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.     

New anticoagulants: moving on from scientific results to clinical implementation

Vitamin K antagonists (VKA) are the only registered oral anticoagulants for the treatment of venous thromboembolism (VTE). VKA have an unpredictable and highly variable effect on coagulation, with a high risk of under- and over-treatment. Novel anticoagulants, such as dabigatran and rivaroxaban, could be a very welcome replacement for VKA, as they show a predictable anticoagulant effect. Results of several phase II and III studies have shown the efficacy and safety of dabigatran and rivaroxaban in the prophylaxis and treatment of VTE, and for the prevention of stroke in atrial fibrillation. It remains to be shown whether these new anticoagulants have the same safety profile in daily clinical practice, where more vulnerable patients will be treated. Lack of information on the proper monitoring method or antidote in case of bleeding may also hinder the translation from science to clinical practice.     

Evaluating coagulation tests in patients with atrial fibrillation using direct oral anticoagulants

Four direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, edoxaban) have been shown to be at least as effective and safe as warfarin for the prevention of stroke in atrial fibrillation and the prevention and treatment of venous thromboembolism. Although they are administered in fixed doses without routine coagulation monitoring, measurement of anticoagulant effect or drug levels may be useful to determine if: anticoagulant effect is present in patients who are bleeding or require an urgent procedure or thrombolysis; levels are within usual on-therapy range in patients with recurrent thromboembolism during treatment; and levels are outside of the usual on-therapy range in patients with overdose or with extreme clinical characteristics. Traditional coagulation assays are widely available but lack sensitivity to detect clinically relevant anticoagulant effects, and lack accuracy in quantitating drug levels. Specific drug assays are less widely available but can accurately measure drug levels and should be preferred.     

Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents

Summary. The most important adverse effect of antithrombotic treatment is the occurrence of bleeding. In the case of severe bleeding in a patient who uses anticoagulant agents or when a patient on anticoagulants needs to undergo an urgent invasive procedure, it may be useful to reverse anticoagulant treatment. Conventional anticoagulants such as vitamin K antagonists may be neutralized by administration of vitamin K or prothrombin complex concentrates, whereas heparin and heparin derivatives can be counteracted by protamine sulphate. The anti‐hemostatic effect of aspirin and other antiplatelet strategies can be corrected by the administration of platelet concentrate and/or desmopressin, if needed. Recently, a new generation of anticoagulants with a greater specificity towards activated coagulation factors as well as new antiplatelet agents have been introduced and these drugs show promising results in clinical studies. A limitation of these new agents may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs, although experimental studies show hopeful results for some of these agents.     

Effects of the oral,direct factor Xa inhibitor edoxaban on routine coagulation assays,lupus anticoagulant and anti-Xa assays

Edoxaban is an oral direct factor Xa inhibitor for prophylaxis and treatment of thromboembolic disorders. The effects on common coagulation assays are clinically valuable information and in certain clinical situations a quick assessment of the anticoagulant is wanted. Our aim was to investigate the effect of edoxaban on routine coagulation methods and evaluate anti-Xa assays, commonly used for other direct factor Xa inhibitors, for estimation of the drug concentration. Edoxaban was spiked to plasma samples from healthy subjects in the concentration range 0–742 µg/L and analyzed using different reagents for activated partial thromboplastin time (APTT) and prothrombin time (PT). Assays for antithrombin, activated protein C resistance, lupus anticoagulant (LA) and chromogenic anti-Xa assays were also included. Edoxaban displayed similar effects in vitro to other oral direct Xa inhibitors. The concentration needed to double the coagulation time varied between assays and reagents; 539–758 µg/L for the APTT and between 329 and 2505 µg/L for the PT. Edoxaban gave false high antithrombin activities in assays based on Xa-inhibition. Two integrated assays for LA, both based on activation with dilute Russell’s viper venom, displayed different results. Chromogenic anti-Xa assays displayed linear dose-response curves with edoxaban up to approximately 500 µg/L. In conclusion, therapeutic concentrations of edoxaban variably affect different coagulation assays, and even different reagents within an assay group. In comparison with other oral Xa-inhibitors, the in vitro effects of edoxaban were more similar to rivaroxaban than apixaban. For measurement of edoxaban concentration in plasma, it is possible to use the chromogenic anti-Xa assays.     

Laboratory testing of rivaroxaban in routine clinical practice: When,how, and which assays

Abstract

A number of target-specific oral anticoagulants (TSOAs) have been developed in recent years, and some have shown considerable promise in large-scale, randomized clinical trials in the prevention and treatment of thromboembolism. Unlike traditional anticoagulants, such as vitamin K antagonists, these TSOAs exhibit predictable pharmacokinetics and pharmacodynamics. Among these agents, rivaroxaban, a direct Factor Xa inhibitor, has been approved for clinical use in many countries for the management of several thromboembolic disorders. As with the other TSOAs, rivaroxaban is given at fixed doses without routine coagulation monitoring. However, in certain patient populations or special clinical circumstances, measurement of drug exposure may be useful, such as in suspected overdose, in patients with a haemorrhagic or thromboembolic event during treatment with an anticoagulant, in those with acute renal failure, or in patients who require urgent surgery. This article summarizes the influence of rivaroxaban on commonly used coagulation assays and provides practical guidance on laboratory testing of rivaroxaban in routine practice. Both quantitative measurement (using the anti-Factor Xa method) and qualitative measurement (using prothrombin time, expressed in seconds) are discussed, together with some practical considerations when performing these tests and interpreting the test results.     

Anticoagulant management in the cardiovascular setting

Vitamin K antagonists have been used as oral anticoagulants (OACs) for over five decades, yet their use in real-world practice is problematic primarily because of their narrow therapeutic window, exacerbated by extensive food and drug interactions, necessitating regular coagulation monitoring and dose adjustment. Around half of patients receiving warfarin are within the therapeutic range, exposing them to the dangers of under-anticoagulation (i.e. thrombosis formation) or over-anticoagulation (i.e. bleeding). A new generation of OACs with improved pharmacology promises to revolutionize antithrombotic management. Rivaroxaban, apixaban (both oral direct Factor Xa inhibitors) and dabigatran (a direct thrombin inhibitor) all exhibit predictable anticoagulant responses and few drug-drug interactions and do not require routine coagulation monitoring.     

Direct oral anticoagulants as alternative treatment options for the effective long-term treatment of patients with pulmonary embolism in primary care: a review

Abstract

Pulmonary embolism (PE) represents a potentially life-threatening venous thromboembolic disorder, and prompt treatment is vital to prevent early mortality. However, diagnosis of PE is complicated by the range of signs and symptoms with which it presents. Clinical risk scores, imaging techniques, and laboratory tests are recommended in clinical guidelines to aid diagnosis, and risk stratification strategies can be used to inform treatment decisions. Long-term anticoagulation is key to avoid the risk of later complications of acute PE, such as recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension. Rivaroxaban is a direct oral anticoagulant that has been approved for the treatment of PE (and deep vein thrombosis) and prevention of recurrent venous thromboembolism; other direct oral anticoagulants have undergone phase III trials for these indications. These agents may provide advantages over traditional anticoagulants, such as vitamin K antagonists, because they are administered at fixed doses and do not require routine coagulation monitoring. These advantages may improve patient adherence and aid general practitioners by simplifying long-term management of PE in daily primary care.     

Phase III studies on novel oral anticoagulants for stroke prevention in atrial fibrillation: a look beyond the excellent results

Summary. In this overview we address the three phase III studies that compared new oral anticoagulants (dabigatran, rivaroxaban and apixaban) with warfarin in the setting of stroke prevention in atrial fibrillation. Strengths and weaknesses of the studies were examined in detail through indirect comparison. We analyze and comment the inclusion and exclusion criteria, the characteristics of randomized patients, the primary efficacy and safety end points and side effects. All new oral anticoagulants resulted in being non‐inferior to vitamin K antagonists in reducing stroke or systemic embolism in patients with atrial fibrillation. Dabigatran 150 mg and apixaban were superior to vitamin K antagonists. Importantly, new oral anticoagulants significantly reduced hemorrhagic stroke in all three studies. Major differences among new oral anticoagulants include the way they are eliminated and side effects. Both dabigatran and apixaban were tested in low‐ to moderate‐risk patients (mean CHADS2 [Congestive heart failure, Hypertension, Age, Diabetes, Stroke] score = 2.1–2.2) whereas rivaroxaban was tested in high‐risk patients (mean CHADS2 score = 3.48) and at variance with dabigatran and apixaban was administered once daily. Apixaban significantly reduced mortality from any cause. The choice of a new oral anticoagulant should take into account these and other differences between the new drugs.     

Anticoagulants. Old and new

Anticoagulants are effective in the prevention and treatment of a variety of arterial and venous thrombotic disorders but are associated with an increased risk of serious bleeding complications. Based on well documented studies of patients using vitamin K antagonists the incidence of major bleeding is 0.5%/year and the incidence of intracranial bleeding is 0.2%/year, however, in real life practice this incidence may be even higher. Risk factors for bleeding are the intensity of anticoagulation, the management strategy to keep the anticoagulant effect in the desired range, and patient characteristics. Recently, a new generation of anticoagulants have been developed and is currently evaluated in clinical trials. Initial results show a similar or superior efficacy over conventional anticoagulant agents with a good safety profile. In case of serious bleeding complications in a patient who uses vitamin K antagonists, this anticoagulant treatment can be quickly reversed by administration of vitamin K or coagulation factor concentrates. For the newer anticoagulants, quick reversal strategies are more cumbersome, although some interventions, including prothrombin complex concentrates, show promising results in initial experimental studies.     

Considerations for routine coagulation monitoring with rivaroxaban:A case report and review of the literature

BACKGROUND Rivaroxaban is a non-vitamin K antagonist oral anticoagulant that does not require coagulation monitoring based on current recommendations. Our goal is to explore whether routine coagulation monitoring should not be required for all patients receiving oral rivaroxaban, what relationship between routine coagulation abnormalities and bleeding, and how to deal with the above clinical situations through our case and review of the literature.CASE SUMMARY We report a 67-year-old woman with a history of atrial fibrillation who presented to the hospital with worsening dyspnea and cough. Based on electrocardiogram,venous compression ultrasonography, and computed tomography pulmonary angiography, the diagnosis of atrial fibrillation, deep venous thrombosis, and acute pulmonary embolism was confirmed. Her coagulation assays and renal function were normal on admission; she was not underweight, did not have a history of hemorrhagic disease, and her CHA2 DS2-VAS, HAS-BLED, and simplified Pulmonary Embolism Severity Index scores were 3, 0, and 0,respectively. Oral rivaroxaban(15 mg twice daily) was administered. The following day, she presented gastrointestinal and gum bleeding, combined with coagulation abnormalities. Following cessation of rivaroxaban, her bleeding stopped and tests improved over the next 2 d. Rivaroxaban was begun again 3 d after recovery. However, she again presented with gastrointestinal and gum bleeding and the abnormal tests, and the therapy was discontinued. At 30-d follow-up after discharge, she presented normal coagulation tests without bleeding.CONCLUSION Although current guidelines recommend that using non-vitamin K antagonist oral anticoagulants including rivaroxaban do not require coagulation monitoring,a small number of patients may develop routine coagulation test changes and bleeding during rivaroxaban therapy, especially in the elderly. Clinicians should pay attention to these patients and further obtain evidence in practice.     

Factor Xa or thrombin: is factor Xa a better target?

Summary.  Existing vitamin K antagonists (VKAs) have drawbacks that limit their effectiveness, safety, and overall frequency of use. Oral anticoagulants in development with targeted action against individual coagulation factors, specifically direct factor (F) Xa and IIa inhibitors, appear to have pharmacokinetic and pharmacodynamic properties that overcome the limitations of the VKAs. Based on the theory of how coagulation factors interact, on the results of in vitro studies, and on clinical outcomes, there is accumulating evidence that FXa may represent a better target for inhibition than FIIa. This is based on an understanding of the amplified nature of coagulation factor interactions and fibrin formation, the need for smaller doses of an anticoagulant to block coagulation progression earlier in the sequence of reactions, the evidence for incomplete suppression of thrombin generation with direct thrombin inhibitors, evidence for rebound hypercoagulability with thrombin inhibitors, and clinical results with the indirect, parenteral, FXa inhibitor (fondaparinux), as well as early phase II results of new oral Xa and IIa inhibitors compared with enoxaparin. The latter studies, although not comparative, provide some evidence for the effectiveness and safety of Xa inhibitors at a range of doses not seen with the direct IIa inhibitors.     

Non-Vitamin K Oral Anticoagulants for Stroke Prevention in Special Populations with Atrial Fibrillation

Atrial fibrillation (AF) is associated with an increased risk of ischemic stroke or systemic embolism compared with normal sinus rhythm. These strokes may efficiently be prevented in patients with risk factors using oral anticoagulant therapy, with either vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) (i.e., direct thrombin inhibitors or direct factor Xa inhibitors). Owing to their specific risk profiles, some AF populations may have increased risks of both thromboembolic and bleeding events. These AF patients may be denied oral anticoagulants, whilst evidence shows that the absolute benefits of oral anticoagulants are greatest in patients at highest risk. NOACs are an alternative to VKAs to prevent stroke in patients with “non-valvular AF”, and NOACs may offer a greater net clinical benefit compared with VKAs, particularly in these high-risk patients. Physicians have to learn how to use these drugs optimally in specific settings. We review concrete clinical scenarios for which practical answers are currently proposed for use of NOACs based on available evidence for patients with kidney disease, elderly patients, women, patients with diabetes, patients with low or high body weight, and those with valve disease.     

New anticoagulants: from bench to bedside

Heparins and vitamin K antagonists have been the cornerstones of anticoagulation therapy for several decades. Although they are very effective at inhibiting the coagulation process, they have several practical limitations. This was a challenge for the development of therapies that will overcome these drawbacks while matching the efficacy of the two classes of anticoagulants. Advances were achieved in the development of safer, convenient, more specific treatments, which should provide predictable anticoagulant responses and substantially improve the prevention and management of thromboembolic disorders. In the search for new agents matching the ideal anticoagulant profile, different steps in the coagulation cascade have been targeted, including direct thrombin inhibition, and inhibition of factor Xa, factor IXa, the factor Vlla-tissue factor complex and the factor Va-factor Vllla complex. The most advanced clinical development has been achieved with direct factor Xa- and factor IIa-inhibitors which may replace conventional anticoagulants for long-term prevention and treatment of venous and arterial thromboembolic complications.     

Effects of anticoagulant strategies on activation of inflammation and coagulation

Acute inflammatory events, such as those that occur in sepsis, lead to dysregulation of the coagulation cascade. The hemostatic imbalance in sepsis, characterized by the excessive activation of procoagulant pathways and the impairment of anticoagulant activity, leads to disseminated intravascular coagulation and results in microvascular thrombosis, tissue hypoperfusion and, ultimately, multiple organ failure and death. Furthermore, natural anti-inflammatory mechanisms of the endogenous anticoagulants are diminished by the impaired coagulation. Supportive strategies aiming at inhibiting activation of coagulation and inflammation by treatment with exogenous anticoagulants have been found to be beneficial in experimental and initial clinical studies. This review summarizes the available experimental and clinical data regarding the interaction between coagulation and inflammation, focusing on the two anticoagulants which are in clinical use, antithrombin and activated protein C. Identification of the different biological mechanisms of the two endogenous anticoagulants might help to determine target patient populations as well as to develop new anticoagulant analogs that differ in there respective effects in coagulation and inflammation.     

Factor Xa or thrombin: Is thrombin a better target?

Summary.  The limitations of the vitamin K antagonists have prompted the development of new oral anticoagulants that target specific clotting enzymes. Most of the novel agents currently under development target either thrombin or factor Xa. As the final effector of blood coagulation and the most potent platelet agonist, thrombin is a logical target for new oral anticoagulants. Clinical trials with parenteral direct thrombin inhibitors revealed that the therapeutic window is wider with reversible inhibitors than with irreversible inhibitors. The results of clinical trials with ximelagatran, an orally active prodrug of melagatran, a reversible direct thrombin inhibitor, validate thrombin as a target. Although ximelagatran was withdrawn from the market because of hepatotoxicity, newer oral thrombin inhibitors, such as dabigatran etexilate, are filling the void. Several oral factor Xa inhibitors also are being tested. Is thrombin a better target for new oral anticoagulants than factor Xa? Only time will tell!     

Effects of anticoagulant strategies on activation of inflammation and coagulation

Acute inflammatory events, such as those that occur in sepsis, lead to dysregulation of the coagulation cascade. The hemostatic imbalance in sepsis, characterized by the excessive activation of procoagulant pathways and the impairment of anticoagulant activity, leads to disseminated intravascular coagulation and results in microvascular thrombosis, tissue hypoperfusion and, ultimately, multiple organ failure and death. Furthermore, natural anti-inflammatory mechanisms of the endogenous anticoagulants are diminished by the impaired coagulation. Supportive strategies aiming at inhibiting activation of coagulation and inflammation by treatment with exogenous anticoagulants have been found to be beneficial in experimental and initial clinical studies. This review summarizes the available experimental and clinical data regarding the interaction between coagulation and inflammation, focusing on the two anticoagulants which are in clinical use, antithrombin and activated protein C. Identification of the different biological mechanisms of the two endogenous anticoagulants might help to determine target patient populations as well as to develop new anticoagulant analogs that differ in there respective effects in coagulation and inflammation.     

Managing Bleeding in Anticoagulated Patients in the Emergency Care Setting

Background

Orally administered anticoagulants that offer alternatives to warfarin have been developed in recent years and are currently available for reduction of stroke risk in patients with non-valvular atrial fibrillation, the prophylaxis of venous thromboembolism after hip or knee replacement surgery, and the treatment and secondary risk reduction of deep vein thrombosis and pulmonary embolism.

Objectives

This article will provide a brief introduction to these new oral anticoagulants and then review the approaches that can be taken for the emergency management of hemostasis in patients bleeding or at risk for bleeding while receiving warfarin or one of two newer agents, the direct thrombin inhibitor dabigatran or the factor Xa inhibitor rivaroxaban.

Discussion

Oral anticoagulant use is widespread and likely to continue to increase. Warfarin has been the standard of care in oral anticoagulation for many years; its bleeding risks are well known and associated emergency protocols are well established. As newer oral anticoagulants become more widely used, similar procedures will need to be developed. Although there are as yet no specific reversal agents for these newer drugs, recommendations for overdose, emergency hemostasis, and preoperative management are available. Further, while the newer agents do not require routine coagulation monitoring, assays for use in non-routine situations are being explored.

Conclusions

The introduction of alternative oral anticoagulants will require emergency procedures that differ in some respects from those currently in place for warfarin and it will be necessary for Emergency Medicine professionals to become familiar with these procedures. Clinical stabilization of the bleeding or at-risk patient remains the emergency physician’s priority.     

The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism

Thromboembolic disorders are among the major causes of morbidity and mortality, and anticoagulation remains the cornerstone of prevention and treatment of these disorders. Although effective, the well-established agents have significant drawbacks. Heparin, low molecular weight heparin, and fondaparinux must be given parenterally, which is inconvenient for long-term or home use. The orally administered vitamin K antagonists (such as warfarin) have a slow onset of action, thus requiring bridging therapy with a parenteral agent when immediate anticoagulation is needed (e.g. inpatients with acute deep vein thrombosis). Because vitamin K antagonists produce a variable anticoagulant response as a result of multiple drug-drug and food-drug interactions and genetic polymorphisms, frequent coagulation monitoring and dose adjustment are required to ensure a therapeutic level of anticoagulation, which is inconvenient for both patients and physicians. In the search for new agents to overcome the drawbacks associated with traditional agents, direct Factor Xa inhibitors (e.g. rivaroxaban, apixaban, and edoxaban) and direct thrombin inhibitors (e.g. dabigatran etexilate) have been developed and are undergoing late-stage clinical evaluation for the prevention and treatment of thromboembolic disorders. These new oral agents have already shown promise in large-scale clinical studies and data suggest that we have entered a new era with novel drugs that are closer than ever to the 'ideal anticoagulant'. Because these new oral agents have a rapid onset of action and can be given at fixed doses without the need for routine coagulation monitoring, they may simplify treatment paradigms and are expected to improve overall clinical outcome.