Editor's Note: This Article of the Month is based on LaHaye SA, Gibbens SL, Ball DG, Day AG, Olesen JB, Skanes AC. Based on A clinical decision aid for the selection of antithrombotic therapy for the prevention of stroke due to atrial fibrillation. Eur Heart J 2012;33:2163-71.

Introduction

Atrial fibrillation (AF) is associated with a 4.8-fold increased risk of stroke.¹ The overall annual risk of 4.5% may be significantly reduced by anticoagulation.² The introduction of three novel anticoagulants – dabigatran,³ rivaroxaban,⁴ and apixaban⁵ – has introduced complexity and uncertainty into choosing an appropriate antithrombotic therapy, which was formerly a straightforward (if limited) choice between warfarin and aspirin (or no treatment). At the same time, the risks of bleeding, which is similar or slightly less with the novel anticoagulants than with warfarin, must be weighed against efficacy ("net risk"). Various risk prediction scores have been developed for both bleeding and thromboembolism to guide anticoagulant choices for patients with AF. In the absence of comparative data between the new agents, the authors attempted to develop a decision aid which would guide the choice of an appropriate anticoagulant based on the balance of risks, costs, and patient preference.

Methods

The authors estimated the risk of thromboembolism and bleeding using the CHA₂DS₂-VASc and HAS-BLED scores, respectively, for a cohort of patients with non-valvular AF from the Danish National Patient Registry, adjusting for antiplatelet use by using the relative risk reduction from a meta-analysis of antiplatelet therapy in AF.⁶ The relative risks of stroke and major bleeding from clinical trials of the new agents (both 110mg and 150mg doses for dabigatran),^3-5 as well as warfarin,⁶ and aspirin plus clopidogrel,⁷ were then extracted and adjusted to derive theoretical relative risks compared to no treatment. The treatment with the lowest theoretical net risk for different CHA₂DS₂-VASc and HAS-BLED scores was selected, and adjusted for different treatment thresholds, bleeding to thromboembolism ratios, and cost thresholds.

Results

Selected treatment recommendation tables are presented, with the full range of tables available on a website (www.afib.ca) and a proprietary tablet application, along with virtual slide-rules allowing the thresholds to be adjusted to the patient's specific values and economic constraints. In one of the presented examples, a patient at high risk of thromboembolism and moderate risk of bleeding (CHA₂DS₂-VASc score of 2; HAS-BLED score of 2), treatment threshold of 0.5%, bleeding to thromboembolism ratio of 2:1, and cost threshold of $4 per day, given the drugs currently available in Canada, elicits a recommendation for aspirin. If that patient is at low risk of bleeding (HAS-BLED score 0), then the recommendation changes to dabigatran 150mg. If, however, the cost threshold was lowered to $0.50 (for instance, for patients or healthcare systems with limited resources), and the risk of bleeding was low, then warfarin would be recommended.

Conclusion:

The authors present treatment recommendation tables designed to guide clinicians in the selection of appropriate antithrombotic therapy for patients with AF and various levels of thromboembolic and bleeding risk, preferences, and cost constraints.

Perspective:

The practicing clinician confronts several challenges regarding anticoagulant decisions when faced with a patient in atrial fibrillation. The decision to treat or not requires careful adjudication, but this is complicated given different choices of measures for assessing risk from either the arrhythmia (e.g. CHADS₂ vs. CHA₂DS₂-VASc) or the treatment itself (HAS-BLED vs. HEMORR₂HAGES) cited in guidelines issued by various professional societies.^8,9 Selection of anticoagulant itself becomes complicated with the recent availability of three new anticoagulants.^3-5 none of which have been compared head-to-head. Indirect comparisons, though appealing since the novel agents were compared against warfarin, are necessarily limited by differences in populations studied.¹⁰ ROCKET-AF, for example, enrolled patients at significantly higher risk for thromboembolism than either RE-LY or ARISTOTLE, and the time in the therapeutic range achieved in the warfarin arm was significantly lower.^3-5 Aspirin usage, which might affect both efficacy and bleeding, was highest in RE-LY (39.7%), slightly lower in ROCKET-AF (36.5%) and lowest in ARISTOTLE (30.9%).^3-5

Given this uneven background, the authors are to be commended for drawing available data from different sources to create a risk prediction model incorporating the several aspects of clinical decision making. The concept of net risk – the balance of the risks posed by the disease and the therapy – is important. Additionally, the inclusion of patient perspective on the decision and the affordability of the prescription are vital, though often ignored, factors in maintaining intended therapy. In this regard, the current decision tool advances on any particular set of guidelines. Nevertheless, a risk prediction model can only be good as the data it receives. In addition to the limitations acknowledged, risk scores derived from the excellent Danish Registry may not apply similarly to different populations or ethnic groups. The CHA₂DS₂-VASc scheme used here, which boasts more accurate classification of truly low-risk patients than older risk prediction scores and has been embraced by both the European and Canadian professional society guidelines, still has only modest predictive ability and awaits independent validation. The advantage of novel anticoagulants over warfarin in those patients able to maintain a stable INR are unknown.

The decision aid also highlights gaps created by differences in drug availability in different countries. For example, given that the 150 mg dose of dabigatran is contraindicated in people >80 years, and that the110 mg formulation is unavailable in the USA, then apixaban is essentially the first line therapy in people over 80, but awaits FDA approval. The online decision aid excludes therapies not yet approved in the US or Canada.

It is unlikely that any single randomized trial will be undertaken that may compare all available therapies and account for all combinations of patient variables (in any case, with several further anticoagulants in the pipeline, the results of such a venture would likely be obsolete before its conclusion). Therefore, the current method offers an aid to navigate a complicated clinical decision process. The Internet based application provides versatility as individual circumstances (and risk/benefit ratios) change over time and also the ability to refresh with new data as they become available. The charts encourage us to elicit our patients' values relating to risk and cost, look critically at the clinical trials, and tailor prescription of novel agents on an individual basis to patients to achieve desired risk reductions.

References

1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-988.
2. Atrial Fibrillation Investigators. 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(13):1449-1457
3. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD,Wallentin L, RE-LY Steering Committee and Investigators. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009;361:1139–1151.
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6. 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.
7. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Pfeffer M, Hohnloser S, Yusuf S. 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.
8. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. 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 Oct;31(19):2369-429.
9. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Huezey JY, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS, Smith SC Jr, Priori SG, Estes NA 3rd, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Jacobs AK, Anderson JL, Albert N, Buller CE, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Kushner FG, Ohman EM, Stevenson WG, Tarkington LG, Yancy CW; American College of Cardiology Foundation/American Heart Association Task Force. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2011 Mar 15;123(10):e269-367.
10. Cannon CP, Kohli P. Danger ahead: watch out for indirect comparisons! J Am Coll Cardiol 2012;60:747-8.

Keywords: Anticoagulants, Aspirin, Atrial Fibrillation, Stroke, Thromboembolism, Warfarin

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