM, INTEM and FIBTEM tests was not affected whatever the DOAC or its concentration.

Conclusion

This study found a DOAC dose‐dependent increase in ROTEM CTs. ROTEM tests were only poorly impacted by low levels of edoxaban, rivaroxaban or dabigatran. Apixaban had only a low effect even at high concentrations.     

Differences in activated clotting time and total unfractionated heparin dose during pulmonary vein isolation in patients on different anticoagulation therapy

BackgroundPeriprocedural pulmonary vein isolation (PVI) anticoagulation requires balancing between bleeding and thromboembolic risk. Intraprocedural anticoagulation is monitored by activated clotting time (ACT) with target value >300 s, and there are no guidelines specifying an initial unfractionated heparin (UFH) dose.MethodsWe aimed to assess differences in ACT values and UFH dosage during PVI in patients on different oral anticoagulants. We conducted an international, multi‐center, registry‐based study. Consecutive patients with atrial fibrillation (AF) undergoing PVI, on uninterrupted anticoagulation therapy, were analyzed. Before transseptal puncture, UFH bolus of 100 IU/kg was administered regardless of the anticoagulation drug.ResultsTotal of 873 patients were included (median age 61 years, IQR 53–66; female 30%). There were 248, 248, 189, 188 patients on warfarin, dabigatran, rivaroxaban, and apixaban, respectively. Mean initial ACT was 257 ± 50 s, mean overall ACT 295 ± 45 s and total UFH dose 158 ± 60 IU/kg. Patients who were receiving warfarin and dabigatran compared to patients receiving rivaroxaban and apixaban had: (i) significantly higher initial ACT values (262 ± 57 and 270 ± 48 vs. 248 ± 42 and 241 ± 44 s, p < .001), (ii) significantly higher ACT throughout PVI (309 ± 46 and 306 ± 44 vs. 282 ± 37 and 272 ± 42 s, p < .001), and (iii) needed lower UFH dose during PVI (140 ± 39 and 157 ± 71 vs. 171 ± 52 and 172 ± 70 IU/kg).ConclusionThere are significant differences in ACT values and UFH dose during PVI in patients receiving different anticoagulants. Patients on warfarin and dabigatran had higher initial and overall ACT values and needed lower UFH dose to achieve adequate anticoagulation during PVI than patients on rivaroxaban and apixaban.     

Uninterrupted anticoagulation with non‐vitamin K antagonist oral anticoagulants in atrial fibrillation catheter ablation: Lessons learned from randomized trials

Catheter ablation has been established as a rhythm control strategy in selected patients with atrial fibrillation (AF) who have failed or wish to avoid anti‐arrhythmic drugs. Uninterrupted oral anticoagulation with vitamin K antagonists (VKAs) peri‐ablation is associated with a lower risk of thromboembolic and bleeding complications as compared to interrupted oral anticoagulation and bridging heparin. However, a substantial portion of patients with AF are treated with non‐vitamin K antagonist oral anticoagulants (NOACs). Herein, we perform an in‐depth review and comparison of three recent randomized trials of uninterrupted oral anticoagulation with NOACs vs VKAs in patients undergoing AF catheter ablation. Furthermore, we report pooled results of these randomized trials. The pooled incidence of major bleeding was significantly lower with NOACs as compared to VKAs (2% vs 4.9%, respectively; odds ratio [OR] 0.40; 95% confidence intervals [CI] 0.16‐0.99). Similarly, cardiac tamponade was also reduced in the NOAC group (0.4% vs 1.5%; OR 0.27; 95% CI 0.07‐0.97). Thromboembolic complications were not significantly different between groups. Overall, these findings support the 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement's class I recommendation for uninterrupted NOAC use in patients undergoing AF catheter ablation.     

Venographic assessment of deep vein thrombosis and risk of developing post-thrombotic syndrome: a prospective study

Abstract. It is well known that patients with deep vein thrombosis (DVT) constitute a risk group for development of pulmonary embolism. However, the relation of DVT and the extent thereof with the subsequent sequelae (post-thrombotic syndrome) are insufficiently investigated. We have prospectively studied a series of consecutive patients admitted because of DVT on lower limbs, trying to correlate venographic findings during acute DVT with post-thrombotic (PTS) symptoms that develop later. Seventy-nine patients (84 limbs) with acute DVT were followed-up in our out-patient clinic at 4-monthly intervals for 3 years. At each visit patients were carefully examined regarding the appearance of PTS symptoms and/or signs from the DVT-affected leg. Three years after discharge, presence of PTS signs was assessed according to a simple scoring system. And then correlated to venographic findings during acute DVT. Patients were classified as having no (37 legs), mild (30 legs), or severe PTS signs (17 legs). Patients with popliteal vein involvement showed a significantly higher incidence of PTS 3 years later (P < 0.001). The risk of PTS also increased as DVT extent increased (P < 0.001). Nevertheless, the logistic regression analysis showed that DVT location explained all the differences (P < 0.001). In other words, DVT extent was overriden by the significance of DVT location, being popliteal the only location that showed a relevant contribution to the PTS incidence (95% confidence interval = 2.49–71.5).     

新型抗凝药与华法林对非瓣膜性心房颤动患者抗凝效果的临床评价

[目的]研究利伐沙班、达比加群酯与华法林对非瓣膜性心房颤动抗凝效果。[方法]收集心内科接收的120例非瓣膜性心房颤动住院患者为研究对象,均服用单一抗凝药物,分为华法林组(40例)、利伐沙班组(40例)和达比加群酯组(40例),接受药物治疗6个月,比较治疗期间栓塞事件、出血事件发生率和血常规、肝肾功能及血栓弹力图指标情况。[结果]治疗6个月后,利伐沙班组和达比加群酯组栓塞事件发生率明显低于华法林组(P<0.05),而利伐沙班组与达比加群酯组比较差异无显著性(P>0.05);三组出血事件发生率、治疗前及治疗后6个月患者血常规指标(白细胞计数、血小板计数、血红蛋白)、肝肾功能指标(血清肌酐、谷丙转氨酶、血尿素氮)比较差异无显著性(P>0.05);治疗6个月后利伐沙班组与达比加群酯组血栓弹力图指标R值、K值、MA值均明显高于华法林组(P<0.05),但利伐沙班组与达比加群酯组比较差异无显著性(P>0.05)。[结论]利伐沙班、达比加群酯治疗非瓣膜性心房颤动相比华法林具有更优的抗凝效果,降低栓塞事件的发生,且对肝肾功能及血常规无明显影响,安全性高。     

Presenting D‐dimer and early symptom severity are independent predictors for post‐thrombotic syndrome following a first deep vein thrombosis

Post‐thrombotic syndrome (PTS) is the most common complication of deep vein thrombosis (DVT). Current preventative strategies are limited to the daily wear of graduated compression stockings (GCS). The aim of this study was to evaluate early predictors of PTS. One hundred and twenty‐two consecutive patients with a first DVT were prospectively recruited from diagnosis and followed for up to 6 months post‐end of anticoagulation. D‐dimer was measured in 107 participants at presentation and Villalta scale was evaluated in 70 participants at a median of 2 weeks following diagnosis. PTS developed in 51·6% of participants. GCS were obtained by 78·1% of participants, with 33·7% reporting daily wear at the end of follow‐up. Mean early Villalta scale was significantly higher in those with PTS (8·1 ± 3·7) compared to those without (2·6 ± 2·7, P < 0·001). Median D‐dimer was significantly higher in those with PTS [3260 ng/ml, interquartile range (IQR) 820–8000 ng/ml] compared to those without (1540 ng/ml, IQR 810–2520 ng/ml, P < 0·001). The adjusted odds ratio for every one point increase in early Villalta scale was 1·78 [95% confidence interval (CI), 1·19–2·64; P = 0·005] and for D‐dimer >1910 ng/ml it was 2·71 (95% CI, 1·05–7·03; P = 0·04). These markers could enable targeted counselling regarding GCS for those at high risk of PTS.     

Progress in the monitoring of direct oral anticoagulant therapy

The availability of direct oral anticoagulants (DOACs) has led to a paradigm shift in the field of anticoagulation, with DOACs increasingly being prescribed for patients in preference to vitamin K antagonists and low molecular weight heparin. Despite good experience with the use of these agents at fixed doses, there are clinical scenarios where monitoring is recommended. Data from phase III studies of the DOACs and small real-world studies suggest a relationship between DOAC concentration and clinical events. The DOACs have differing impacts on the common tests of haemostasis and it is important that clinicians are familiar with the sensitivity of the reagents used in their laboratory to individual DOACs. The specific DOAC drug concentrations can be assayed in the laboratory, when required, to guide appropriate clinical decision-making. Studies from the real world with sufficient numbers evaluating the association of DOAC concentrations with outcomes should be a research priority in order to understand if we could do better through dose individualisation.