Atrial fibrillation (AF) is the most common sustained abnormal rhythm of the heart, affects an estimated 5.5 million individuals in the U.S., and is a major cause of stroke. Preventive strategies for stroke reduction in patients with AF continue to be both a focus of attention and a challenge for health care providers. For those with a history of AF and other stroke risk factors, chronic anticoagulation is recommended to prevent thromboembolic events.¹ However, these recommendations are applied to patients based on fixed risk factors and fail to consider an individual's AF burden either spontaneously or as a result of rhythm control interventions.² This standard of care is based upon several key observations including: 1) the limited efficacy of rhythm control strategies; 2) the unreliable nature of symptoms in judging successful rhythm control; 3) the uncertainty surrounding the threshold of AF duration and stroke risk; 4) the limited sensitivity of short-term external monitoring for the detection of paroxysmal AF; 5) the inability to continuously monitor patients over long time periods for AF recurrence with external monitors; and 6) the absence or rapid-onset oral anticoagulants in the warfarin-only era.

Though anticoagulation is highly effective at preventing AF-related strokes, chronic anticoagulation exposes patients to a non-trivial risk of anticoagulant-induced hemorrhage. Major developments in both long-term continuous electrocardiogram (ECG) monitoring and oral anticoagulation, however, hold promise that continuous chronic anticoagulation may be avoidable in some subsets of AF patients who otherwise meet guideline criteria for lifelong anticoagulation. The use of a small, leadless subcutaneous insertable cardiac monitors (ICM) with remote data transmission capabilities (Reveal XT™ and Reveal LINQ™, Medtronic Inc.) provide the ability to remotely and continuously evaluate a patient for AF recurrences. In addition, the novel oral anticoagulants (NOACS) (dabigatran, rivaroxaban, and apixaban) result in rapid onset anticoagulation within hours of a single oral dose. Together, these developments allow for continuous AF monitoring with targeted anticoagulation based on AF recurrence.

The Rhythm Evaluation for AntiCoagulaTion with COntinuous Monitoring (REACT.COM) pilot study (ClinicalTrials.gov NCT01706146) is designed to assess the feasibility of "pill-in-the-pocket" anticoagulation using daily remote transmissions from an ICM. Major inclusion criteria include a CHADS₂ score of 1 or 2, non-permanent AF, no documented AF lasting over a one hour on two consecutive months on a previously implanted ICM, and compliance with a NOAC for 30 consecutive days prior to enrollment. Enrolled patients are maintained on aspirin therapy (81 mg) and transmit daily from their ICM. Daily transmissions allow for AF detection within 24 hours of an episode. Any AF episode lasting ≥ one hour results in re-initiation of a patient's prescribed NOAC for 30 days. A patient with an episode of AF every month, for example, may never be able to discontinue anticoagulation. However, a patient with an episode once a year would only require one month of anticoagulation and a patient with no recurrent AF episodes would be able to discontinue anticoagulation indefinitely. This three-center pilot study has completed enrollment, and results are expected in 2015. A randomized trial comparing "pill-in-the-pocket," ICM-guided intermittent oral anticoagulation with chronic anticoagulation is being planned. If proven superior to current treatment methods, this approach may improve a critical aspect of AF management and allow for patient-directed, point-of-care monitoring and treatment. Furthermore, ICM-guided intermittent anticoagulation may prove cost-effective and has the potential to include anticoagulation avoidance as an indication for rhythm control.

While advances in technology and pharmacology make "pill-in-the-pocket" anticoagulation feasible, there are remaining uncertainties that such an approach is safe. The major etiology of stroke in AF is presumed to be thromboembolism from the left atrium, but structural and functional alterations in the left atrium may also predispose the patient with AF to stroke, even if sinus rhythm is maintained. Factors independent of rhythm control, including endothelial dysfunction, inflammation, platelet activation, and hypercoagulability are increasingly recognized as important contributors to stroke risk in AF and may persist even in sinus rhythm.^3-6 Clinical observations also support a temporal dissociation between episodes of AF and stroke. In studies enrolling patients with dual-chamber pacemakers and ICDs capable of recording all AF episodes, strokes often occurred weeks to months after the last AF episode or even in the absence of any recorded episodes altogether.^7-9 Whether these cerebrovascular events are cardioembolic and AF-related, or simply represent the baseline stroke risk in patients with multiple other risk factors is unknown. Moreover, whether rapid recognition and anticoagulation can prevent downstream events is a major aim of the pivotal "pill-in-the-pocket" study.

Decisions surrounding anticoagulation are among the most challenging aspects in the care of the AF patient. In our desire to protect our patients from the devastating consequences of stroke, we inevitably expose them to the risk of bleeding with anticoagulants. Though this calculated risk is favorable for most patients, ICM-guided "pill-in-the-pocket" anticoagulation may maximize benefit while reducing risk, ushering an era of personalized medicine that leverages technologic and pharmacologic advances to improve patient care.

References

1. January CT, Wann L, Alpert JS, et al. 2014 AHA/ACC/HRS guideline 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 Heart Rhythm Society. J Am Coll Cardiol 2014;64:2246-80.
2. Calkins H, Kuck KH, Cappato R, et al. HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm 2012;9:632-696.e21.
3. Chung MK, Martin DO, Sprecher D, et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation 2001;104:2886-91.
4. Guazzi M, Arena R. Endothelial dysfunction and pathophysiological correlates in atrial fibrillation. Heart 2009;95:102-6.
5. Lip GY, Blann AD. Atrial fibrillation and abnormalities of hemostatic factors. Am J Cardiol 2001;87:1136-7.
6. Azarbal F, Welles CC, Wong JM, Whooley MA, Schiller NB, Turakhia MP. Association of CHADS2, CHA2DS2-VASc, and R2CHADS2 scores with left atrial dysfunction in patients with coronary heart disease (from the Heart and Soul study). Am J Cardiol 2014;113:1166-72.
7. Glotzer TV, Daoud EG, Wyse DG, et al. The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk: the TRENDS study. Circ Arrhythm Electrophysiol 2009;2:474-80.
8. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012;366:120-9.
9. Martin D on Behalf of the IMPACT Investigators. Randomized Trial of Anticoagulation Guided by Remote Rhythm Monitoring in Patients With Implanted Cardioverter-Defibrillator and Resynchronization Devices. Presented at March 2014 ACC Scientific Sessions.

Keywords: Anticoagulants, Arrhythmias, Cardiac, Aspirin, Atrial Fibrillation, Benzimidazoles, Electrocardiography, Heart Atria, Precision Medicine, Inflammation, Morpholines, Platelet Activation, Pyrazoles, Pyridones, Recurrence, Risk Factors, Stroke, Thiophenes, Thromboembolism, Thrombophilia, Warfarin, beta-Alanine

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