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Kim, Song, Soh, Kwak, and Shim: Perioperative management of patients receiving non-vitamin K antagonist oral anticoagulants: up-to-date recommendations

Abstract

Indications of non-vitamin K antagonist oral anticoagulants (NOACs), consisting of two types: direct thrombin inhibitor (dabigatran) and direct factor Xa inhibitor (rivaroxaban, apixaban, and edoxaban), have expanded over the last few years. Accordingly, increasing number of patients presenting for surgery are being exposed to NOACs, despite the fact that NOACs are inevitably related to increased perioperative bleeding risk. This review article contains recent clinical evidence-based up-to-date recommendations to help set up a multidisciplinary management strategy to provide a safe perioperative milieu for patients receiving NOACs. In brief, despite the paucity of related clinical evidence, several key recommendations can be drawn based on the emerging clinical evidence, expert consensus, and predictable pharmacological properties of NOACs. In elective surgeries, it seems safe to perform high-bleeding risk surgeries 2 days after cessation of NOAC, regardless of the type of NOAC. Neuraxial anesthesia should be performed 3 days after cessation of NOACs. In both instances, dabigatran needs to be discontinued for an additional 1 or 2 days, depending on the decrease in renal function. NOACs do not require a preoperative heparin bridge therapy. Emergent or urgent surgeries should preferably be delayed for at least 12 h from the last NOAC intake (better if > 24 h). If surgery cannot be delayed, consider using specific reversal agents, which are idarucizumab for dabigatran and andexanet alfa for rivaroxaban, apixaban, and edoxaban. If these specific reversal agents are not available, consider using prothrombin complex concentrates.

INTRODUCTION

Atrial fibrillation, the most frequently encountered arrhythmia, is associated with thromboembolism and stroke which need to be prevented amongst other therapies involving rhythm control [1]. For that purpose, vitamin K antagonist, warfarin, has long been used despite its inconstant and unpredictable anticoagulation effect which requires constant dose adjustments and laboratory monitoring [2,3]. Non-vitamin K antagonist oral anticoagulants (NOACs), also called direct oral anticoagulants (DOACs), were developed as an alternative to warfarin in order to overcome the aforementioned pharmacological limitations of warfarin [4,5].
Based on cumulating clinical evidence stemming from large multicenter randomized trials, NOACs were shown to be non-inferior to warfarin in preventing stroke and thromboembolism with lower risk of serious bleeding events in patients with non-valvular atrial fibrillation [6-9]. Additionally, owing to the reliable pharmacokinetic properties of NOACs, they were prescribed in fixed doses without laboratory monitoring. This led to the incorporation of NOACs as valuable therapeutic options for anticoagulation in atrial fibrillation patients, by the American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) in 2014 [1]. With the emergence of newer evidences showing favorable clinical efficacy and safety of NOACs in various subsets of patients [10-12], focused update of the 2014 guideline by the AHA/ACC/HRS in 2019 recommended the use of NOACs as first-line agents over warfarin in eligible patients with non-valvular atrial fibrillation (i.e., except those with moderate-to-severe mitral stenosis or a mechanical heart valve) [13]. A similar preference of NOACs over warfarin was also advocated by the European Heart Rhythm Association in 2018 [14]. Furthermore, current indications of NOACs include treatment or prevention of deep vein thrombosis and pulmonary embolism, promoting its widespread use [15-17].
Accordingly, increasing number of patients presenting for surgery are exposed to NOACs, despite the fact that NOACs can inevitably increase risk of bleeding as other anticoagulants. This review aimed to provide essential knowledge on NOACs, and evidence-based up-to-date recommendations regarding the perioperative management of NOACs.

PHARMACOLOGICAL ASPECTS OF NOACS

Unlike warfarin which affects multiple vitamin K-dependent coagulation factors II, VII, IX, and X, NOACs were designed to directly act on a single target factor to yield a more predictable anticoagulant response [18]. Currently, there are 4 approved NOACs which can be divided in 2 types depending on their action mechanisms (Fig. 1): the direct thrombin inhibitor (dabigatran) [19], and the direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) which imped the conversion of prothrombin to thrombin [20].
Compared to warfarin, the pharmacokinetic advantages of NOACs include a more rapid onset (time to peak: 1 to 3 h), shorter elimination half-life (5 to 15 h), lower predisposition to food and drug interaction (do not require restriction on vitamin K-containing food), and a more predictable anticoagulation effect (Table 1) [18,20]. These features allow fixed-dose administration in the absence of routine therapeutic laboratory monitoring. Thus, the major studies that compared the efficacy of NOACs with warfarin did not carry out dose adjustments or perform routine laboratory testing to detect the therapeutic level of NOACs [6-9].
NOACs undergo hepatic metabolism and plasma hydrolysis, and are substrates for the multidrug transporter P-glycoprotein and CYP 3A4 metabolism, while edoxaban exists mostly in an unchanged form in plasma, being minimally metabolized through CYP 3A4 [18,20]. Therefore, concomitant administration of drugs that strongly inhibit these pathways, such as dronedarone, amiodarone, and verapamil, may increase the active drug levels of the NOACs, except edoxaban [21]. NOACs are mostly excreted via the kidney, and approximately 80%, 33%, 27%, and 50% of dabigatran, rivaroxaban, apixaban, and edoxaban, respectively, undergo unchanged renal elimination, mandating the need for regular monitoring of renal function [4].

BLEEDING RISK ASSOCIATED WITH NOACS AND REVERSAL AGENTS

Although NOACs were shown to be associated with lower rates of intracranial and life-threatening bleeding when compared with warfarin [22], all anticoagulants have the innate potential to increase bleeding risk. In patients with non-valvular atrial fibrillation treated with NOACs, the estimated pooled incidence of hemorrhagic stroke was 0.4% [22]. In contrast, NOACs conferred a 1.5-fold increased risk of gastrointestinal bleeding, which accounted for approximately 90% of the major extracranial bleeding, compared to warfarin [6,7,9,23], with an overall 3.3% incidence of major bleeding [24].
Unlike warfarin which can be readily reversed by vitamin K, prothrombin complex concentrates (PCC), or fresh frozen plasma (FFP), there were no available reversal agents for NOACs during the major phase III clinical trials. Still, the fatality rate of patients on NOACs who exhibited major bleeding was similar or even less than that of patients on warfarin [22]. Nonetheless, bleeding complications happen, whether spontaneous in nature or associated with an invasive procedure/surgery. Accordingly, the reversal agents developed for NOACs were shown to be effective in stopping major bleeding events [25-27]. Although there is limited clinical evidence on these agents due to the unexpected nature of spontaneous bleeding events, two reversal agents were approved by the U.S. Food and Drug Administration (FDA): idarucizumab for dabigatran reversal and andexanet alfa for rivaroxaban and apixaban reversal [13]. Additionally, another reversal agent, ciraparantag, which can theoretically reverse the anticoagulation effects of all NOACs is being studied, and the results are being awaited [26].

Idarucizumab

Idarucizumab is a humanized monoclonal antibody fragment (antigen-binding fragment; Fab) which has a 350-fold higher binding affinity to dabigatran than thrombin [28]. Thus, it frees thrombin from dabigatran inhibition and immediately reverses the anticoagulation effect in a dose-dependent manner after intravenous administration [29]. The recommended administration protocol suggests two 2.5 g intravenous boluses (total of 5 g), each given in 50 ml infusion over 5-10 min in order to reverse 99% of the estimated dabigatran’s anticoagulation effect [27]. Although its elimination half-life is approximately 45 min, doses of 2 g or more have been shown to exert a complete and sustained effect over 72 h [29]. Yet, administration of a second dose of 5 g may be considered, if necessary.
While relevant clinical evidence is limited, overall, idarucizumab has been shown to be effective in reversing dabigatran-induced major bleeding. Its efficacy has also been shown in patients requiring emergency surgery, and normal hemostasis with its use could be confirmed by the surgeons in approximately 93% of the patients, while the incidence of thromboembolic events at 30 days after idarucizumab administration was 4.8% [27]. Thus, despite the paucity of related clinical evidence, the U.S. FDA has approved the use of idarucizumab for patients receiving dabigatran who exhibit life-threatening bleeding or require emergent surgery as incorporated in the 2019 update of AHA/ACC/HRS guidelines (class I recommendation, level of evidence B-NR) [13].

Andexanet alfa

Andexanet is an inactive variant of human recombinant factor Xa in which the active serine-residue is replaced by alanine to eliminate its catalytic activity and to prevent the formation of prothrombin complex [30]. Thus, theoretically, andexanet can reverse the anticoagulant effect of all NOACs that are factor Xa inhibitors, except dabigatran. Andexanet’s binding affinity to factor Xa inhibitors is similar to that of the native factor Xa [26].
Considering the importance of a specific reversal agent, the U.S. FDA has recently approved (accelerated-approval pathway) the use of andexanet alfa for reversal of rivaroxaban- or apixaban-induced life-threatening or uncontrolled bleeding, based on the limited evidence from healthy volunteers, and this has newly been incorporated in the 2019 update of AHA/ACC/HRS guidelines (class IIa recommendation, level of evidence B-NR) [13]. Shortly after the approval of andexanet and the publication of relevant focused update by the AHA/ACC/HRS in 2019, full study results of a prospective multicenter trial addressing the efficacy of andexanet alfa for bleeding associated with factor Xa inhibitors (ANNEXA-4 trial) were published [25]. In that study, treatment with andexanet resulted in immediate reduction of anti-factor Xa activity (92% reduction in both apixaban and rivaroxaban), yielding good hemostatic efficacy in 82% of the patients at 12 h, with a thromboembolic event rate of 10% at 30 days.
Current dosing recommendations are intravenous bolus over 15-30 min, followed by 2 h of continuous infusion: 1) 400 mg bolus, 480 mg infusion in patients who received rivaroxaban (last intake > 7 h) or apixaban, and 2) 800 mg bolus, 960 mg infusion in patients who received rivaroxaban within 7 h (or unknown timing) or edoxaban [14,25].
Notably, andexanet also binds to heparin-antithrombin III complex, reversing the actions of low molecular-weight heparin and unfractionated heparin [31].

Ciraparantag

Ciraparantag is a synthetic cationic molecule that was developed to reverse the anticoagulation effect of unfractionated or low molecular-weight heparin via non-covalent hydrogen linkage and charge-charge interaction [32]. Also, it directly binds to Xa inhibitors and thrombin inhibitors in a similar manner [20]. Thus, it would be able to reverse the anticoagulation effect of all NOACs, irrespective of their action mechanism. Available data which show its promising results in reversing the anticoagulation effect of all NOACs are limited to animal studies or healthy volunteers [33]. Currently, ciraparantag is not approved for clinical use.

ELECTIVE SURGERY AND NOACS

Approximately 10% of patients who require oral anticoagulants undergo surgery or invasive procedures yearly [34,35]. For patients’ safety, it is unarguable that NOACs should be appropriately discontinued in patients undergoing intermediate/high bleeding risk procedures. So far, clinical evidence is not enough to support a uniform guideline, and current recommendations by responsible societies including the AHA, European Heart Rhythm Association, and the European Society of Anaesthesiologists published in 2017, 2018, and 2017, respectively, are largely based on limited clinical studies and expert consensus [14,20,36-38]. Nonetheless, NOACs’ reliable pharmacologic profiles would permit safe surgery and recovery by maintaining the balance between bleeding and thromboembolic risk.
To provide the patients with a safe perioperative milieu, two major questions arise: 1) when to discontinue NOACs before surgery, and 2) the need for bridge-anticoagulation therapy. First, NOACs have a relatively short half-life, ranging from 5 to 15 h in patients with normal renal function [20]. Thus, discontinuing NOACs for 2 days before surgery with high bleeding risk would allow negligible residual drug concentration (usually < 10% corresponding to discontinuation for 3 to 4 half-lives), whereas discontinuation for 1 day would suffice for surgeries or procedures with low bleeding risk (15 to 25% residual activity) [38]. Notably, the elimination of NOACs depends on the renal function to various degrees which must be assessed and properly taken into consideration before surgery. Based on creatinine clearance (CrCl), dabigatran needs to be discontinued for 3 days and 4 days with CrCl of 50 to 79 ml/min and 30 to 49 ml/min, respectively [14]. In case of rivaroxaban, apixaban, and edoxaban, 2 days would suffice in most of the patients, regardless of the renal function. In all patients, further consideration should be given when receiving concomitant dronedarone, amiodarone, or verapamil, such as discontinuation for an additional 1 day when the thromboembolic risk is not high [14,21].
Second, preoperative bridge therapy with heparin is usually recommended for patients at high-risk of thromboembolic complication, such as those with mechanical heart valve [13]. However, as NOACs are currently not indicated in patients with mechanical heart valve, this recommendation does not apply to patients receiving NOACs. Also, the short elimination half-lives of NOACs require a short duration of cessation before surgery as opposed to the 5 days required in warfarin [20,39]. Moreover, discontinuation of NOACs has not been shown to result in rebound hypercoagulability [7-9]. Indeed, sub-analysis of major NOAC trials showed a low incidence of thromboembolic events ranging from 0.2 to 0.6% without bridging, whereas bridging with heparin resulted in increased bleeding complications without any benefit in terms of thromboembolic risk [24,40,41]. Thus, bridging therapy for NOACs in the preoperative period is currently not recommended, but it should be restarted after surgery as soon as possible [14].
So far, clinical evidence adhering to the above-mentioned recommendations for interruption of NOACs before surgery resulted in a similar rate of postoperative bleeding events when compared to patients receiving warfarin [38]. Data from pivotal NOACs studies including the German and Canadian registry, reported major bleeding incidences ranging from 0.6 to 3% after surgery [24,42]. Recently, full data from the perioperative anticoagulation use for surgery evaluation (PAUSE) cohort trial was published, and so far, it is the largest prospective multicenter trial that provided more insights regarding the perioperative NOACs management [43]. In that study, NOACs were discontinued for 1 day and 2 days for low- and high-bleeding risk procedures, respectively. In patients receiving dabigatran, longer interruption was applied accounting for CrCl. NOACs were resumed 1 day and 2 to 3 days after low- and high-bleeding risk surgeries, respectively. Overall, major bleeding rates were less than 2%, and the rates of thromboembolism were less than 1%, showing similar efficacies as with warfarin and confirming the clinical usefulness of the simple management strategy.
Neuraxial anesthesia, such as spinal or epidural, is considered a high-bleeding risk procedure. The most recent recommendations by the American Society of Regional Anesthesia and Pain Medicine published in 2018 approaches NOACs on a more conservative basis considering the even more limited clinical evidence in that regard [44]. Dabigatran was recommended to be discontinued for 3, 4, and 5 days in patients with CrCl of > 80, 50 to 79, and < 50 ml/min, respectively. Rivaroxaban, apixaban, and edoxaban were recommended to be discontinued for 3 days before Neuraxial anesthesia.
A summary of the current recommendations incorporating the most recent clinical evidences are displayed in Fig. 2.

EMERGENT/URGENT SURGERY AND NOACS

In an emergent situation, NOACs should be immediately stopped, and the following detailed knowledge should be acquired: 1) type of NOAC used, 2) last time of intake, 3) renal function, and 4) full panel of coagulation tests (prothrombin time [PT], activated partial thromboplastin time [aPTT], and possibly chromogenic anti-factor Xa assay, or diluted thrombin time [dTT]/ecarin-based assays [ECA]) [14].
In life-threatening or salvage emergencies such as cardiac, vascular, or neurosurgical surgeries that cannot be delayed even for a few hours, consideration should be given to administer specific reversal agents: idarucizumab for dabigatran and andexanet for rivaroxaban, apixaban, and edoxaban [14]. Yet, in case of surgeries requiring systemic heparinization, such as cardiac or vascular, the use of andexanet may be deferred until heparin reversal with protamine, as it may inhibit the anticoagulant effect of heparin [31] which is an absolute necessity for surgery. It should be noted that the incidence of thromboembolic events showed a dramatic increase to 18% after administration of the reversal agents [45,46], whereas it was less than 1% in case of planned interruption of NOACs [43]. Thus, apart from their high cost, the use of specific reversal agents should be carefully decided.
If these specific reversal agents are not accessible, PCC may be given, although the supporting clinical evidence is limited and controversial [47-49]. Suggested regimens of PCC include 2 doses of 4-factor PCC or an initial bolus of 50 IU/kg followed by an additional 25 IU/kg if necessary [14]. FFP is not likely to effectively reverse NOACs, unless used in large volumes (at least 8-16 units of FFP would equal the dose of 25-50 IU/kg of 4-factor PCC), and thus, it is not recommended for that purpose [50]. Also, without related clinical evidence, other therapies aimed at reducing perioperative blood loss, such as tranexamic acid, which is an antifibrinolytic agent that may be considered due to its proven efficacy and relative safety in major surgeries [36].
In urgent cases that need to be done within hours, consideration should be given to delaying the surgery for at least 12 h (preferably 24 h) after the last NOAC administration, as a considerable amount of the given NOAC would be eliminated within this timespan. After delay, the coagulation tests should be performed again. Routine coagulation tests, such as PT and aPTT, cannot quantify or determine the activity of any given NOAC. Yet, a normal dTT or aPTT would most likely exclude high therapeutic levels of dabigatran, whereas normal PT would rule out high levels of rivaroxaban as well as edoxaban (to a lesser extent) [51]. Despite these associations, it should be noted that none of the routine coagulation tests ensure the absence of clinically significant levels of NOACs even when the test results are normal [51]. Preferably, specific tests to measure the activity of NOACs should be performed to guide the need for reversal agents. These include ECA for dabigatran and anti-factor Xa assays for rivaroxaban, apixaban, or edoxaban [52-54]. However, these tests may not be readily available in all institutions, and clinical evidence on targeting therapies according to the specific test results is lacking, leaving the clinical judgment at the discretion of the attending physician.
In case of dabigatran, hemodialysis may be considered, as it has been shown that approximately 50 to 60% of the drug was removed after 4 h of hemodialysis administration [55]. But, the practicability of hemodialysis remains questionable considering that it requires anticoagulation. Other NOACs are unlikely to be removed by hemodialysis due to their high-protein binding properties [56].
Other non-specific measures to decrease its absorption is the use of activated charcoal (30 to 50 g), which has been shown to effectively reduce the absorption of recently overdosed NOACs [36]. Thus, it may be considered in patients who ingested NOAC within 2 to 4 h before urgent surgery. However, its efficacy in patients who received a prescribed dose of NOAC, and not accidental overdosed, remains questionable considering the side effects of charcoal including nausea/vomiting and aspiration [57].
A summary of the current recommendations incorporating the most recent clinical evidences are displayed in Table 2 and Fig. 3.

CONCLUSIONS

Emerging evidence advocates the use of NOACs over warfarin in patients with non-valvular atrial fibrillation, with indications expanding to patients at increased risk of deep vein thrombosis or pulmonary embolism [13,14,16,58]. As the field of anesthesiology has expanded to perioperative medicine, critical care, and pain medicine, patients receiving NOACs will be encountered more frequently in our daily practice. Practice guidelines regarding the management of NOACs should be available in every institution incorporating the recent evidence regarding the interruption strategy and specific reversal agents to provide optimal care in patients requiring surgeries.

Notes

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Conceptualization: Kwang-Sub Kim, Jae-Kwang Shim. Data acquisition: Sarah Soh, Jong Wook Song. Supervision: Young-Lan Kwak. Writing—original draf: Kwang-Sub Kim, Jae-Kwang Shim.

Fig. 1.
Comparison of action mechanisms between warfarin and non-vitamin K antagonists.
apm-2020-15-2-133f1.jpg
Fig. 2.
Perioperative management of non-vitamin K antagonists for elective surgery.
apm-2020-15-2-133f2.jpg
Fig. 3.
Perioperative management of non-vitamin K antagonists for emergent/urgent surgery. PT: prothrombin time, aPTT: activated partial thromboplastin time, dTT: diluted thrombin time, ECT: ecarin-based assay.
apm-2020-15-2-133f3.jpg
Table 1.
Pharmacological Properties of Non-vitamin K Antagonists
Non-vitamin K antagonists Dabigatran Rivaroxaban Apixaban Edoxaban
Inhibitory target Thrombin Factor Xa Factor Xa Factor Xa
Time to peak 1-2 h 2-4 h 1-4 h 1-2 h
Half-life 12-17 h 5-9 h 8-15 h 10-14 h
Renal elimination 80% 33% 20% 50%
Dialyzable Yes No No No
Reversal agent Idarucizumab Andexanet Andexanet Andexanet
Table 2.
Reversal Agents and Alternative Options for Patients on Non-vitamin K Antagonist Requiring Emergent/Urgent Surgery
Non-vitamin K antagonists Dabigatran Rivaroxaban, apixaban, edoxaban
Reversal agents Idarucizumab Andexanet alfa
 Mode of action Humanized monoclonal antibody fragment Inactive variant of human recombinant factor Xa
Binds to dabigatran with 350-fold higher affinity than thrombin Binds to factor Xa inhibitors with similar affinity to native factor Xa
Also binds to heparin-antithrombin III complex
 Dosage IV bolus of 5 g (2.5 g over 5-10 min × 2) IV bolus over 15-30 min + 2 h of continuous infusion:
1) 400 mg bolus, 480 mg infusion (rivaroxaban intake > 7 h or apixaban)
2) 800 mg bolus, 960 mg infusion (rivaroxaban intake within 7 h [or unknown] or edoxaban)
Alternative options Hemodialysis for 4 h Hemodialysis not applicable
PCC, 2 doses of 4-factor PCC or bolus of 50 IU/kg (+ 25 IU/kg as necessary)
Tranexamic acid, bolus 10-30 mg/kg (10-20 min) + continuous infusion 3-5 mg/kg/h

IV: intravenous, PCC: prothrombin complex concentrates.

REFERENCES

1. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, et al.; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64: e1-76.
crossref pmid
2. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133(6 Suppl): 160S-98S.
crossref pmid
3. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(2 Suppl): e44S-88S.
crossref pmid pmc
4. Yeh CH, Hogg K, Weitz JI. Overview of the new oral anticoagulants: opportunities and challenges. Arterioscler Thromb Vasc Biol 2015; 35: 1056-65.
crossref pmid
5. Levy JH, Faraoni D, Spring JL, Douketis JD, Samama CM. Managing new oral anticoagulants in the perioperative and intensive care unit setting. Anesthesiology 2013; 118: 1466-74.
crossref
6. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al.; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-51.
crossref pmid
7. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al.; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-91.
crossref pmid
8. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al.; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-92.
crossref pmid
9. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al.; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093-104.
crossref pmid
10. Fanola CL, Giugliano RP, Ruff CT, Trevisan M, Nordio F, Mercuri MF, et al. A novel risk prediction score in atrial fibrillation for a net clinical outcome from the ENGAGE AF-TIMI 48 randomized clinical trial. Eur Heart J 2017; 38: 888-96.
crossref pmid
11. Ezekowitz MD, Nagarakanti R, Noack H, Brueckmann M, Litherland C, Jacobs M, et al. Comparison of dabigatran and warfarin in patients with atrial fibrillation and valvular heart disease: the RE-LY trial (randomized evaluation of long-term anticoagulant therapy). Circulation 2016; 134: 589-98.
crossref pmid
12. Piccini JP, Hellkamp AS, Washam JB, Becker RC, Breithardt G, Berkowitz SD, et al. Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Circulation 2016; 133: 352-60.
crossref pmid
13. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC Jr, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines and the Heart Rhythm Society in collaboration with the Society of Thoracic Surgeons. Circulation 2019; 140: e125-51.
pmid
14. Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, et al. The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018; 39: 1330-93.
crossref pmid pdf
15. Chan NC, Eikelboom JW, Weitz JI. Evolving treatments for arterial and venous thrombosis: role of the direct oral anticoagulants. Circ Res 2016; 118: 1409-24.
crossref pmid
16. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149: 315-52.
crossref pmid
17. Yeh CH, Gross PL, Weitz JI. Evolving use of new oral anticoagulants for treatment of venous thromboembolism. Blood 2014; 124: 1020-8.
crossref pmid pmc pdf
18. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development. Clin Pharmacokinet 2009; 48: 1-22.
crossref pmid
19. Levy JH, Spyropoulos AC, Samama CM, Douketis J. Direct oral anticoagulants: new drugs and new concepts. JACC Cardiovasc Interv 2014; 7: 1333-51.
crossref pmid
20. Raval AN, Cigarroa JE, Chung MK, Diaz-Sandoval LJ, Diercks D, Piccini JP, et al.; American Heart Association Clinical Pharmacology Subcommittee of the Acute Cardiac Care and General Cardiology Committee of the Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; and Council on Quality of Care and Outcomes Research. Management of patients on non-vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation 2017; 135: e604-33.
crossref pmid pmc
21. Godier A, Dincq AS, Martin AC, Radu A, Leblanc I, Antona M, et al. Predictors of pre-procedural concentrations of direct oral anticoagulants: a prospective multicentre study. Eur Heart J 2017; 38: 2431-9.
crossref pmid pdf
22. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955-62.
crossref pmid
23. Fang MC, Go AS, Chang Y, Hylek EM, Henault LE, Jensvold NG, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med 2007; 120: 700-5.
crossref pmid pmc
24. Beyer-Westendorf J, Gelbricht V, Förster K, Ebertz F, Köhler C, Werth S, et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 2014; 35: 1888-96.
crossref pmid pdf
25. Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al.; ANNEXA-4 Investigators. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019; 380: 1326-35.
crossref pmid pmc
26. Levy JH, Douketis J, Weitz JI. Reversal agents for non-vitamin K antagonist oral anticoagulants. Nat Rev Cardiol 2018; 15: 273-81.
crossref pmid pdf
27. Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017; 377: 431-41.
crossref
28. Glund S, Moschetti V, Norris S, Stangier J, Schmohl M, van Ryn J, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015; 113: 943-51.
crossref pmid pdf
29. Glund S, Stangier J, Schmohl M, Gansser D, Norris S, van Ryn J, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet 2015; 386: 680-90.
crossref
30. Crowther M, Crowther MA. Antidotes for novel oral anticoagulants: current status and future potential. Arterioscler Thromb Vasc Biol 2015; 35: 1736-45.
crossref pmid
31. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19: 446-51.
crossref pmid pdf
32. Sullivan DW Jr, Gad SC, Laulicht B, Bakhru S, Steiner S. Nonclinical safety assessment of PER977: a small molecule reversal agent for new oral anticoagulants and heparins. Int J Toxicol 2015; 34: 308-17.
crossref pmid
33. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014; 371: 2141-2.
crossref pmid
34. Douketis JD, Berger PB, Dunn AS, Jaffer AK, Spyropoulos AC, Becker RC, et al. The perioperative management of antithrombotic therapy: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008; 133(6 Suppl): 299S-339S.
crossref pmid
35. Healey JS, Eikelboom J, Douketis J, Wallentin L, Oldgren J, Yang S, et al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation 2012; 126: 343-8.
crossref pmid
36. Eikelboom JW, Kozek-Langenecker S, Exadaktylos A, Batorova A, Boda Z, Christory F, et al. Emergency care of patients receiving non-vitamin K antagonist oral anticoagulants. Br J Anaesth 2018; 120: 645-56.
crossref
37. Kozek-Langenecker SA, Ahmed AB, Afshari A, Albaladejo P, Aldecoa C, Barauskas G, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: first update 2016. Eur J Anaesthesiol 2017; 34: 332-95.
crossref pmid
38. Verma A, Ha ACT, Rutka JT, Verma S. What surgeons should know about non-vitamin K oral anticoagulants: a review. JAMA Surg 2018; 153: 577-85.
crossref
39. Gallego P, Apostolakis S, Lip GY. Bridging evidence-based practice and practice-based evidence in periprocedural anticoagulation. Circulation 2012; 126: 1573-6.
crossref
40. Douketis JD, Healey JS, Brueckmann M, Eikelboom JW, Ezekowitz MD, Fraessdorf M, et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE-LY trial. Thromb Haemost 2015; 113: 625-32.
crossref pmid pdf
41. Sherwood MW, Douketis JD, Patel MR, Piccini JP, Hellkamp AS, Lokhnygina Y, et al.; ROCKET AF Investigators. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 2014; 129: 1850-9.
crossref pmid pmc
42. Schulman S, Carrier M, Lee AY, Shivakumar S, Blostein M, Spencer FA, et al.; Periop Dabigatran Study Group. Perioperative management of dabigatran: a prospective cohort study. Circulation 2015; 132: 167-73.
crossref pmid
43. Douketis JD, Spyropoulos AC, Duncan J, Carrier M, Le Gal G, Tafur AJ, et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant. JAMA Intern Med 2019; 179: 1469-78.
crossref pdf
44. Horlocker TT, Vandermeuelen E, Kopp SL, Gogarten W, Leffert LR, Benzon HT. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (fourth edition). Reg Anesth Pain Med 2018; 43: 263-309.
crossref
45. Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al.; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016; 375: 1131-41.
crossref pmid pmc
46. Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373: 511-20.
crossref pmid
47. Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost 2014; 111: 189-98.
crossref pmid pdf
48. Grottke O, Aisenberg J, Bernstein R, Goldstein P, Huisman MV, Jamieson DG, et al. Efficacy of prothrombin complex concentrates for the emergency reversal of dabigatran-induced anticoagulation. Crit Care 2016; 20: 115.
crossref pmid pmc pdf
49. Raphael J, Mazer CD, Subramani S, Schroeder A, Abdalla M, Ferreira R, et al. Society of Cardiovascular Anesthesiologists clinical practice improvement advisory for management of perioperative bleeding and hemostasis in cardiac surgery patients. Anesth Analg 2019; 129: 1209-21.
crossref
50. Kaatz S, Crowther M. Reversal of target-specific oral anticoagulants. J Thromb Thrombolysis 2013; 36: 195-202.
crossref pdf
51. Eikelboom JW, Quinlan DJ, Hirsh J, Connolly SJ, Weitz JI. Laboratory monitoring of non-vitamin K antagonist oral anticoagulant use in patients with atrial fibrillation: a review. JAMA Cardiol 2017; 2: 566-74.
crossref pmid
52. Cuker A. Laboratory measurement of the non-vitamin K antagonist oral anticoagulants: selecting the optimal assay based on drug, assay availability, and clinical indication. J Thromb Thrombolysis 2016; 41: 241-7.
crossref pmid pdf
53. Dale BJ, Chan NC, Eikelboom JW. Laboratory measurement of the direct oral anticoagulants. Br J Haematol 2016; 172: 315-36.
crossref pmid
54. van Ryn J, Grottke O, Spronk H. Measurement of dabigatran in standardly used clinical assays, whole blood viscoelastic coagulation, and thrombin generation assays. Clin Lab Med 2014; 34: 479-501.
crossref pmid
55. Khadzhynov D, Wagner F, Formella S, Wiegert E, Moschetti V, Slowinski T, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 2013; 109: 596-605.
crossref pmid pdf
56. Siegal DM, Garcia DA, Crowther MA. How I treat target-specific oral anticoagulant-associated bleeding. Blood 2014; 123: 1152-8.
crossref pmid pdf
57. Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015; 17: 1467-507.
crossref pmid pdf
58. Bromley A, Plitt A. A review of the role of non-vitamin K oral anticoagulants in the acute and long-term treatment of venous thromboembolism. Cardiol Ther 2018; 7: 1-13.
crossref pdf


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