Article

Anticoagulation in Atrial Fibrillation – Current Concepts

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare: ReprintsWarehouse@springernature.com.

For permissions and non-commercial reprint enquiries, please visit Copyright.com to start a request.

For author reprints, please email rob.barclay@radcliffe-group.com.

  • Views: 1774

  • Likes: 0

  • Citations: 8

Average (ratings)
No ratings
Your rating

Abstract

This article presents the current status of the use of anticoagulation for the treatment of AF, particularly with the use of non-vitamin K-dependent anticoagulants. Comparisons between these agents and warfarin are made and methods for assessment of anticoagulant activity and reversal are discussed.

Keywords

Atrial fibrillation, guidelines, anticoagulants, thromboprophylaxis,

Disclosure:The authors have no conflicts of interest to declare

Received:

Accepted:

DOI:https://doi.org/10.15420/aer.2015.04.02.100

Acknowledgements:Andrew Grace, Section Editor– Arrhythmia Mechanisms/Basic Science acted as Editor for this article. This article is adapted from Chapter 52: Atrial Fibrillation. In: Katritsis D, Camm AJ, Gersh BJ. Clinical Cardiology: Current Practice Guidelines. Oxford, UK: Oxford University Press, with kind permission. © Oxford University Press, 2013.

Correspondence Details:Dr D Katritsis, Division of Cardiology, Beth Israel Deaconess Medical Center, 185 Pilgrim Rd, Baker 4, Boston, MA 02215. E: dkatrits@bidmc.harvard.edu

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.

Thrombotic material in atrial fibrillation (AF) usually develops in the left atrial appendage as a result of decreased flow and stasis, possible endothelial dysfunction and a hypercoagulable state as indicated by increased fibrinogen, D-dimer, thromboglobulin and platelet factor 4 levels.1 In the Framingham Heart Study, the percentage of strokes attributable to AF increases steeply from 1.5 % in patients aged 50–59 years to 23.5 % in those aged 80–89 years.2 In patients with a history of hypertension but no prior diagnosis of clinical AF, subclinical AF predisposes them to embolic events.3 Undiagnosed silent AF is a probable cause of cryptogenic strokes,4,5 and subclinical episodes of AF are associated with silent cerebral infarcts, particularly in patients with diabetes.6,7

The frequency of AF-related incident ischaemic strokes in patients aged ≥80 years have increased threefold over the last 25 years, despite the introduction of anticoagulants, and are projected to futher increase threefold by 2050.8 Among patients with AF who are at moderate- to-high risk of stroke and are receiving anticoagulation, those with persistent AF have a higher risk of thromboembolic events and worse survival rates compared with those with paroxysmal AF.9 The risk of stroke is similar in patients with and without valvular disease.10 Serial ECGs, Holter monitoring mobile outpatient telemetry, external loop recorders and implantable loop recorders detect post-stroke AF in 23.7 % of patients.11 However, AF that occurs early after stroke can be caused by a transient neurogenic mechanism, and AF that occurs several months post-stroke can be an incidental finding; therefore, it cannot be concluded that the cause of cryptogenic stroke has been identified in all patients found to have post-stroke AF.11

Anticoagulation

Adjusted-dose warfarin and antiplatelet agents reduce the risk of stroke by approximately 60 % and 20 %, respectively, in patients with AF.12 In general, oral anticoagulation is preferred in patients with CHA2DS2-VASc score ≥2, and no anticoagulation in patients with a score of 0 (see Figure 1 and Table 1). In patients with CHA2DS2-VASc score of 1, anticoagulation should be individualised as the risk of stroke is low.13 However, patients aged >65 years, especially women, are at high risk of ischaemic stroke,14 and in these individuals anticoagulation reduces the rate of mortality.15,16 The risk of bleeding is assessed by schemes such as the HAS-BLED, ATRIA and HEMORR2HAGES scoring systems.17 A HAS-BLED score ≥3 indicates ‘high risk’. New oral anticoagulants are now recommended for nonvalvular AF as a potential alternative to warfarin. Nonsteroidal anti-inflammatory drugs increase the risk of both serious bleeding and thromboembolism in anticoagulated patients with AF.18

Aspirin

The protective value of acetylsalicylic acid (aspirin) as monotherapy has come under question, and there are concerns that it may even increase risk of stroke in elderly patients (aged >75 years).19,20 Warfarin is superior to aspirin in patients aged >75 years, offering a 52 % reduction in yearly risk of a combined end-point of stroke, intracranial haemorrhage and peripheral embolism (1.8 % versus 3.8 %; Birmingham Atrial Fibrillation Treatment of the Aged Study [BAFTA]).15 Thus, the use of aspirin for stroke prevention in patients with AF should be limited to those who refuse any form of oral anticoagulation,21 or, perhaps, to those with a CHA2DS2-VASc score of 1.1

Aspirin and Clopidogrel

The combination of aspirin and clopidogrel offers increased protection compared with aspirin alone, albeit at an increased risk of major bleeding,22 and is preferred when warfarin is contraindicated. However, aspirin and clopidogrel together offer less protection than warfarin alone (RR of 1.44 for stroke, peripheral embolism, MI and vascular death).22 In patients who sustain an ischaemic stroke despite international normalised ratio (INR) of 2.0–3.0, targeting a higher INR should be considered (3.0–3.5) rather than adding an antiplatelet agent, as major bleeding risk starts at INR >3.5.23

Warfarin

Warfarin is a racemic mixture of isomers that inhibits the synthesis of vitamin K-dependent coagulation factors. The effective dose of warfarin varies significantly among individuals, as a result of genetic variations in its receptor, metabolism via the cytochrome P450 (CYP) system and interactions with other drugs, vitamins and green vegetables.1

The risk of AF increases with INR >3.5–4.0. Recommended INR values for AF are 2–3. Pharmacogenetic testing for guiding doses, by means of genotyping for the variants CYP2C9 and VKORG1, which are associated with reduced clearance and thus a decrease in warfarin requirement, is not clinically useful.24 Patients initiating warfarin may be at an increased risk of stroke during the first 30 days of treatment, probably owing to rapid deactivation of proteins S and C, two endogenous anticoagulants.25 In high-risk cases, warfarin should be started with concomitant low molecular weight heparin administration for the initial 3–5 days of treatment. Increased levels of coronary calcification have been recently reported in patients on long‑term therapy with vitamin K antagonists.26

Non-vitamin K Oral Anticoagulants

Non-vitamin K oral anticoagulants (NOACs) are direct thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban) inhibitors. Thrombin catalyses the final step in the coagulation cascade by converting fibrinogen to fibrin. Factor Xa, in conjuction with factor Va, mediates activation of prothrombin to thrombin. In patients with non- valvular AF (ie not mechanical valves or mitral valve disease), they are associated with a relative 50 % reduction in the risk of intracranial haemorrhage and haemorrhagic stroke compared with warfarin that is also maintained in elderly patients. There is no need for frequent laboratory monitoring and dose adjustments.27,28 The main problems associated with NOACs are the lack of antidotes and specific assays to measure anticoagulant effect, and the considerably higher cost than warfarin.29 It should be also noted that all major clinical trials with warfarin have included patients without severe renal impairment (CrCl <25–30 ml/min), and renal function should always be considered, especially when treated with dabigatran (see Table 2). They are not indicated in patients on haemodialysis because they may precipitate inadvertent bleeding.30 NOACs do not interact with food but with inhibitors (or inducers) of P-glycoprotein transporters and CYP3A4. Caution is required when they are coadministered with drugs such as verapamil, amiodarone and dronedarone. In patients taking warfarin, switching to a new agent is appropriate when the INR is <2. The mode of action of novel oral anticoagulants in the coagulation cascade is presented in Figure 2. A comparison of new anticoagulants is presented in Tables 3 to 5. A practical guide by EHRA on the use of NOACs in patients with AF has been published (www.NOACforAF.eu).31

Direct Thrombin Inhibitors

Dabigatran

Dabigatran is preferred to warfarin for nonvalvular AF as recommended by the European Society of Cardiology21 and the Canadian Cardiovascular Society.32 In 2010, the US Food and Drug Administration (FDA) approved dabigatran at a dose of 150 mg twice daily (CrCl >30 ml/min), or 75 mg twice daily (CrCl 15–30 ml/min) based on the results of the Randomised Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.33 However, in the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial, during 2.3 years of continued treatment with dabigatran, there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg, and similar rates of stroke and death.34 The European Medicines Agency (EMA) has approved both the 110 mg twice-daily and 150 mg twice-daily doses for nonvalvular AF. Elective cardioversion may be performed in patients taking dabigatran for at least 3 weeks.21 Dabigatran is excreted through the kidneys and no dosing recommendation is given for clearance <15 ml/min. In elderly patients a reduced dose is reasonable (75 mg twice daily),35 especially for those aged >80 years. It can be used safely together with aspirin.33,36 A higher risk of major and gastrointestinal haemorrhage compared with warfarin has been seen in African Americans and patients with chronic kidney disease, but the risk of inrtracranial haemorrhage remains lower.37 Main side-effects of dabigatran are dyspepsia and stomach pain (11 %), and transaminase elevations 0.9–2.0 %, although with a frequency similar to that caused by warfarin. There is no evidence of liver toxicity as observed with ximelagatran.

Choice of Anticoagulant for Atrial Fibrillation

A trend in the RE-LY study towards more MIs in the dabigatran arm as compared with warfarin was not confirmed in a subsequent post-hoc analysis.38 A recent meta-analysis of seven trials including the RE-LY detected a higher risk of MI (1.19 % versus 0.79 %; p=0.03),39 and this was also observed in the recent Secondary Prevention of Venous Thromboembolism (RE-MEDY) trial.40 However, in the recent Danish Registry report (4,978 patients on dabigatran and 8,936 patients on warfarin), rates of mortality, pulmonary embolism, and MI were lower with dabigatran compared with warfarin. Stroke/systemic embolism and major bleeding rates were similar in the two treatment groups.41 Thrombin time in diluted plasma (dilute TT using hemoclot direct thrombin inhibitor assay) and ecarin clotting time are precise methods to assess the anticoagulant effect of dabigatran. Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are prolonged by dabigatran but the correlation is not linear to guide dosage.42 However, in the presence of a normal aPTT dabigatran is unlikely to contribute to bleeding, and aPTT can be used in emergencies as a rough estimate.43

Prevention of Thromboembolism in Non-valvular Atrial Fibrillation

 

Additional Recommendations on the Prevention of Thromboembolism in Atrial Fibrillation

 

Antidotes

Fornonspecificandspecificantidotestodirectthrombininhibitors,please see the article by Rahmat and Lip, Monitoring the Effects and Antidotes of the Non-vitamin K Oral Anticoagulants, in this issue of the journal.

Factor Xa Inhibitors

Apixaban

Apixaban, an oral factor Xa inhibitor, is approved in Europe and Canada, and by the FDA for nonvalvular AF, and may be the most cost-effective NOAC.29,44 Apixaban has demonstrated reduced risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial haemorrhage in patients with nonvalvular AF for whom vitamin K antagonist therapy was unsuitable (apixaban versus aspirin; AVERROES trial).45 In the Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE) trial, apixaban was found superior to warfarin in preventing embolic or haemorrhagic stroke, and resulted in less bleeding and lower mortality rates (11 % reduction; p=0.047).46 Benefits of apixaban have been seen in both paroxysmal and persistent/permanent AF.47 Rates of intracranial bleeding have been demonstrated to be significantly lower in patients treated with apixaban than with warfarin, regardless of renal function.48 Benefits of apixaban are irrespective of concomitant aspirin use49 or of patients’ age.50

 

New Anticoagulants (NOACs) vs Warfarin in Nonvalvular AF

 

A substudy of the ARISTOTLE trial has also shown that cardioversion of AF can be safely performed in apixaban-treated patients.51 The drug is metabolised in the liver via P450-dependent and -independent mechanisms and 25 % is excreted renally. It is not recommended for use in patients with severe hepatic impairment. Apixaban is also not recommended in patients receiving concomitant treatment with strong inhibitors of both CYP3A4 and P-glycoprotein, such as azole antimycotics and HIV protease inhibitors, and should be used with caution in patients taking rifampicin, phenytoin, carbamazepine and phenobarbital. There are limited clinical data on patients with a CrCl of 15–29 ml/min, and the drug is not recommended in patients with a CrCl of <15 ml/min. Anti- factor Xa assays may be used to estimate the anticoagulant effect. APTT and PT are prolonged by apixaban but they cannot be used to guide dosage as the correlation is not linear, especially with PT.42 Concomitant use with diltiazem results in increased apixaban levels.

EHRA Practical Guide on the Use of New Oral Anticoagulants

 

EHRA 2013: Last Intake of NOAC before Elective Surgical Intervention

Rivaroxaban

Rivaroxaban is an oral factor Xa inhibitor that has been approved by the FDA and EMA for nonvalvular AF. In the ROCKET-AF trial (Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation), rivaroxaban was not found to be inferior to warfarin (INR 2–3) in patients with nonvalvular AF for the prevention of stroke or systemic embolism, and offered a lower rate of intracranial bleeding, but a higher rate of gastrointestinal bleeding.52 In a substudy of this trial, rivaroxaban demonstrated equal safety and efficacy with warfarin in patients aged >75 years.53 The half-life of rivaroxaban is 7–11 hours, but factor Xa is inhibited for up to 24 hours, allowing once-daily dosage. Its bioavailability increases with food consumption. The drug is metabolised in the liver via P450- dependent and -independent mechanisms, and is not recommended in patients receiving concomitant treatment with strong inhibitors of both CYP3A4 and P-glycoprotein inhibitors (see the apixaban section). The drug is not recommended in patients with a CrCl of <15 ml/min. Anti-factor Xa assays are used to estimate the anticoagulant effect.21 APTT and PT are prolonged by rivaroxaban but they cannot be used to guide dosage as the correlation is not linear.42 However, prolonged PT bleeding can be attributed to rivaroxaban, and PT can be used as a rough estimate in case of emergencies.43

Coagulation Cascade

 

Edoxaban

Edoxaban has been demonstrated as noninferior to warfarin with respect to prevention of stroke or systemic embolism and shown to be associated with significantly lower rates of bleeding and death from cardiovascular causes (ENGAGE AF-TIMI 48 trial), and it is approved by the FDA.54 Both the 30 and 60 mg doses were not inferior to warfarin, but in the intention-to- treat analysis with the 60 mg dose there was a trend favoring edoxaban.

Betrixaban

Betrixaban has also been found equivalent to warfarin.55

Antidotes

For nonspecific and specific antidotes to factor Xa inhibitors, please see the article by Rahmat and Lip, Monitoring the Effects and Antidotes of the Non-vitamin K Oral Anticoagulants, in this issue of the journal. Although clinical experience is limited, antidotes for Xa inhibitors should be effective for all available agents.

Transition between NOACs/Warfarin

Transitioning from one anticoagulant to another is a period of high risk for both strokes and bleeding. A reasonable strategy is to reduce the NOAC dose by half, start warfarin and stop the NOAC when the INR is ≥2. When the patient is on warfarin, the NOAC is started after cessation of therapy and three-daily INR measurements to detect a value <2.56

Management of Bleeding in Patients Taking Nonvitamin K Oral Anticoagulants

 

Conclusion

In conclusion, the new, non-vitamin K dependent oral anticoagulants, ie direct thrombin or Xa inhibitors, appear to be safer and more effective than warfarin in preventing thromboembolism in patients with non-valvular AF (ie absence of prosthetic valves or rheumatic mitral valve disease).

References

  1. 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
  2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham study. Stroke 1991;22:983–8.
    Crossref | PubMed
  3. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012;366:120–9.
    Crossref | PubMed
  4. Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014;370:2467–77.
    Crossref | PubMed
  5. Sanna T, Diener H-C, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:2478–86.
    Crossref | PubMed
  6. Gaita F, Corsinovi L, Anselmino M, et al. Prevalence of silent cerebral ischemia in paroxysmal and persistent atrial fibrillation and correlation with cognitive function. J Am Coll Cardiol 2013:62:1990–7.
    Crossref | PubMed
  7. Marfella R, Sasso FC, Siniscalchi M, et al. Brief episodes of silent atrial fibrillation were associated with an increased risk of silent cerebral infarct and stroke in type 2 diabetic patients. J Am Coll Cardiol, 2013:62:525–30.
    Crossref | PubMed
  8. Yiin GS, Howard DP, Paul NL, et al, on behalf of the Oxford Vascular Study. Age-specific incidence, outcome, cost, and projected future burden of atrial fibrillation-related embolic vascular events: A population-based study. Circulation 2014;130:1236–44.
    Crossref | PubMed
  9. Steinberg BA, Hellkamp AS, Lokhnygina Y, et al. Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: Results from the ROCKET-AF trial. Eur Heart J 2015:36:288–96.
    Crossref | PubMed
  10. Breithardt G BH, Berkowitz SD, Hellkamp AS, et al, ROCKET AF Steering Committee & Investigators. Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET-AF trial. Eur Heart J 2014;35:3377–85.
    Crossref | PubMed
  11. Sposato LA, Cipriano LE, Saposnik G, et al. Diagnosis of atrial fibrillation after stroke and transient ischaemic attack: A systematic review and meta-analysis. Lancet Neurol 2015;14:377–87.
    Crossref | PubMed
  12. 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
  13. Friberg L, Skeppholm M, Terent A. Benefit of anticoagulation unlikely in patients with atrial fibrillation and a CHA2DS2- Vasc score of 1. J Am Coll Cardiol 2015;65:225–32.
    Crossref | PubMed
  14. 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
  15. Mant J, Hobbs FD, Fletcher K, et al; BAFTA investigators, Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham atrial fibrillation treatment of the aged study, BAFTA): A randomised controlled trial. Lancet 2007;370:493–503.
    Crossref | PubMed
  16. Siu CW, Tse HF. Net clinical benefit of warfarin therapy in elderly Chinese patients with atrial fibrillation. Circ Arrhythm Electrophysiol 2014;7:300–6.
    Crossref | PubMed
  17. Roldan V Marín F, Fernández H, et al. Predictive value of the HAS-BLED and ATRIA bleeding scores for the risk of serious bleeding in a ‘real-world’ population with atrial fibrillation receiving anticoagulant therapy. Chest 2013;143:179–84.
    Crossref | PubMed
  18. Lamberts M, Lip GY, Hansen ML, et al. Relation of nonsteroidal anti-inflammatory drugs to serious bleeding and thromboembolism risk in patients with atrial fibrillation receiving antithrombotic therapy: A nationwide cohort study. Ann Intern Med 2014;161:690–8.
    Crossref | PubMed
  19. Själander S, SjälanderA, Svensson PJ, Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid. Europace 2013;15:1407–11.
    Crossref | PubMed
  20. Ben Freedman S, Gersh BJ, Lip GYH. Misperceptions of aspirin efficacy and safety may perpetuate anticoagulant underutilization in atrial fibrillation. Eur Heart J 2015:36:653–6.
    Crossref | PubMed
  21. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation: An update of the 2010 ESC guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719–47.
    Crossref | PubMed
  22. Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE W): A randomised controlled trial. Lancet 2006;367:1903–12.
    Crossref | PubMed
  23. Camm AJ, Kirchhof P, Lip GY, 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). Europace 2010;12:1360–420.
    Crossref | PubMed
  24. Furie B. Do pharmacogenetics have a role in the dosing of vitamin K antagonists? N Engl J Med 2013;369:2345–6.
    Crossref | PubMed
  25. Azoulay L, Dell’Aniello S, Simon TA, et al. Initiation of warfarin in patients with atrial fibrillation: Early effects on ischaemic strokes. Eur Heart J 2014;35:1881–7.
    Crossref | PubMed
  26. Weijs B, Blaauw Y, Rennenberg RJ, et al. Patients using vitamin K antagonists show increased levels of coronary calcification: An observational study in low-risk atrial fibrillation patients. Eur Heart J 2011;32:2555–62.
    Crossref | PubMed
  27. De Caterina R, Husted S, Wallentin L, et al. New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC working group on thrombosis–task force on anticoagulants in heart disease position paper. J Am Coll Cardiol, 2012;59:1413–25.
    Crossref | PubMed
  28. 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 2013;383:955–62.
    Crossref | PubMed
  29. Canestaro WJ Patrick AR, Avorn J, et al. Cost-effectiveness of oral anticoagulants for treatment of atrial fibrillation. Circ Cardiovasc Qual Outcomes 2013;6:724–31.
    Crossref | PubMed
  30. Chan KE, Edelman ER, Wenger JB, et al. Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis, Circulation, 2015;131:972–9.
    Crossref | PubMed
  31. Heidbuchel H, Verhamme P, Alings M, et al; European Heart Rhythm Association. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625–51.
    Crossref | PubMed
  32. Gillis AM, Verma A, Talajic M, et al. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: Rate and rhythm management. Can J Cardiol 2011;27:47–59.
    Crossref | PubMed
  33. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51.
    Crossref | PubMed
  34. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation 2013;128:237–43.
    Crossref | PubMed
  35. 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
  36. Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO study). Am J Cardiol 2007;100:1419–26.
    Crossref | PubMed
  37. Hernandez I, Baik SH, Piñera A, et al. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med 2014; 175:18–24.
    Crossref | PubMed
  38. Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (randomized evaluation of long-term anticoagulation therapy) trial. Circulation 2012;125:669–76.
    Crossref | PubMed
  39. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: Meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012; 172:397–402.
    Crossref | PubMed
  40. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709–18.
    Crossref | PubMed
  41. Larsen TB, Rasmussen LH, Skjøth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in ‘real world’ patients with atrial fibrillation: A prospective nationwide cohort study. J Am Coll Cardiol 2013:61:2264–73.
    Crossref | PubMed
  42. Cuker AM, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;64:1128–39.
    Crossref | PubMed
  43. Blann AD, Lipp GY. Laboratory monitoring of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;64:1140–2.
    Crossref | PubMed
  44. Dorian P, Kongnakorn T, Phatak H, et al. Cost-effectiveness of apixaban vs. current standard of care for stroke prevention in patients with atrial fibrillation. Eur Heart J 2014;35:1897–906.
    Crossref | PubMed
  45. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92.
    Crossref | PubMed
  46. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92.
    Crossref | PubMed
  47. Al-Khatib SM, Thomas L, Wallentin L, et al. Outcomes of apixaban vs. warfarin by type and duration of atrial fibrillation: results from the ARISTOTLE trial. Eur Heart J 2013;34:2464–71.
    Crossref | PubMed
  48. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: Insights from the aristotle trial. Eur Heart J 2012;33:2821–30.
    Crossref | PubMed
  49. Alexander JH, Lopes RD, Thomas L, et al. Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: Insights from the ARISTOTLE trial. Eur Heart J 2014;35:224–32.
    Crossref | PubMed
  50. Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: Observations from the ARISTOTLE trial. Eur Heart J 2014;35:1864–72.
    Crossref | PubMed
  51. Flaker G, Lopes RD, Al-Khatib SM, et al. Efficacy and safety of apixaban in patients following cardioversion for atrial fibrillation: Insights from the ARISTOTLE trial. J Am Coll Cardiol 2014;63:1082–7.
    Crossref | PubMed
  52. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91.
    Crossref | PubMed
  53. Halperin JL Hankey GJ, Wojdyla DM, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in 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; 130:138–46.
    Crossref | PubMed
  54. Giugliano RP, Ruff CT, Braunwald E, for the ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. NEJM 2013;369:2093–104.
    Crossref | PubMed
  55. Connolly SJ Eikelboom J, Dorian P, et al. Betrixaban compared with warfarin in patients with atrial fibrillation: Results of a phase 2, randomized, dose-ranging study (EXPLORE-Xa). Eur Heart J 2013;34:1498–505.
    Crossref | PubMed
  56. Ruff CT, Giugliano RP, Braunwald E, et al. Transition of patients from blinded study drug to open-label anticoagulation: The ENGAGE AF-TIMI 48 trial. J Am Coll Cardiol 2014;64:576–84.
    Crossref | PubMed
Previous Volume Article Next Volume Article