Article

Using Direct Oral Anticoagulants in Patients with Atrial Fibrillation: Assessment, Monitoring and Treatment Reversal

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Abstract

It is essential to prevent thromboembolic events in atrial fibrillation. The risks of thromboembolic and haemorrhagic events must be carefully assessed and weighed against one another, both in routine situations and in relation to invasive procedures. Vitamin K antagonists, until recently the first-line treatment for prophylaxis against thromboembolic events in patients with atrial fibrillation, have various drawbacks. Direct-acting oral anticoagulants overcome these limitations and are efficacious and safe. The recent developments of tests to monitor anticoagulant levels, and of target-specific reversal agents for these newer drugs, has facilitated their use in several situations, including emergencies. For these reasons, the European Society of Cardiology and other scientific societies now recommend direct-acting oral anticoagulants as first-line treatment for preventing thromboembolic events in atrial fibrillation.

Disclosure:AMR has participated in activities and been a member of scientific advisory boards for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo and Pfizer, and has received research grants from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer.

Received:

Accepted:

Correspondence Details: Antoni Martínez-Rubio, University Hospital Sabadell, Department of Cardiology, Autonomous University of Barcelona, Parc Taulí 1, E-08208 Sabadell, Barcelona, Spain. E: amartinezrubio@icloud.com

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Atrial fibrillation (AF) is the most commonly encountered arrhythmia in clinical practice in Western countries. The prevalence of AF depends on the population studied1 and especially on age.2–9 It is affected by increasing longevity and is modulated by the prevalence of cardiovascular risk factors, especially arterial hypertension and related habits. In Spain, for example, the prevalence of AF among people >40 years of age is about 4.4 %,9 rising to 8.5 % among those >60 years and reaching 16.5 % among those >85 years.4 The prevalence of AF is expected to double in the next 50 years.10,11

AF is characterised by the anarchic (fast and disorganised) and unpredictable contraction of atrial muscle fibres. This arrhythmia is appears on an electrocardiogram as an absence of P-waves and irregular R-R intervals. It is usually associated with tachycardia. The resulting asynchrony leads to ineffective contraction, decreased ventricular ejection fraction and blood pooling, predisposing to coagulation inside the atrium and increasing the risk of thromboembolic events.

AF increases the risk of mortality and morbidity, resulting in high healthcare costs. It increases the probability of stroke by two- to sixfold and the probability of death by 1.5-fold to 2.2-fold.12–18 Moreover, the risk of stroke recurrence is higher in patients with AF than in those without. AF has been also associated with cognitive dysfunction, diminished quality of life and diminished functional capacity.19–22

The prevention and treatment of AF is important for both patients and healthcare systems. The complexity of the mechanisms involved calls for a multidimensional approach. Since AF is potentially dangerous,efforts to correct and/or control it are required; however, for various reasons these efforts often fall short. The efficacy of antiarrhythmic drugs is unpredictable, depending mainly on the duration of AF and the patient’s underlying heart disease. Moreover, antiarrhythmic drug treatment can cause proarrhythmia. AF can also recur after catheter ablation. Given the uncertain success of attempts to directly treat AF, it is therefore important to manage the attendant increased risk of thromboembolic events; most patients with AF will eventually need anticoagulant therapy to prevent thromboembolism.21,23,24

During the past 50 years, vitamin K antagonists (VKAs) have become the first-line oral anticoagulant treatment of choice for preventing thromboembolic events.25 Although VKAs improve prognosis by reducing thromboembolic events, they have diverse clinical limitations (see Figure 1).1 VKAs significantly increase the risk of minor and major bleeding complications, of which intracranial haemorrhage is particularly harmful. They can interact with many drugs and foods, and their effects are also influenced by hepatic metabolism. Regular monitoring and dose adjustments are thus essential to keep patients within the narrow therapeutic range throughout VKA treatment.

The novel direct-acting oral anticoagulants (DOACs) such as dabigatran, rivaroxaban, apixaban and edoxaban have been developed to overcome the limitations of VKAs and are now considered a valid alternative.21 Compared to VKAs, DOACs are at least as effective in reducing stroke and systemic embolism and are associated with a lower risk of haemorrhage.26–29 Another benefit is their predictable, dose-related effects that do not require close monitoring.26–30 The beneficial effects of DOACs over VKAs have been documented in several subsets of patients with AF including patients with diabetes mellitus, with heart failure and with previous stroke.31

Until recently, the main drawback of novel anticoagulants was the lack of an agent to reverse their effects. Now, however, various clinically-effective antidotes have been developed.32–35 Another factor against the use of DOACs is their cost. Although they are more expensive than VKAs, comparisons of the overall costs of the two treatment strategies in various contexts have demonstrated that DOACs can be a cost-effective alternative to dose-adjusted warfarin for stroke prevention in AF in most patients.36–41 For these reasons, the European Society of Cardiology and several other scientific societies now recommend using DOACs as first-line therapy.23,42,43

This review presents the current recommendations for the use of DOACs in patients with nonvalvular AF at high risk of bleeding.

Stratifying the Risk of Thromboembolism and Bleeding in AF

All anticoagulants increase the risk of bleeding. The benefits of decreasing the risk of thromboembolism must be weighed against the potential harm of increasing the risk of bleeding. Several scores have been proposed to assess these risks. Currently, the most widely recommended and used scores are the CHA2DS2-VASc (Congestive heart failure, Hypertension, Age >75 years, Diabetes, prior Stroke/transient ischemic attack, Vascular disease, Age 65–74 years, Sex category) for thromboembolism and the HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history of/predisposition, Labile international normalised ratio (INR), Elderly, Drug therapy/alcohol intake) for bleeding. These scores have been validated in very broad populations.44–48

The European Society of Cardiology has proposed an algorithm for managing thromboembolic and haemorrhagic risk in patients with AF.23 Other strategies for reducing thromboembolic risk include aspirin and antiplatelet drugs; however, compared to anticoagulation alone, aspirin alone provokes similar indexes of intracranial bleeding and higher rates of other major bleeding events.47 There is thus no argument for using aspirin instead of anticoagulation because of bleeding risk.49 Aspirin plus antiplatelet therapy or, less effectively, aspirin alone may, however, be considered in patients who refuse oral anticoagulant treatment. Importantly, the HAS-BLED score should not be used to exclude patients from treatment; rather it should be used to correct potentially reversible risk factors and to determine whether selected patients with the highest risk of bleeding could benefit from low doses of DOACs. Chao et al. recently analysed the risk of stroke in 186,570 patients with AF not using antiplatelet or anticoagulant agents to determine whether patients with a single risk factor (apart from sex) should receive oral anticoagulation.50 Analysing the impact of the components of the CHA2DS2-VASc score, they found that the weight of the components differed; the risk of stroke was highest for age, followed by the presence of diabetes mellitus. Thus, given the high risk of ischaemic stroke, oral anticoagulation is recommended in all patients with CHA2DS2-VASc scores greater than two and in most patients with CHA2DS2-VASc scores of one, unless the only risk factor is female sex.49,50

Results of Pivotal Clinical Trials Using DOACs

To date, four extensive randomised clinical trials comparing four DOACs (dabigatran, rivaroxaban, apixaban and edoxaban) with warfarin in different cohorts of patients with nonvalvular AF have been published.26–29Table 1 summarises the results of these trials, which have led to the authorisation of these DOACs for clinical use in AF in several countries. Since the publication of these trials, the results of two large observational studies that equalled or surpassed the clinical results obtained in the clinical trials have been published, further supporting the use of DOACs.51,52 The efficacy and safety of DOACs can thus be considered as good as or possibly better than those of VKAs,26–29,53 and DOACs have the additional advantage that their effects are dose-dependent and predictable. Furthermore, the advantages of DOACs over VKAs have been demonstrated in several specific groups of patients with AF (e.g. patients of both genders or with comorbidities such as heart failure, arterial hypertension, diabetes mellitus and previous stroke).31

Figure 1: Limitations of Treatment with Vitamin K Antagonists

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Monitoring of DOACs

Although routine monitoring of coagulation levels is not necessary in patients on DOACs, simple and widely-available tests (see Table 2) help measure their anticoagulant effects if unexpected situations, such as urgent surgery, haemorrhagic events, overdose or acute renal failure, require it.

Dabigatran prolongs the activated partial thromboplastin time (aPTT), but this effect is not linear and the sensitivity of aPTT reagents varies greatly. A trough aPTT (>12 hours after the most recent dose) >80 seconds or two- to three-times higher than the baseline value is associated with a higher risk of bleeding, whereas a normal aPTT indicates that dabigatran has no clinically-significant anticoagulant effect.54 A normal thrombin time (TT) is an indicator of a drug concentration outside the clinically-relevant range.55 The ecarin clotting time (ECT) measures dabigatran activity and the diluted thrombin time with an appropriate dabigatran calibrator (Hemoclot® thrombin inhibitor assay) measures dabigatran concentration. Dabigatran plasma concentration >200 ng/ml or an ECT three to four times the baseline value or >65 seconds at trough is associated with increased bleeding risk.54 Prothrombin time (PT) and INR are not useful for measuring dabigatran’s effects.56

PT is of limited value for monitoring the anti-Xa anticoagulants rivaroxaban, apixaban and edoxaban. Rivaroxaban and apixaban may prolong PT, but PT is highly dependent on the reagent used in the assay.55–57 A normal PT, however, indicates that these drugs are not having a clinically-significant effect. PT, aPTT and INR should not be used to measure edoxaban’s effects due to this lack of evidence, presumed insensitivity, the significant variation between reagents and lack of standardisation, which also effect the measurements of other direct anti-Xa inhibitors.56 Anti-factor Xa assays using rivaroxaban, apixaban and edoxaban standards do, however, provide accurate information and seem the best approach to quantifying the anticoagulant effects of these drugs.55,57

Table 1: Percentage Relative Risk Reduction for Major Events Determined by the Pivotal Clinical Trials of Direct-acting Oral Anticoagulants versus Warfarin

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Table 2: Measurement of the Anticoagulant Effects of Direct Oral Anticoagulants using Specific and Non-specific Assays

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Table 3: Agents that Reverse the Effects of Direct-acting Anticoagulants

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Reversal of DOAC effects

To reverse the effects of a DOAC, it is essential to know the type of DOAC administered, the dosing regimen, the time since the last dose was administered and factors influencing plasma concentration, e.g.renal failure. Time reduces the effects of anticoagulants. Currentlyavailable DOACs have short half-lives (about 12–15 hours), and their effects would be expected to completely disappear by four drug half-lives (after about 48–60 hours).58 DOACs are absorbed and have an anticoagulant effect 1–4 hours after consumption, so early gastric lavage can be considered if little time has elapsed since the last dose. The administration of oral activated charcoal is useful within 2 hours of dabigatran intake and within 6 hours of apixaban intake.58 The clearance of all DOACs depends to varying extents on renal function, so adequate hydration and diuresis are essential. Haemodialysis can be used for the emergency elimination of dabigatran; however, the risk of bleeding at puncture sites for dialysis needs to be carefully balanced against the risk of waiting. Nonspecific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used to treat serious bleeding, but the results are controversial.58,59

The recent advent of target-specific reversal agents that enable the effects of DOACs to be reversed within a few minutes (Table 3) represents a major safety advance in urgent situations.32–35,60 One such agent, idarucizumab, is a humanised monoclonal antibody fragment with 350 times higher affinity for dabigatran than thrombin but lacks thrombin-like enzymatic activity and does not bind thrombin substrates.60 It is easily administered intravenously (5 g as two 50-ml bolus infusions, no more than 15 minutes apart) and specifically and completely reverses the anticoagulant effects of dabigatran in few minutes.Ex vivo studies in rats have shown that steady-state dabigatran levels of 200 ng are completely reversed within 1 minute after the administration of an intravenous bolus of idarucizumab.60 The safety and efficacy of idarucizumab have also been demonstrated in patients requiring urgent procedures or presenting with severe bleeding.32 This drug is available for clinical use in some countries, obviating the need for dialysis in emergencies.32,33

Another target-specific reversal agent, andexanet alfa, has been designed specifically to reverse the anticoagulant effects of factor Xa inhibitors.34,35,60 Andexanet alfa is a recombinant modified decoy of factor Xa. Its efficacy has been demonstrated in healthy volunteers treated with apixaban or rivaroxaban; it reverts anticoagulant activity within minutes after administration and for the duration of infusion.35 In these healthy volunteers, transient increases in D-dimer and prothrombin fragments 1 and 2 without clinical thrombotic events have been observed. The dose of andexanet alfa depends on the DOAC. Whereas a 400-mg intravenous bolus followed by a continuous infusion of 4 mg/min for 120 minutes reverses the effects of 5 mg of apixaban twice daily, reversing the effects of 20 mg of rivaroxaban once daily requires 800 mg as an intravenous bolus (30 mg/min) followed by continuous infusion of 8 mg/min for 120 minutes.35

PER977, also called aripizine or ciraparantag, can also reverse the effects of factor Xa inhibitors. This small, synthetic, water-soluble molecule binds to direct inhibitors of factor Xa and factor IIa as well as to heparin-based anticoagulants. It antagonises the effects of all anticoagulants except VKAs and argatroban within 30 minutes after intravenous administration, and has a clearance half-life of about 1.5 hours.60,61 To date, however, very few clinical data have been published62 and the drug is not yet clinically and commercially available.

Periprocedural Management of Patients Treated with DOACs

One of the most important issues related to DOACs in daily clinical practice is appropriate periprocedural management to reduce the risk of bleeding events and the inherent risk of thromboembolic events. This challenge encompasses a wide range of clinical scenarios, including elective and urgent surgery as well as circumstances involving the risk of fatal haemorrhage, such as multiple traumas.

The first step in the periprocedural management of a patient on a DOAC is to determine the risks of thromboembolism with the CHADS-VASc score and bleeding with the HAS-BLED score.23,24 Next, the inherent risk of bleeding associated with the invasive procedure to be undertaken must be determined and weighed against the benefit of remaining on anticoagulants on a case-by-case basis. Clinical guidelines detailing the risks involved in different invasive procedures and recommendations to minimise them63,64 have proven very useful in clinical practice.65

The decision to continue or to pause anticoagulant treatment should be based on pharmacokinetic principles and the estimated thromboembolic and bleeding risks. Interestingly, accumulating evidence is leading to a consensus that bridging with heparin is unnecessary in patients treated with a DOAC64–66 and that the availability of fast-acting reversal agents minimises anticoagulant-related bleeding during urgent or emergent interventions.

Conclusion

AF is very common and is associated with increased morbidity, mortality and healthcare costs. Appropriate clinical management, including the prevention of thromboembolic events, is thus crucial. Preventing thromboembolic events with VKAs has various clinical limitations; DOACs overcome these limitations and have proven efficacious and safe. The recent developments of tests that allow the monitoring of anticoagulant levels and of target-specific reversal agents for DOACs have facilitated the use of these drugs in several situations, including emergencies.

References

  1. Martínez-Rubio A, Pujol Iglesias E, Bonastre Thió, M, et al. Epidemiologia de la fibrilación auricular en España. Rev Esp Cardiol 2013;13:3–8.
    Crossref
  2. Masià R, Sala J, Marrugat J, Pena A. Prevalence of atrial fibrillation in the province of Girona, Spain: the REGICOR study. Rev Esp Cardiol 2001;54:1240.
    Crossref | PubMed
  3. Garcia-Acuna JM, Gonzalez-Juanatey JR, Alegria Ezquerra E, et al. Permanent atrial fibrillation in heart disease in Spain. The CARDIOTENS study 1999. Rev Esp Cardiol 2002;55:943–52 [Article in Spanish].
    Crossref | PubMed
  4. Cea-Calvo L, Redón J, Lozano JV et al. Prevalence of atrial fibrillation in the Spanish population aged 60 years or more. The PREV-ICTUS study. Rev Esp Cardiol 2007;60:616–24 [Article in Spanish].
    Crossref | PubMed
  5. Morillas P, Pallarés V, Llisterri JL, et al. Prevalence of atrial fibrillation and use of antithrombotics in hypertensive patients aged >or=65 years. The FAPRES trial. Rev Esp Cardiol 2010;63:943–50.
    Crossref | PubMed
  6. López Soto A, Formiga F, Bosch X, et al.; en representación de los investigadores del estudio ESFINGE. Prevalence of atrial fibrillation and related factors in hospitalized old patients: ESFINGE study. Med Clínica 2012;138:231–7 [Article in Spanish].
    Crossref | PubMed
  7. Barrios V, Calderón A, Escobar C, et al. Patients with atrial fibrillation in a primary care setting: Val-FAAP study. Rev Esp Cardiol 2012;65:47–53.
    Crossref | PubMed
  8. Clua-Espuny JL, Lechuga-Duran I, Bosch-Princep R, et al. Prevalence of undiagnosed atrial fibrillation and of that not being treated with anticoagulant drugs: the AFABE study. Rev Esp Cardiol (Engl Ed) 2013;66:545–52.
    Crossref | PubMed
  9. Gómez-Doblas JJ, Muñiz J, Martin JJA, et al.; OFRECE Study Collaborators. Prevalence of atrial fibrillation in Spain. OFRECE Study Results. Rev Esp Cardiol (Engl Ed) 2014;67: 259–69. 
    Crossref | PubMed
  10. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370–5. 
    Crossref | PubMed
  11. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114:119–25.
    Crossref | PubMed
  12. Anonymous. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449–57.
    PubMed
  13. Stewart S, Hart CL, Hole DJ, et al. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med 2002;113:359–64.
    Crossref | PubMed
  14. Flegel KM, Shipley MJ, Rose G. Risk of stroke in nonrheumatic atrial fibrillation. Lancet 1987;1 :526–9.
    Crossref | PubMed
  15. Krahn AD, Manfreda J, Tate RB, et al. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med 1995;98:476–84.
    Crossref | PubMed
  16. Benjamin EJ, Wolf PA, D’Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946–52.
    Crossref | PubMed
  17. Vidaillet H, Granada JF, Chyou Po, et al. A population-based study of mortality among patients with atrial fibrillation or flutter. Am J Med 2002;113:365–70.
    Crossref | PubMed
  18. Benjamin EJ, Levy D, Vaziri SM, et al. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA 1994;271 :840–4.
    Crossref | PubMed
  19. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation – executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Comm. J Am Coll Cardiol 2006;48:854–906.
    Crossref | PubMed
  20. Kelly-Hayes M, Beiser A, Kase CS, et al. The influence of gender and age on disability following ischemic stroke: the Framingham study. J Stroke Cerebrovasc Dis 2003;12:119–26.
    Crossref | PubMed
  21. European Heart Rhythm Association, European Association for Cardio-THoracic Surgery, Camm AJ, Kirchhof P, Lip GYH, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31 :2369–429.
    Crossref | PubMed
  22. Knecht S, Oelschlager C, Duning T, et al. Atrial fibrillation in stroke-free patients is associated with memory impairment and hippocampal atrophy. Eur Heart J 2008;29:2125–32.
    Crossref | PubMed
  23. John Camm A, Lip GYH, De Caterina R, et al.; ESC Committee for Practice Guidelines (CPG). 2012 focused update of the ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2012;33:2719–47.
    Crossref | PubMed
  24. January CT, Wann, LS Alpert JS, et al. 2014 AHA/ACC/ HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary. J Am Coll Cardiol 2014;64:2246–80.
    Crossref
  25. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67.
    Crossref | PubMed
  26. Connolly SJ, Ezekowitz MD, Yusuf S, 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 | PubMed
  27. Patel MR, Mahaffey KW, Garg J, et al.; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91.
    Crossref | PubMed
  28. Granger CB, Alexander JH, McMurray JJV, et al.; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92.
    Crossref | PubMed
  29. Giugliano RP, Ruff CT, Braunwald E, et al.; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104.
    Crossref | PubMed
  30. Martínez-Rubio A, Dan GA, Kaski JC. Rivaroxaban and stroke prevention in patients with atrial fibrillation: new evidence. Expert Rev Cardiovasc Ther 2014;12:933–47.
    Crossref | PubMed
  31. Martínez-Rubio A, Martínez-Torrecilla R. Current evidence for new oral anticoagulants in the treatment of nonvalvular atrial fibrillation: comparison of substudies. Rev Esp Cardiol (Engl Ed) 2015;68:185–9.
    Crossref | PubMed
  32. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511–20.
    Crossref | PubMed
  33. Eikelboom JW, Quinlan DJ, Van Ryn J, et al. Idarucizumab: the antidote for reversal of dabigatran. Circulation 2015;132: 2412–22.
    Crossref | PubMed
  34. Ansell JE. Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants. J Thromb Thrombolysis 2016;41 :248–52.
    Crossref | PubMed
  35. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of Factor Xa inhibitor activity. N Engl J Med 2015;373:2413–24.
    Crossref | PubMed
  36. Sorensen S V, Kansal AR, Connolly S, et al. Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: a Canadian payer perspective. Thromb Haemost 2011;105:908–19.
    Crossref | PubMed
  37. Pink J, Lane S, Pirmohamed M, et al. Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses. BMJ 2011;343:d6333.
    Crossref | PubMed
  38. Shah SV, Gage BF. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation 2011;123:2562–70.
    Crossref | PubMed
  39. Freeman J V, Zhu RP, Owens DK, et al. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern Med 2011;154:1–11.
    Crossref | PubMed
  40. Lee S, Anglade MW, Pham D, et al. Cost-effectiveness of rivaroxaban compared to warfarin for stroke prevention in atrial fibrillation. Am J Cardiol 2012;110:845–51.
    Crossref | PubMed
  41. González-Juanatey JR, Álvarez-Sabin J, Lobos JM, et al. Cost-effectiveness of dabigatran for stroke prevention in non-valvular atrial fibrillation in Spain. Rev Esp Cardiol (Engl Ed) 2012;65:901–10.
    Crossref | PubMed
  42. January CT, Wann LS, Alpert JS, et al. 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 | PubMed
  43. Verma A, Cairns JA, Mitchell LB, et al; CCS Atrial fibrillation guidelines committee. Can J Cardiol 2014;30:1114–30.
    Crossref | PubMed
  44. Lip GYH, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137: 263–72. 
    Crossref | PubMed
  45. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010;138:1093–100.
    Crossref | PubMed
  46. Lip GYH, Frison L, Halperin JL, et al. Identifying patients at high risk for stroke despite anticoagulation: a comparison of contemporary stroke risk stratification schemes in an anticoagulated atrial fibrillation cohort. Stroke 2010;41 : 2731–8.
    Crossref | PubMed
  47. Friberg L, Rosenqvist M, Lip GYH. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012;33:1500–10.
    Crossref | PubMed
  48. Olesen JB, Lip GYH, Hansen ML, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124.
    Crossref | PubMed
  49. Lip GYH, Skjøth F, Rasmussen LH, et al. Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHA2DS2-VASc score. J Am Coll Cardiol 2015;65:1385–94.
    Crossref | PubMed
  50. Chao TF, Liu CJ, Wang KL, et al. Should atrial fibrillation patients with 1 additional risk factor of the CHA2DS2-VASc score (beyond sex) receive oral anticoagulation? J Am Coll Cardiol 2015;65:635–42.
    Crossref | PubMed
  51. Tamayo S, Frank Peacock W, Patel M, et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol 2015;38:63–8.
    Crossref | PubMed
  52. Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015;131 :157–64.
    Crossref | PubMed
  53. Ruff CT, Giugliano RP, Braunwald E, 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 | PubMed
  54. Huisman MV, Lip GYH, Diener HC, et al. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice. Thromb Haemost 2012;107(5):838–47
    Crossref | PubMed
  55. Cuker A, Siegal DM, Crowther MA, Garcia DA. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;64:1128–39.
    Crossref | PubMed
  56. Nutescu EA, Burnett A, Fanikos J, et al. Pharmacology of anticoagulants used in the treatment of venous thromboembolism. J Thromb Thrombolysis 2016;41 :15–31.
    Crossref | PubMed
  57. Nagakari K, Emmi M, Iba T. Prothrombin time tests for the monitoring of direct oral anticoagulants and their evaluation as indicators of the reversal effect. Clin Appl Thromb Hemost 2016;
    Crossref | PubMed
  58. Sartori MT, Prandoni P. How to effectively manage the event of bleeding complications when using anticoagulants. Expert Rev Hematol 2016;9:37–50. 
    Crossref | PubMed
  59. Franchini M, Bonfanti C, Mannucci PM. Management of bleeding associated with new oral anticoagulants. Semin Thromb Hemost 2015;41 :788–801.
    Crossref | PubMed
  60. Das A, Liu D. Novel antidotes for target specific oral anticoagulants. Exp Hematol Oncol 2015;4:25.
    Crossref | PubMed
  61. Gomez-Outes A, Suarez-Gea ML, Lecumberri R, et al. Specific antidotes in development for reversal of novel anticoagulants: a review. Recent Pat Cardiovasc Drug Discov 2014;9:2–10.
    Crossref | PubMed
  62. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014;371 :2141–42.
    Crossref | PubMed
  63. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/ AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery A report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2014;130:e278–333.
    Crossref | PubMed
  64. Kristensen SD, Knuuti J. New ESC/ESA guidelines on non-cardiac surgery: Cardiovascular assessment and management. Eur Heart J 2014;35:2344–5.
    Crossref | PubMed
  65. Schulman S, Carrier M, Lee AYY, et al. Perioperative management of dabigatran: a prospective cohort study. Circulation 2015;132:167–73.
    Crossref | PubMed
  66. Healey JS, Eikelboom J, Douketis J, 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 | PubMed