REVISED Anticoagulation module 3: anticoagulant therapy

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Which drug to choose for stroke prevention?

Based on this data, all four NOACs are now approved by NICE as an option for stroke prevention within their licensed indications (i.e. non-valvular AF with one or more risk factors for stroke). Given their equivalent or superior efficacy, with apparently superior safety, ESC guidelines advise choosing a NOAC first line, in the absence of contraindication (see figure 8). NICE have suggested that a NOAC might be preferred if a patient’s time in therapeutic range on warfarin is <65%.

Trial data will only be a part of the decision-making process. Patients should be involved; some will not wish to switch, or be nervous of new medications. Financial considerations will also play a part. In the UK, some Clinical Commissioning Groups (CCGs) have sought to limit use of NOACs to reduce cost.25 While NOACs are considerably more expensive than warfarin, it is likely that this cost will be at least partially offset by the improved efficacy and safety (with consequently reduced costs of stroke care/management of bleeding), and by reduced monitoring costs. NICE have undertaken a number of costing analyses:
http://www.nice.org.uk/guidance/ta249/resources/ta249-atrial-fibrillation-dabigatran-etexilate-costing-template2

Economic analyses have also been undertaken in other healthcare settings.26 NOACs have not been directly compared in head-to-head trials, and direct comparison between trials is difficult, as the risk profile of patients in each trial was different (for example the mean CHADS2 score of patients in the RE-LY study was 2.1, compared to 3.47 in the ROCKET-AF trial).

Other issues which should be considered are the twice-daily dosing of dabigatran and apixaban; the greater reliance on renal excretion of dabigatran; and drug interactions (as discussed above). Local policies should be followed where these exist.

Figure 9: Oral anticoagulation for stroke prevention
Figure 8. Oral anticoagulation for stroke prevention

Cardioversion of AF

ispIschaemic stroke rates following cardioversion are between 5 and 7% in non-anticoagulated patients, which can be reduced to 0.5 to 1.6% with warfarin.24 Current ESC guidelines advise anticoagulation with an INR of 2–3 for at least three weeks before and four weeks after cardioversion.16 Based on analysis of data on over 1,200 patients who underwent cardioversion during the RE-LY trial, dabigatran appears to be as safe and effective as warfarin, and is approved by ESC as an option.16

Since these guidelines were published, a similar analysis of data from the ARISTOTLE trial (apixaban) has been performed,27 and a randomised trial of rivaroxaban versus warfarin for cardioversion published (EX-VeRT28). Again this shows similar efficacy and safety to warfarin, including in the context of early cardioversion with the use of transoesophageal echocardiography to exclude thrombus.

Strict compliance with treatment is crucial if NOACs are to be used pre-cardioversion, as adequacy of anticoagulation cannot be confirmed by measurement of INR, as it can with warfarin. However, it is likely that local protocols will begin to adopt NOACs for this indication.

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References

1. Monroe DM, Hoffman M. What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol 2006;26:41–8. http://dx.doi.org/10.1161/01.ATV.0000193624.28251.83

2. Blann AD, Khoo CW. The prevention and treatment of venous thromboembolism with LMWHs and new anticoagulants. Vasc Health Risk Manag 2009;5:693–704. http://dx.doi.org/10.2147/VHRM.S4621

3. Roffi M, Patrono C, Collet J et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2015;pii:ehv320. [Epub ahead of print]

4. Watson H, Davidson S, Keeling D. Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. Br J Haematol 2012;159: 528–40. http://dx.doi.org/10.1111/bjh.12059

5. National Institute for Health and Care Excellence. Bivalirudin for the treatment of ST-segment-elevation myocardial infarction. Technology appraisal guidance [TA230]. London: NICE, July 2011 (accessed 15.9.2015)

6. Barnes GD, Ageno W, Ansell J, Kaatz S, for the Subcommittee on the Control of Anticoagulation. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost 2015;13:1154–6.
http://dx.doi.org/10.1111/jth.12969

7. 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. http://dx.doi.org/10.1056/NEJMoa1009638

8. Wisler JW, Becker RC. A guidance pathway for the selection of novel anticoagulants in the treatment of atrial fibrillation. Crit Pathw Cardiol 2012;11:55–61. http://dx.doi.org/10.1097/HPC.0b013e31825298ef

9. Pollack CV, Reilly PA, Eikelboom J et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511–20.
http://dx.doi.org/10.1056/NEJMoa1502000

10. Makris M, Van Veen JJ, Tait CR, Mumford AD, Laffan M. Guideline on the management of bleeding in patients on antithrombotic agents. Br J Haematol 2013;160:35–46.
http://dx.doi.org/10.1111/bjh.12107

11. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;369:1206–14. http://dx.doi.org/10.1056/NEJMoa1300615

12. Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J 2012;33:2569-619.
http://dx.doi.org/10.1093/eurheartj/ehs215

13. National Institute of Health and Care Excellence. Myocardial infarction with ST-segment elevation: the acute management of myocardial infarction with ST-segment elevation [CG167]. London: NICE, July 2013 (accessed 17.9.2015).

14. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. 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. http://dx.doi.org/10.1378/chest.09-1584

15. National Institute of Health and Care Excellence. Atrial fibrillation: the management of atrial fibrillation [CG180]. London: NICE, June 2014 (accessed 21.9.2015).

16. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2012;33:2719–47. http://dx.doi.org/10.1093/eurheartj/ehs253

17. Friberg L, Rosenqvist M, Lip GY. 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. http://dx.doi.org/10.1093/eurheartj/ehr488

18. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. 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. http://dx.doi.org/10.1378/chest.10-0134

19. An J, Niu F, Lang D, et al. Original research – health services and outcomes research: stroke and bleeding risk associated with antithrombotic therapy for patients with nonvalvular atrial fibrillation in clinical practice. J Am Heart Assoc 2015;4:e001921. http://dx.doi.org/10.1161/JAHA.115.001921

20. Mant J, Hobbs F, Fletcher K, et al. 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. http://dx.doi.org/10.1016/S0140-6736(07)61233-1

21. 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. Erratum in: N Engl J Med 2010;363:1877. http://dx.doi.org/10.1056/NEJMoa0905561

22. Graham DJ, et al. Cardiovascular, Bleeding, and Mortality Risks in Elderly Medicare Patients Treated with Dabigatran or Warfarin for Non-Valvular Atrial Fibrillation. Circulation 2014. http://dx.doi.org/10.1161/CIRCULATIONAHA.114.012061

23. Granger CB, Alexander JH, McMurray JJ, et al. ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. http://dx.doi.org/10.1056/NEJMoa1107039

24. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104. http://dx.doi.org/10.1056/NEJMoa1310907

25. Gorog D. Rivaroxaban in non-valvular AF – UK experience in perspective. Br J Cardiol 2014;21(suppl 1):S1–S11.

26. Deitelzweig S, Amin A, Jing Y, Makenbaeva D, Wiederkehr D, Lin J, Graham J. Medical cost reductions associated with the usage of novel oral anticoagulants vs warfarin among atrial fibrillation patients, based on the RE-LY, ROCKET-AF, and ARISTOTLE trials. J Med Econ 2012;15:776–85. http://dx.doi.org/10.3111/13696998.2012.680555

27. Flaker G, Lopes RD, Al-Khatib SM et al. Efficacy and safety of apixaban in patients after cardioversion for atrial fibrillation: insights from the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). J Am Coll Cardiol 2014;63: 1082–7. http://dx.doi.org/10.1016/j.jacc.2013.09.062

28. Cappato R, Ezekowitz MD, Klein AL et al. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J 2014;35:3346–55.
http://dx.doi.org/10.1093/eurheartj/ehu367

All available from http://journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443 (accessed 14/02/13)

Online resources

The Scottish Medicine Consortium: http://www.scottishmedicines.org.uk

The British National Formulary: http://www.bnf.org

The National Institute for Health and Clinical Excellence (NICE): http://www.nice.org.uk

Further reading

Hicks T, Stewart F, Eisinga A. NOACs versus warfarin for stroke prevention in patients with AF: a systematic review and meta-analysis. Open Heart 2016;3:e000279. http://dx.doi.org/10.1136/openhrt-2015-000279

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